study-specific manual of procedures

IMPAACT 2017

Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting Injectable Cabotegravir and Long-

Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected Children and

Adolescents

MOCHA: More Options for Children and Adolescents

Study-Specific Manual of Procedures

IMPAACT 2017 Overview and Version History Document, updated: 28 December 2020 Page 1 of 2

IMPAACT 2017 Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-

Acting Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected Children and Adolescents

MOCHA: More Options for Children and Adolescents

Study-Specific Manual of Procedures Overview and Version History Document

Section Number and Title Version Number(s) and Date(s) Summary of Changes from Previous Version

Section 1 Introduction and Study Overview

2.0, dated 18 December 2020 • Updated per protocol Version 3.0

1.1, dated 05 April 2019

• Section 1.1.3 revised to incorporate DAIDS delegation of duties log policy

1.0, dated 14 November 2018 • First implementation version per protocol v2.0

Section 2 Study-Related Communications


1.2, dated 28 January 2020 • Updated email addresses and hyperlinks; corrected minor typo

1.1, dated 05 April 2019 • Change in Protocol Data Manager, per CM #1


Section 3 Participant Accrual



Section 4 Informed Consent and Assent



Section 5 Study Visits, Scheduling, and Select Visit Procedures



Section 6 Acceptability and Tolerability Assessments



Section 7 Study Product and Pharmacy Considerations


1.1, dated 05 April 2019 • Clarification of returning unused oral study

product and instructions for preparing the RPV LA injections


Section 8 Counseling Considerations



IMPAACT 2017 Overview and Version History Document, updated: 28 December 2020 Page 2 of 2

Section 9 Participant Management Considerations and Expedited Adverse Event Reporting



Section 10 Laboratory Considerations



Section 11 Data Management Considerations



Section 12 Qualitative Interview Considerations


1.1, dated 05 April 2019 • Section 12.12 Frequently Asked Questions

was relocated to the separate IMPAACT 2017 FAQ document


IMPAACT 2017 Manual of Procedures Version 2.0 18 December 2020 Section 1, Page 1 of 5

SECTION 1 INTRODUCTION AND STUDY OVERVIEW

Table of Contents 1.1 Investigator Responsibilities .............................................................................................................. 1

1.1.1 Sub-Investigators Listed on the Form FDA 1572 ......................................................................... 2

1.1.2 Financial Disclosure Requirements ............................................................................................ 3

1.1.3 Study-Specific Delegation of Duties Log ..................................................................................... 3

1.2 IRB/EC Submissions ........................................................................................................................ 4

1.3 Protocol Registration ........................................................................................................................ 4

1.4 Site-Specific Study Activation ............................................................................................................ 4

IMPAACT 2017 is a Phase I/II, multi‐center, open‐label, non‐comparative study to confirm the dose and evaluate the safety, tolerability, acceptability, and PK of oral CAB, long-acting injectable CAB (CAB LA), and long-acting injectable RPV (RPV LA) among up to 155 virologically suppressed HIV‐1 infected children and adolescents aged 12 to <18 years. Up to 60 parents/caregivers of adolescent participants will also be enrolled to take part in in-depth qualitative interviews. The study design includes two cohorts of participants and two sequential steps in each cohort. In each cohort, participants will enter the study in the oral lead-in phase (Step 1, or Step 3) and then transition to the injectable phase (Step 2, or Step 4) if eligibility criteria for the injectable phase are met. Interim analyses will be conducted in Cohort 1 to determine the dosing and timing of opening Cohort 2 to accrual, first limited to Cohort 1 participants and then fully opened to participants newly enrolling to the study (i.e., Cohort 1-naïve participants). Upon permanent discontinuation of injectable study product (during Cohort 1 Step 2, and Cohort 2 Step 4), participants will be followed, per the long-term safety and washout PK follow-up (LSFU) schedule, for an additional 48 weeks after their last study product injection. IMPAACT 2017 protocol Schema and Section 3 provide greater details on the overall study design, the design for each cohort, and the LSFU visits. The IMPAACT 2017 protocol, related protocol documents, and the study-specific Laboratory Processing Chart (LPC) are available on the study-specific web page:

http://impaactnetwork.org/studies/IMPAACT2017.asp All IMPAACT 2017 visits and procedures must be conducted in accordance with the study protocol. The purpose of this manual is to supplement the protocol, not to replace or substitute for it. In the event this manual is inconsistent with the protocol, the specifications of the protocol take precedence. Please notify the IMPAACT Operations Center Clinical Trial Specialists of any such inconsistencies. This manual will be reviewed and updated as corrections are needed. Additional reviews for any indicated updates will occur with each protocol modification (clarification memorandum, Letter of Amendment, or full protocol amendment). Operational guidance will be released as study-wide communications and/or frequently asked questions between these planned updates, as needed. 1.1 Investigator Responsibilities IMPAACT 2017 must be conducted in accordance with the United States (US) Code of Federal Regulations (CFR) and the International Conference on Harmonisation (ICH) Consolidated Guidance for

http://impaactnetwork.org/studies/IMPAACT2017.asp


Good Clinical Practice (GCP). Sites must also comply with the Division of AIDS (DAIDS) policies on Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials and Requirements for Essential Documents at Clinical Research Sites Conducting DAIDS Funded and/or Sponsored Clinical Trials, which are useful for interpreting and operationalizing the regulations and guidelines in accordance with DAIDS expectations. These policies are available at the following web site and must be followed throughout implementation of IMPAACT 2017:

https://www.niaid.nih.gov/research/daids-clinical-site-implementation-operations IMPAACT 2017 also must be conducted in accordance with the IMPAACT Network Manual of Procedures, as well as all site-specific regulations, policies, and guidelines applicable to human subjects research in general and/or the conduct of study procedures. Copies of all applicable regulations, policies, and guidelines should be maintained in on-site essential document files. The IMPAACT Network Manual of Procedures is available at:

http://impaactnetwork.org/resources/policies-procedures.htm The Investigator of Record (IoR), i.e., the Principal Investigator for the study, at each site must sign both a Protocol Signature Page (PSP) and a Form FDA 1572 to formally indicate his or her agreement to conduct the study in accordance with the protocol and all applicable regulations, policies, and guidelines. A copy of the PSP can be found in the IMPAACT 2017 protocol. A PSP must be signed by the IoR and uploaded to the DAIDS Protocol Registration System (DPRS) for all initial protocol versions, all full protocol amendments, and all letters of amendment (LOAs). Sites should keep copies of protocol signature page(s) and Form FDA 1572(s) on site with their essential documents. The obligations and responsibilities assumed by the IoR when signing the Form FDA 1572 and PSP are listed on the respective forms, and for the Form FDA 1572 available on the DAIDS Regulatory Support Center (RSC) web site:

https://rsc.niaid.nih.gov/clinical-research-sites/protocol-registration-forms

Updates to the Form FDA 1572 should be submitted to the DAIDS Protocol Registration Office (PRO). The IoR may delegate his/her obligations and responsibilities for conducting IMPAACT 2017 to other study staff members; however, delegation does not relieve the IoR of his/her ultimate responsibility for all study procedures performed and all study data collected. Delegation of IoR responsibilities must be formally documented on the site’s study-specific delegation log throughout study implementation. If there is a change in IoR, a revised Form FDA 1572 and a new PSP should be submitted to the DAIDS PRO. Sites should follow guidance in the current Protocol Registration Manual regarding procedures for a change in IoR with the DAIDS PRO. Outgoing investigators should complete the end of study financial disclosure form(s) and close-out all delegation log entries. Incoming IoRs must complete required financial disclosure form(s), and complete a new delegation log, including obtaining study staff signatures. Additional details on financial disclosure form and delegation of duties log requirements for this study are provided below in Sections 1.1.2 and 1.1.3, respectively. 1.1.1 Sub-Investigators Listed on the Form FDA 1572 Generally, staff who are regularly involved in the source documentation of safety data or are delegated to perform critical trial related procedures should also be included on the Form FDA 1572. Critical trial related procedures may include, but are not limited to: obtaining informed consent/assent, collecting participant safety information, confirming participant eligibility, adverse event (AE) assessment, reporting of AEs (including reporting of expedited adverse events), or prescribing and/or dispensing study

https://www.niaid.nih.gov/research/daids-clinical-site-implementation-operations

http://impaactnetwork.org/resources/policies-procedures.htm

https://rsc.niaid.nih.gov/clinical-research-sites/protocol-registration-forms


product. Ultimately, inclusion as a sub-investigator on the Form FDA 1572 is dependent on the responsibilities that have been delegated to staff and is at the discretion of the IoR. See the DAIDS Protocol Registration Manual for further details on the requirements for listing sub-investigators on the Form FDA 1572. All sub-investigators listed on the Form FDA 1572 must complete financial disclosure form(s) in accordance with IMPAACT and DAIDS policies. 1.1.2 Financial Disclosure Requirements In compliance with US Food and Drug Administration (FDA) regulations for studies conducted under an Investigational New Drug (IND) application, a financial disclosure form must be completed by the IMPAACT 2017 Investigator of Record (IoR) at each site as well as by each person listed on the Form FDA 1572 for this study. For IMPAACT 2017, the GSK/ViiV-specific financial disclosure forms must be used to disclose their own financial interests as well as those of their spouses and dependent children:

• Financial Disclosure Form A must be used and completed by each person listed on the Form FDA 1572 prior to the initiation of the study at the site and as a condition of study activation.

• Financial Disclosure Form B must be used in the event any information recorded on Form A and/or on Form FDA 1572 change over time. For example, if any new staff are added to the Form FDA 1572 after the study initiation date at the site (i.e., study activation), these staff must complete, sign, and file Form B on site before performing study-related activities. Likewise, staff must complete, sign, and file Form B when they are no longer assigned to the study. Additionally, Form B will completed and signed by all staff listed on the Form FDA 1572 at the completion of the clinical trial.

Sample financial disclosure forms may be found on the IMPAACT 2017 website. As specified in the DAIDS Protocol Registration Manual, original completed and signed forms must be filed on-site, along with the Form FDA 1572. Completed forms do not need to be submitted to DAIDS PRO as part of initial protocol registration but must be filed and retained in the clinical research site’s regulatory binder along with the original and/or updated, signed Forms FDA 1572 for the study, and available for review by site monitors and other sponsor, IMPAACT, and regulatory authority representatives. Please note that the FDA requirement to maintain financial disclosure documentation for this study is separate and distinct from NIH requirements to identify conflicts of interest, which is done periodically through the Office of HIV/AIDS Network Coordination (HANC). While there may be some overlap in the information collected through these two mechanisms, financial disclosure documentation must be compiled and maintained on-site for each IND study conducted at each site. 1.1.3 Study-Specific Delegation of Duties Log A study-specific delegation of duties log must be completed as a requirement for site-specific study activation and maintained throughout the conduct of the study. Per the DAIDS Office for Policy in Clinical Research Operations (OPCRO) memo (distributed to sites on March 4, 2019), all IMPAACT 2017 sites must use the DAIDS delegation of duties log template. Additional information regarding the DAIDS policy on study-specific delegation of duties logs is available on the RSC website:

https://rsc.niaid.nih.gov/clinical-research-sites/delegation-duties-logs


1.2 IRB/EC Submissions Consistent with the regulations, guidelines, and policies cited above, the IoR at each site must obtain all applicable drug regulatory and ethical review approvals for IMPAACT 2017 prior to study initiation; the IoR must also maintain these approvals in good standing throughout the period of study implementation. With regards to institutional review boards and ethics committees (IRBs/ECs), further guidance on initial and continuing review requirements is available in 45 CFR 46 and the ICH GCP guidance, as well as on the web site of the US Office for Human Research Protections (OHRP):

http://www.hhs.gov/ohrp/

Sites are responsible for knowing which documents, data collection tools, and participant materials require IRB/EC review and approval. All sites are encouraged to request an acknowledgement of receipt for all documents submitted to their IRBs/ECs and to request that IRBs/ECs note the effective and expiry dates of all approvals. Because IMPAACT 2017 involves children and adolescents, IRBs/ECs must consider the potential risks and benefits of the study for children as described in protocol Section 14. Complete documentation of all correspondence to and from all responsible IRBs/ECs (i.e., complete copies of all submissions, responses, and approvals) must be maintained in on-site essential document files. All submission letters should list the date of the submission, the contents of the submission, and the version number and/or version date of each document submitted. 1.3 Protocol Registration After obtaining all required IRB/EC approvals, each participating study site is responsible for submitting documentation of the approvals, and other required documents, to the DAIDS Protocol Registration Office (PRO). Further information on the protocol registration process can be found in protocol Section 15 and in the DAIDS Protocol Registration Manual, which is available at:

http://rsc.tech-res.com/clinical-research-sites/protocol-registration/policy-manual Upon confirming receipt of all required documentation, the PRO will issue an Initial Registration Notification that indicates successful completion of the process. Site staff are responsible for maintaining documentation of all submissions for the study, along with all associated approvals, notifications and other correspondence from the PRO. Sites initiating the study under protocol Version 3.0 must obtain an Initial Registration Notification for protocol Version 3.0 from the PRO as a condition for study activation (see Section 1.4 below). Sites which were activated to the study under protocol Version 2.0 are required to submit an amendment registration packet for IMPAACT 2017 protocol Version 3.0 to the PRO. These sites will receive a registration notification for the amendment after the PRO verifies that all required registration documents have been received and are complete. Approval from the PRO is not required prior to implementing the amendment, however each site must receive IMPAACT 2017 protocol team approval prior to implementing protocol Version 3.0. 1.4 Site-Specific Study Activation Prior to conducting any study procedures, each site must obtain all required approvals (as described above) and must complete study activation procedures with the Protocol Team, as applicable to the protocol version under which the site is initiating the study. To help ensure site readiness for study initiation, the Protocol Team has specified a set of study activation requirements that must be met to



http://rsc.tech-res.com/clinical-research-sites/protocol-registration/policy-manual


obtain approval to begin study implementation. These requirements are listed on the IMPAACT 2017 Site-Specific Study Activation Checklist, which is available upon request from the IMPAACT Operations Center Clinical Trial Specialists. Any questions related to the study activation process should be directed to the IMPAACT Operations Center Clinical Trial Specialists (CTS). On a site-by-site basis, when all activation requirements have been met, the Operations Center will issue a Site-Specific Study Activation Notice. At each site, no study procedures may be conducted prior to receipt of an activation notice.


SECTION 2 STUDY-RELATED COMMUNICATIONS

Table of Contents Section 2 Study-Related Communications............................................................................................... 1

The IMPAACT 2017 Protocol Team has identified study-specific contacts for various types of issues and questions, as shown in Figure 2-1. For site queries directed to either the IMPAACT 2017 Protocol Team or the Clinical Management Committee (CMC), a response from the appropriate team member can generally be expected within 24 hours. The IMPAACT 2017 Protocol Team members comprising the CMC are specified in protocol Section 7.1.2. Additional detail guiding CMC responsibilities and activities are described in the IMPAACT Network MOP. Active communication is expected between site staff and the CMC throughout study implementation. To help ensure that CMC members have adequate information for a timely response, sites should submit queries and notifications to the CMC following the format in Figure 2-2. The study number “IMPAACT 2017” and the PID in the subject line of the email are requested for communications with the CMC. The study number and CRS in the subject line of the email are requested for communications with the Protocol Team. Sites are responsible for maintaining copies of correspondence with the CMC in the relevant participant’s study chart. In addition to contacting a site directly, the Protocol Team may also utilize one of three study-specific email groups which include site representatives: • Prot 2017: The Protocol Team will use this email group to communicate global study

announcements. This email group includes all Protocol Team members, the Investigator and Study coordinator email groups (described below), plus any individual site staff who wish to receive these global study communications.

• IoR and Study Coordinator: The Protocol Team will use these email groups to communicate to a

more limited number of site representatives for items which are pertinent to the IoR and Study Coordinator roles, such as determining call or meeting schedules, or requesting site-level study updates. Site investigators or study coordinators may also utilize these email groups for cross-sharing study-related information. These groups respectively include the IoRs and Co-IoRs listed in the protocol’s Study Site Roster, and study coordinators, back-up study coordinators and anyone specifically requested to be kept updated on operational and implementation emails.


Figure 2-1: IMPAACT 2017 Study-Related Communications

Topic/Issue Contact

Clinical, adverse event, and study product administration and/or management

IMPAACT 2017 Clinical Management Committee [email protected] (See communication guidelines in Figure 2-2 below)

Participant eligibility, potential enrollment of an ineligible participant, and/or deviation from protocol requirements for eligibility determination and/or enrollment Co-enrollment Adding site staff to Prot 2017 protocol email group Sites are requested to contact the User Support Group at the Data Management Center (DMC) to add/remove site staff to the impaact.prot2017 email group

User Support [email protected] (include “IMPAACT 2017” in the subject line of your email message)

Adding site staff to IoR or Study Coordinator protocol email groups Sites may contact the study CTSs to request adding/removing site staff to these email groups, noting that ideally only staff in the role of IoR or Study Coordinator are included

Clinical Trials Specialists: Kat Calabrese ([email protected]), Sarah Buisson ([email protected]) (include “IMPAACT 2017” and CRS number in the subject line of your email message)

Data management computer and screen problems User Support [email protected] (or by phone: 716-834-0900 x7302)

Subject Enrollment System DMC Randomization Support Office [email protected] (or by phone: 716-834-0900 x7301)

eCRF completion and query resolution

Protocol Data Managers: Barbara Heckman ([email protected]), and Yvonne Woolwine-Cunningham ([email protected]), and Jared Kneebone ([email protected])

Study product issues (other than study product orders)

Protocol Pharmacist: Irene Rwakazina [email protected] (or by phone: 301-761-7269)

Study product orders Clinical Research Products Management Center [email protected] (or by phone: 301-294-0741)

mailto:[email protected]












Qualitative phone interviews: scheduling the interviews with the protocol interview team (for U.S. sites)

Protocol Interview Team at Children’s Hospital of Philadelphia (CHOP): Liz Lowenthal ([email protected]), and Jennifer Chapman ([email protected]) (include “IMPAACT 2017” and CRS number in the subject line of your email message)

Qualitative phone interviews: protocol interpretation or study implementation (for U.S. sites)

Qualitative Management Team [email protected] (include “IMPAACT 2017” and CRS number in the subject line of your email message)

Any aspect of protocol interpretation or study implementation not otherwise listed above

IMPAACT 2017 Protocol Team [email protected] (include “IMPAACT 2017” and CRS number in the subject line of your email message)

Figure 2-2: Communications with IMPAACT 2017 Clinical Management Committee

Questions and notifications for IMPAACT 2017 CMC: Copy and paste the below listing into the body of your email message to [email protected] to help ensure that all required information is included.

Email subject line must include both “IMPAACT 2017” and PID 1. CRS number 2. Name of person submitting query 3. PID 4. Cohort: Cohort 1C, Cohort 1R, or Cohort 2 5. Step number: 1, 2, 3, 4 or LSFU 6. Current week on study 7. Reason for query (choose one of the following and provide further description in

#9 case narrative): a. Consultation on eligibility or enrollment b. Consultation on adverse event or toxicity management c. Consultation on study drug management d. Other

8. Age of participant 9. Case narrative 10. Question or notification for CMC

File a copy of the email exchange in the participant’s study chart.






SECTION 3 PARTICIPANT ACCRUAL

Table of Contents 3.1 Cohort 1 Accrual Targets and Interim Analyses ........................................................................... 1

3.2 Cohort 2 Accrual Targets .............................................................................................................. 2

3.3 Site-Specific Accrual .................................................................................................................... 3

3.4 Participant Recruitment, Screening, and Enrollment Process ....................................................... 4

3.4.1 Obtaining Informed Consent/Assent ..................................................................................... 4

3.4.2 Assigning Participant Identification Numbers ...................................................................... 4

3.4.3 Screening and Enrollment Logs ............................................................................................ 5

3.5 Screening for Cohort 1 Step 1 and/or Cohort 2 Step 3 Eligibility ................................................ 5

3.6 Enrolling Eligible Participants ...................................................................................................... 6

3.7 Progressing from Oral Lead-In to Injections (from Cohort 1 Step 1 to Step 2, and from Cohort 2 Step 3 to Step 4) ........................................................................................................................................ 6

3.8 Cohort 1 Step 2 Participants Screening and Enrolling into Cohort 2 Step 3 ................................ 7

This section describes accrual relating to adolescent participants. Protocol Section 3 and Section 4 provide detailed descriptions of the study design, screening, and enrollment processes and requirements. Section 12 of this manual provides details regarding accrual of parents/caregivers of adolescent participants for participation for the in-depth qualitative interview (applicable to U.S. sites only). 3.1 Cohort 1 Accrual Targets and Interim Analyses Up to 55 participants will be enrolled in Cohort 1 to achieve approximately 30 to 35 dose-evaluable participants. Within this cohort, participants will be assigned either to Cohort 1C (to receive only the CAB study product) or to Cohort 1R (to receive only the RPV study product). As described in protocol Section 5, assignment to either Cohort 1C or Cohort 1R will be based on each participant’s pre-study cART regimen, which they will continue throughout Cohort 1 participation. Cohort 1C and Cohort 1R have different target sample sizes. To ensure there are sufficient PK data across participant weights and sexes, the target sample size for each arm is further stratified by weight and sex. Cohort 1 will be considered fully accrued when approximately 15 to 20 dose-evaluable participants have enrolled in Cohort 1C and approximately 15 dose-evaluable participants have enrolled in Cohort 1R, and each of these arms meets the sex and weight sample size requirements, as shown in Figure 3-1. These weight and sex sample size requirements only apply to the full Cohort 1 accrual and do not apply to the interim analyses described further below.


Figure 3-1: Cohort 1 Accrual Targets and Stratification Requirements

Cohort 1C Cohort 1R

Maximum sample size Up to 30 participants Up to 25 participants

Target sample size Target of approx. 15 to 20 dose-

evaluable participants Target of approx. 15 dose-

evaluable participants

Sex (among target sample size)

Minimum 4 females, and a minimum of 4 males

Minimum 4 females, and a minimum of 4 males

Weight (among target sample size)

Minimum 5 participants weighing 35 kg to <50 kg, and a Minimum of 5 participants weighing >50 kg

Minimum 5 participants weighing 35 kg to <50 kg, and a Minimum of 5 participants weighing >50 kg

Interim Analyses: Throughout Cohort 1 follow-up, the CMC will review available safety and PK data to determine whether each participant is considered dose-evaluable (see protocol Section 9 for the definition of dose-evaluable). Two interim analyses will be conducted to determine the Cohort 2 study drug dose and determine timing of opening Cohort 2 to accrual. Accrual to Cohort 1 will continue while the interim analyses are conducted. The first interim analysis was conducted under protocol Version 2.0 after the first 7 evaluable participants in each arm completed their Step 2 Week 16 visit. Based on this interim analysis, with the safety and PK criteria having been met (per protocol Version 2.0 Sections 9 and 10), Cohort 2 will open to accrual to Cohort 1 participants under protocol Version 3.0. See Section 3.8 below for more details on Cohort 1 participants screening and enrolling to Cohort 2. The second interim analysis to each Cohort 1 group will be conducted once:

• approximately 15-20 participants in Cohort 1C and approximately 15 participants in Cohort 1R who could contribute to the dose-finding algorithm are enrolled, and

• 80% of these participants (approximately 12 participants in each arm) have completed the Step 2 Week 8 visit.

Based on this second interim analysis, the CMC will determine whether study data meets safety and PK criteria to open Cohort 2 to accrual for participants who were not previously enrolled to Cohort 1 (i.e., fully open Cohort 2 to accrual). When Cohort 2 is fully opened to accrual, accrual into Cohort 1 will close. Participants enrolled to Cohort 1 will continue their Cohort 1 study visit schedule as planned until they are eligible to enroll to Cohort 2 or exit the study. Because this second interim analysis will occur when 80% of the above participants complete the Step 2 Week 8 visit, Cohort 2 may fully open to accrual (and Cohort 1 may close to accrual) prior to the Cohort 1 target sample size being confirmed as met. Therefore, CMC determination of when to fully open Cohort 2 to accrual will be made such that it is highly likely for the remaining Cohort 1 participants to meet the dose-evaluable targets, and sex and weight sample size requirements, for Cohort 1. 3.2 Cohort 2 Accrual Targets Upon entry into Cohort 2, all participants will discontinue their pre-study cART regimen and receive both oral study products (oral CAB and oral RPV in Step 3) followed by both long-acting injectable study


products (CAB LA and RPV LA in Step 4). The maximum accrual into Cohort 2 is up to 155 participants. Cohort 2 accrual targets do not require sex or weight stratification. There are two target sample sizes for Cohort 2 within the overarching accrual maximum:

• Approximately n=70 evaluable participants who have not participated in Cohort 1 • At least n=100 Cohort 2 participants

Cohort 1 participants who enroll into Cohort 2 will not count towards the first target sample size (approximately n=70 evaluable), as this target is specific to participants who only participate in Cohort 2. Cohort 1 participants who enroll to Cohort 2 may count towards the second target (at least n=100), as long as the Cohort 2 dose and study product regimen onto which they are enrolled is the final dose recommended by the protocol, and they have taken at least one dose in Cohort 2. 3.3 Site-Specific Accrual A study-specific accrual plan was established during the site selection process and based on site-specific accrual projections. Throughout the study accrual period, site-specific accrual projections will be updated annually, or more frequently as determined by the Protocol Team and IMPAACT Operations Center. For each site, accrual will begin after all required approvals are obtained and a site-specific study activation notice is issued by the IMPAACT Operations Center. As a condition for study activation, each site will establish SOPs for participant accrual, which should minimally contain the following elements:

• Site-specific monthly targets for recruitment • Recruitment methods and materials • Pre-screening procedures • Considerations for recruitment of minors • Methods for tracking recruitment • Ethical and human subjects considerations • Staff responsibilities for all of the above (direct and supervisory) • QC/QA procedures (if not specified elsewhere)

All sites are responsible for following these SOPs and updating them throughout the study accrual period, as needed. Once accrual is initiated, the Statistical and Data Management Center (SDMC) will routinely report the number of participants screened and enrolled at each site — by month and cumulatively — to the Protocol Team; monthly and cumulative data on the screen-to-enroll ratio will also be reported to the team. The team will monitor these data in relation to site-specific accrual projections to determine whether accrual targets should be adjusted across sites to achieve the study objectives most efficiently and to determine when to discontinue recruitment and/or accrual at each site. Findings and recommendations from these reviews will be communicated to all sites, and all sites will adjust their accrual efforts accordingly. Similar adjustments may be made in response to SMC reviews of the study. Due to the various requirements of Cohort 1 and Cohort 2 accrual targets, the protocol team will engage in close communication with sites as any sample size or stratification requirement is nearing its maximum. Sites are expected to take these communications (and any sample size maximums) into account as they consider approaching potential participants.


3.4 Participant Recruitment, Screening, and Enrollment Process Refer to protocol Section 4.7 for an overview of the participant recruitment, screening, and enrollment process for this study. Participant recruitment methods may vary across sites but are expected to rely on current patients being seen at a study clinic or from active identification and referral of HIV-1-infected children and adolescents who are ART-experienced and virologically suppressed. While recruitment methods may vary across sites, screening and enrollment methods will be more standardized across sites and consistent with the requirements of protocol Section 6. A schematic overview of the recruitment, screening, and enrollment process is provided in Figure 3-2; selected operational considerations related to this process are described in the remainder of this section.

Figure 3-2: IMPAACT 2017 Recruitment, Screening, and Enrollment Process

3.4.1 Obtaining Informed Consent/Assent Refer to Section 4 of this manual for detailed guidance on obtaining informed consent and assent for this study. Site investigators and their designees will be required to determine participant age and ability to provide independent informed consent for study participation consistent with IRB/EC policies and procedures. Written informed consent and assent (as applicable) for participation will be obtained before any study-specific procedures are performed. 3.4.2 Assigning Participant Identification Numbers A participant identification (PID) number must be assigned to each potential participant for whom informed consent (or assent) for study participation is obtained. The exceptions to this requirement are:

• A participant has previously been assigned a PID for another IMPAACT or ACTG study. In that case, the previously-assigned PID would be used for IMPAACT 2017.

• A Cohort 1 participant is screening for Cohort 2 Step 3 entry. In this case, previous Cohort 1 participants will retain their PID as assigned during Cohort 1 procedures. See Section 3.8 below for additional considerations for these participants.


Study site staff should assign PIDs from lists provided by the DMC. Contact the DMC with any questions related to use of PID lists. 3.4.3 Screening and Enrollment Logs Per the DAIDS policy on Requirements for Essential Documents at Clinical Research Sites Conducting DAIDS Funded and/or Sponsored Clinical Trials, study sites are required to document screening (including screening failures) and enrollment activity on screening and enrollment logs. These logs may be maintained electronically but must be 21 CFR Part 11 compliant if the log is considered a source document. Screening and enrollment logs should be updated in real time and completed after a participant provides informed consent for screening. Screening and enrollment logs are not required for documenting activities relating to progressing from Step 1 to Step 2 (within Cohort 1), or from Step 3 to Step 4 (within Cohort 2). However, screening and enrollment activities for Cohort 1 participants screening for Cohort 2 Step 3 entry will be documented on the log. 3.5 Screening for Cohort 1 Step 1 and/or Cohort 2 Step 3 Eligibility The study eligibility criteria are provided in protocol Sections 4.1 and 4.2. All eligibility criteria are initially assessed at the Screening Visit, and some are reconfirmed at the Entry Visit; procedural eligibility screening requirements are described in protocol Section 6.2 (Screening Visit), Section 6.3.1 (Cohort 1 Step 1 Entry Visit), and Section 6.4.1 (Cohort 2 Step 3 Entry Visit). Screening may be initiated only after written informed consent/assent is obtained. All screening procedures must be performed within 28 days prior to study (or Cohort) entry. It is the responsibility of the IoR and other designated study staff to ensure that all required screening procedures are performed and adequately source documented, and that only adolescents who meet the study eligibility criteria are enrolled. Each site must have on file a study-specific SOP for eligibility determination procedures, minimally including the following:

• During-visit eligibility assessment procedures, • Post-screening visit eligibility assessment and confirmation procedures (e.g. reviewing screening

laboratory results), • Final confirmation and sign-off procedures prior to enrollment, • Documentation of each eligibility criterion (this information could otherwise be included in the

study-specific SOP for source documentation) • Description of process for completing the paper-based eligibility checklist • Describe study staff responsibilities (direct and supervisory) for the above, • QA/QC procedures (if not specified elsewhere).

All sites must follow their SOPs when assessing eligibility for all potential participants. In the event that study staff identify that an ineligible participant has been enrolled, the CMC must be consulted as soon as possible and within no more than 24 hours per the communication procedures described in Section 2 of this manual. For screened adolescents who are found to be ineligible, or who do not enroll in the study for any reason, the SCR10003 eCRF must be entered to record the screening outcome.


Re-Screening for Cohort 1 Step 1 or Cohort 2 Step 3 The term “screening attempt” is used to describe each time a participant screens for the study and each time the screening window for that participant closes. A total of two screening attempts for Cohort 1 and two screening attempts for Cohort 2 are allowed (i.e., participants may rescreen once per Cohort). If all screening and enrollment procedures are not completed within 28 days of obtaining written informed consent (or assent) for screening, the participant must repeat the entire screening process except:

• A new PID should not be assigned • A new screening number should be obtained from the SES (subject enrollment system) for the

participant’s second screening attempt (Note: the SCR10003 eCRF must be entered using the first screening number to record the first screening failure.)

• Confirmatory HIV testing, if conducted during first screening attempt, need not be repeated • Previously documented medical and medications history information should be reviewed and

updated through the date of re-screening (it is not necessary to re-record history information that was previously documented)

Informed consent/assent is required for each screening attempt, and previously provided consent/assent does not “roll over” to a subsequent screening attempt/window. 3.6 Enrolling Eligible Participants

Definition of Study Enrollment: Participants will be considered enrolled in this study upon passing all eligibility criteria and successful entry of eligibility checklist data into the SES. As stated in the Cohort 1 Step 1 Entry and Cohort 2 Step 3 Entry visit procedural tables (protocol Sections 6.3.1 and 6.4.1), a paper-based eligibility checklist must be completed prior to entering the information into the electronic eligibility checklist in the SES. It is recommended that a blank form of the study’s electronic eligibility checklist for the relevant Step (and Cohort) be printed from the SES. Sites are expected to manually complete this paper-based eligibility checklist, assessing the source documentation for each inclusion and exclusion criterion. The completed paper-based eligibility checklist is to be filed with each participant’s chart and may serve as documentation that each eligibility criterion was assessed by the designated site staff. This process should also be described in the site’s eligibility determination (or source documentation SOP). Note that the paper-based eligibility checklist does not serve as the source documentation informing each criterion. Sites may then enter the information from the completed paper-based eligibility checklist into the SES; upon successful entry, a study identification number (SID) and the prescribing information for the Cohort and Step will be generated. An email containing this information will be sent to the site as confirmation of the enrollment and should be filed in essential files. 3.7 Progressing from Oral Lead-In to Injections (from Cohort 1 Step 1 to Step 2, and from Cohort 2 Step 3

to Step 4) In both Cohort 1 and Cohort 2, safety data through the Week 4a visit are assessed for participant eligibility to progress from the oral lead-in phase to the injection phase, with the Week 4b visit as the entry visit for the subsequent step – for Cohort 1, the Week 4b visit is the Step 2 Entry visit, and for Cohort 2, the Week 4b visit is the Step 4 Entry visit. Section 5 of this manual provides further guidance on scheduling and procedural considerations for these visits.


Similar to enrolling participants on-study (i.e., in Step 1 and Step 3), the definition of enrollment to Step 2 or Step 4 is passing of all eligibility criteria and the successful entry of the relevant step’s eligibility checklist data into the SES. Additionally, a paper-based eligibility checklist is required to be completed prior to entering the information into the electronic eligibility checklist in the SES. The process regarding the paper-based eligibility checklist described in Section 3.6 above is the same for entering Step 2 or Step 4. For example, it is recommended that a blank form of the study’s electronic eligibility checklist for Cohort 1 Step 2 be printed from the SES. Sites are expected to manually complete this paper-based eligibility checklist, assessing the source documentation for each inclusion and exclusion criterion for progressing from Step 1 to Step 2. Sites may then enter the information from the completed paper-based eligibility checklist into the SES for Step 2 enrollment. Note that the PID assigned at study entry will remain the same for participants as they enter Step 2 or Step 4. A new SID will be assigned as participants enter Step 2 or Step 4. 3.8 Cohort 1 Step 2 Participants Screening and Enrolling into Cohort 2 Step 3 Cohort 2 is anticipated to open to accrual after the first Cohort 1 interim analysis, as described above, and initially limited to only Cohort 1 participants who are eligible. Any adolescent screening for Cohort 2 Step 3 is required to meet eligibility criteria per Protocol Sections 4.1-4.2. Protocol Section 6.2 provides requirements and additional considerations for Cohort 1 Step 2 participants (current or former participants) screening for Cohort 2 Step 3. For previous Cohort 1 Step 2 participants, a new screening number will not be obtained from SES for the Cohort 2 Step 3 screening attempt. See Section 5 of this manual for recommendations on the timing and order of visit procedures for Cohort 1 participants screening and enrolling to Cohort 2 Step 3.


SECTION 4 INFORMED CONSENT AND ASSENT

Table of Contents 4.1 Overview ....................................................................................................................................... 1

4.2 General Considerations for Obtaining Informed Consent ............................................................ 3

4.3 Deliver all Required Information in a Manner that is Understandable to the Consenter/Assenter4

4.4 Assure that Informed Consent/Assent is Obtained in a Setting Free of Coercion and Undue Influence ................................................................................................................................................... 4

4.5 Confirm that the Consenter/Assenter Comprehends the Information ........................................... 5

4.6 Document the Process ................................................................................................................... 5

4.7 Additional Considerations and Resources .................................................................................... 6

4.1 Overview This section contains reference information and guidance for obtaining informed consent/assent in IMPAACT 2017. This study involves four different informed consent/assent processes: A. Informed consent for adolescent study participation in Cohort 1: Informed consent/assent for

adolescent study participation in Cohort 1 must be obtained before any study-specific screening or on-study procedures are performed. Per local site IRB/EC policies, if the adolescent participant is not of legal age to provide independent informed consent for study participation in Cohort 1, the parent, legal guardian or otherwise legally authorized representative will provide written informed consent for study participation and the potential participant will provide written informed assent for study participation. Each participant is expected to take part in the informed consent process with his or her parent or legal guardian and, in general, both the assent of the participant and the consent of the parent or legal guardian will be required for all consent decisions. However, should the participant be unaware of his/her HIV infection status, the informed consent process may be conducted with the parent or legal guardian separately and without the presence of the participant, per IRB/EC policies. In these circumstances, the assent process must be conducted with both the parent or legal guardian and the participant present. Note that, per protocol Section 14.3, informed consent for continued study participation must be obtained from participants who reach the legal age of consent during follow-up at their next study visit and prior to conducting any study-specific procedures. Additional details regarding informed consent, informed assent, and considerations for these processes are provided in protocol Section 14.3.

B. Informed consent for adolescent study participation in Cohort 2: Informed consent/assent for adolescent study participation in Cohort 2 must be obtained before any study-specific screening or on-study procedures are performed. Adolescent participants who participated in Cohort 1 and are eligible to rollover into Cohort 2 must provide separate informed consent/assent for Cohort 2.

Per local site IRB/EC policies, if the adolescent participant is not of legal age to provide independent informed consent for study participation in Cohort 2, the parent, legal guardian or otherwise legally authorized representative will provide written informed consent for study participation and the potential participant will provide written informed assent for study participation. Each participant is


expected to take part in the informed consent process with his or her parent or legal guardian and, in general, both the assent of the participant and the consent of the parent or legal guardian will be required for all consent decisions. However, should the participant be unaware of his/her HIV infection status, the informed consent process may be conducted with the parent or legal guardian separately and without the presence of the participant, per IRB/EC policies. In these circumstances, the assent process must be conducted with both the parent or legal guardian and the participant present. Note that, per protocol Section 14.3, informed consent for continued study participation must be obtained from participants who reach the legal age of consent during follow-up at their next study visit and prior to conducting any study-specific procedures. Additional details regarding informed consent, informed assent, and considerations for these processes are provided in the protocol Section 14.3.

C. Informed consent for adolescent specimen storage and future use: Informed consent must be requested for storage and future research of specimens that are left over after all protocol-specified testing has been performed. Parents/guardians and participants may choose to either provide or decline informed consent and assent (as applicable) for specimen storage and future use with no impact on other aspects of their study participation. As indicated on the sample signature page in protocol Appendix II-C, III-C and IV-C, this informed consent/assent form must be signed or marked regardless of whether permission to use samples for future research is provided or declined. In addition, specific notations must be recorded on the form to document consent decisions for genetic testing. Informed consent/assent for the specimen storage and future use must be obtained separately for Cohort 1 and Cohort 2. Adolescent participants who participated in Cohort 1 and are eligible to rollover into Cohort 2 must provide separate informed consent/assent for specimen storage and future use for specimens collected in Cohort 2.

D. Informed consent for parent/caregiver participation in qualitative interview (for U.S. sites only): Parents/caregivers must provide consent prior to enrollment and conducting the phone interview. Obtaining informed consent from the parent/caregiver for the phone interview is ideally conducted in person and in writing by the parent/caregiver signing the informed consent form. As noted in Appendix V-A, sites may seek a waiver from their IRB/EC of written informed consent for parent/caregiver participation in the qualitative phone interview. If a waiver is granted, the IRB/EC reviews a written description of the information that will be provided, either verbally or in writing, to the parents/caregivers. Appendix V-C provides a sample of a script or statement which may be modified for use, should an IRB/EC grant a waiver of written documentation. Additionally, sites also have the option of seeking IRB/EC approval for obtaining parent/caregiver consent by telephone, rather than in person. In such instances, a witness to the consent process (e.g., another study or non-study staff member) must be present at the time of the study site staff obtaining consent from the parent/caregiver and should ideally also listen in to the consenting discussion between the parent/caregiver and study staff member. Appendix V-C may be modified for use as a verbal script to obtain consent by telephone. If telephone consent is used and the parent/caregiver is seen at the site prior to conducting the phone interview, it is recommended to re-confirm the parent/caregiver’s understanding of the phone interview and willingness to participate through an additional, brief consent process, as required by the IRB.

The remainder of this section provides background information and operational guidance that is applicable to all the informed consent processes noted above.


4.2 General Considerations for Obtaining Informed Consent Informed consent is a process by which an individual voluntarily expresses his or her willingness to participate in research, after having been informed of all aspects of the research that are relevant to the decision. Informed consent and assent are rooted in the ethical principle of respect for persons. It is not merely a form or a signature, but a process involving information exchange, comprehension, voluntariness, and documentation. Each of these aspects of the informed consent process is described in greater detail below. Please also refer to Section 4.8 of the International Conference on Harmonization (ICH) Consolidated Guidance for Good Clinical Practice (GCP) and the informed consent section of the DAIDS policy on Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials for further information. US regulations (45 CFR 46 and 21 CFR 56) specify the elements of informed consent that must be conveyed to consenters through the informed consent process. It is the responsibility of the IoR, and by delegation all study staff involved in conducting the informed consent process, to deliver all required information to consenters. Based on the reviews completed as part of the IMPAACT 2017 protocol development and study activation processes, there is adequate assurance that once a site-specific study activation notice has been issued, a site’s informed consent forms (ICFs) and informed assent forms include all information required by the regulations. However, responsibility for informed consent/assent does not end with preparation of an adequate ICF. It also is the responsibility of the Investigator of Record (IoR) and designated study staff to: • Deliver all required information in a manner that is understandable to the consenter/assenter • Assure that informed consent/assent is obtained in a setting free of coercion and undue influence • Confirm that the consenter/assenter comprehends the information • Document the process Further guidance related to each of these requirements is provided in Sections 4.3-4.6 below. Each site must have on file a study-specific SOP for obtaining informed consent/assent that addresses all aspects of the informed consent process consistent with all applicable regulations, DAIDS policies and procedures, and protocol specifications. All sites must follow their SOPs consistently for all IMPAACT 2017 informed consent/assent processes. All site staff involved in obtaining informed consent/assent must be designated on the study-specific delegation of duties log and listed on the FDA Form 1572 for the study. These staff must be qualified by education, experience, training, and knowledge of the study, as determined by the IoR, and appropriate training documentation must be available to support the IoR’s delegation to these staff.


IMPORTANT NOTE

Per protocol Section 14.3, should the consenting parent (or guardian) of a participant die or no longer be available for any reason, sites should follow the guidelines and procedures in protocol Section 8.8, in addition to those described by their IRBs/ECs. Study sites may continue to provide care for the participant as needed and appropriate (outside of the study), consistent with local standard of care. If a guardian cannot be identified, or if the guardian does not consent to continued study participation, the participant must be withdrawn from the study. In accordance with the DAIDS policy on Enrolling Children (including Adolescents) in Clinical Research (available at the website referenced in protocol Section 14.2), all sites must establish and maintain written procedures describing the standards that will be followed to identify who may serve as guardian for an enrolled child or adolescent, reflective of applicable IRB/EC guidance for conduct of human subjects research within the context of available local law, regulation, or government policy.

4.3 Deliver all Required Information in a Manner that is Understandable to the Consenter/Assenter The informed consent/assent process should be conducted in the consenter’s/assenter’s preferred language and should reflect whether the consenter/assenter is determined to be literate per site SOPs. If the consenter/assenter is literate, begin the informed consent/assent process by providing the consenter (and assenter, as appropriate) with a copy of the ICF/assent form to read. Also provide her with any other informational materials developed to complement the ICF/assent form. If the consenter/assenter is not literate, read the materials to her/him. After the consenter/assenter has read the materials (or had them read to her/him), verbally review the information provided. A checklist or the ICF/assent form itself may serve as a useful guide for this. For example, you may note the main points described in each paragraph of the ICF/assent form and ask if the consenter/assenter has questions or concerns about each point. Sample checklists for Cohort 1 and Cohort 2 are included in Section 4.7, below. Listen carefully to the questions and/or concerns expressed by the consenter/assenter and discuss these thoroughly. Take as much time as needed to address each question or concern. If the consenter/assenter is not literate, an impartial literate witness must be present during the entire informed consent/assent process. As part of the documentation steps detailed below, the witness will be asked to sign and date the ICF to attest that the information in the ICF was accurately explained to, and apparently understood by, the consenter/assenter, and that informed consent/assent was freely given by the consenter/assenter. ICH-E6 identifies an “impartial” witness as a person who is independent of the study, who cannot be unfairly influenced by people involved with the study. The IMPAACT Operations Center has previously received guidance from the US Food and Drug Administration’s GCP office stating that the witness need not be “totally unaffiliated with the study. It may be possible, for example, to designate a “subject advocate” who would be available at each site. Sites with questions about who may serve as an impartial witness are encouraged to consult with their IRBs/ECs on possible options. Refer to Figure 4-2 for a summary of considerations for obtaining informed consent/assent from illiterate consenters/assenters. Figure 4-3 provides an example of completion of informed consent signature blocks for illiterate consenters. 4.4 Assure that Informed Consent/Assent is Obtained in a Setting Free of Coercion and Undue Influence During informed consent/assent discussions, take care to not overstate the possible benefits of the study, nor to understate the risks. Also describe the alternatives to study participation and emphasize that the availability of medical care and other services (outside the study) will not be affected by the


consenter/assenter’s decision whether to take part in the study. Encourage the consenter/assenter to take as much time as s/he needs — and to talk about study participation with others if s/he chooses — before making a decision. When a witness is present during the informed consent/assent process, care should be taken to minimize the perception of coercion due to the presence of the witness. For example, the purpose of having the witness present should be clearly explained to the consenter/assenter, with emphasis on the fact that the witness is there as a protection for the consenter/assenter, not as an agent of the study per se. 4.5 Confirm that the Consenter/Assenter Comprehends the Information The consenter/assenter must not be asked to agree to take part in the study, or to sign or make her/his mark on the ICF, until s/he fully understands the study. Study staff are responsible for ensuring that each consenter/assenter understands all aspects of study participation before signing or marking the ICF. A variety of approaches can be taken to assess comprehension. One approach uses a semi-structured checklist to guide a discussion in which the consenter/assenter responds to open-ended questions designed to elicit her understanding of key concepts. Sample checklists of this type for Cohorts 1 and 2, with accompanying guidance for use, are provided in Figure 4-4, Figure 4-5, and Figure 4-6. Other approaches may include documented discussions with the consenter/assenter as well as structured knowledge quizzes administered to the consenter/assenter. Regardless of the method used to assess comprehension, if the assessment indicates misunderstanding of aspects of the study, study staff should review those aspects again until the consenter/assenter fully understands them. If after additional review and discussion the consenter/assenter is not able to demonstrate adequate understanding, s/he should not be asked to sign or make her mark on the ICF. Similarly, if the consenter/assenter has concerns about possible adverse impacts if s/he were to provide consent, or indicates that s/he may have difficulty adhering to the study requirements, s/he should not be asked to sign or mark the ICF unless or until such issues can be resolved to the satisfaction of the consenter/assenter and the IoR (or designee). 4.6 Document the Process US regulations require that informed consent/assent be documented through the use of a written informed consent/assent form approved by the IRB/EC and signed and dated by the consenter/assenter or the consenter’s/assenter’s legally authorized representative at the time of consent. Note that for parents/caregivers, as noted in protocol Appendix V-A, sites may seek a waiver from their IRB/EC of written informed consent for parent/caregiver participation in the qualitative phone interview. To fulfill this requirement, all signature and date blocks on the consent/assent form should be completed in ink. Legal names should be used. Fabricated/falsified names should not be used. Initials may not be used in place of a consenter’s/assenter’s full surname, and it is strongly recommended that initials not be used in place of a consenter’s/assenter’s full first name. However, if a consenter/assenter commonly signs her name using an initial for her/his first name, the initial may be used, provided this practice is acceptable per the policies of the study site institution(s). If the consenter/assenter is not literate, the witness who was present during the informed consent/assent process must sign and date the consent/assent form to attest that the information in the form and any other written information was accurately explained to, and apparently understood by, the consenter/assenter, and that informed consent/assent was freely given by the consenter. The consenter’s/assenter’s printed


name, signature, and signature date blocks on the consent/assent form should be completed as described in Figure 4-2. The DAIDS policy on Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials lists detailed requirements and suggestions for documenting the informed consent process. Study sites must comply with all requirements and are encouraged to comply with all suggestions. To assist with compliance, study staff may use informed consent/assent coversheets similar to the examples provided in


Figure 4-7 and Figure 4-8. Sites choosing to use coversheets should identify the coversheets as source documents in their study-specific SOPs for source documentation and should use the coversheets consistently to document each informed consent/assent process conducted with each consenter/assenter. All informed consent/assent documentation must be maintained on file in participant study records. In addition to completing the documentation requirements of the ICF itself, each informed consent/assent process should be documented in a signed and dated chart note. For the main study informed consent/assent process, the note should document that informed consent/assent was obtained before conducting any study procedures. The note also should document adherence to the requirements of the informed consent section of the DAIDS policy on Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials. However, if an informed consent/assent coversheet is used, it is not necessary to transcribe information recorded on the coversheet into the chart note. Informed consent decisions will also be entered into eCRFs for adolescents and parents/caregivers: • Informed consent for adolescent study participation will be entered into the LGW10004; Informed

Consent Status Log eCRF. • Informed consent for parent/caregiver study participation in the qualitative phone interview will be

entered into the LGW10004: Informed Consent Status Log eCRF. • Informed consent for adolescent participant specimen storage and future use will be entered into the

TRK10000, Specimen Consent for Non-Protocol Defined Testing eCRF. Regulations require that consenters be given a signed copy of their ICF. If a consenter opts not to receive a copy, this should be documented, and the consenter should be offered an alternate form of study contact information (e.g., a contact card or appointment card) in lieu of the full ICF. 4.7 Additional Considerations and Resources

Figure 4-1. FAQ regarding the Informed Consent/Assent process in IMPAACT 2017

1. What should we do if, during the informed consent process, an adolescent indicates that s/he would like to take part in the study but is not willing to undergo certain procedures, such as a genital exam for sexual maturity rating?

The protocol team would generally advise against enrolling an adolescent who refuses certain

exams.

The scenario described in this question should be distinguished from an alternate scenario in which an adolescent indicates that s/he is willing to undergo all procedures as part of the study informed consent process, but then refuses a procedure later in follow-up. In this scenario, the participant’s wishes should be respected. Her/his refusal should be documented in her/his study records, and s/he should continue in follow-up for the full scheduled duration of study participation.

Figure 4-2. Summary of Considerations for Obtaining Informed Consent from Illiterate Consenters


• Each site must specify procedures for obtaining and documenting informed consent from illiterate persons in its SOP for obtaining informed consent. These procedures must be consistent with the DAIDS policy on Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials and must be followed each time informed consent is obtained from an illiterate consenter. It is recommended that each site seek IRB/EC review and approval of these procedures.

• An impartial witness must be present during the entire informed consent process with an

illiterate consenter. The witness must sign and date the informed consent form to attest that the information in the consent form was accurately explained to, and apparently understood by, the consenter, and that informed consent was freely given by the consenter.

• The site SOP for obtaining informed consent should define who may serve as the witness to the

informed consent process. • Care must be taken to minimize the perception of coercion due to the presence of the witness. • Unless other conventions that have been endorsed by DAIDS are specified in site SOPs, the

study staff member who completes the informed consent process with the consenter should print the consenter’s name below the consenter’s printed name line on the informed consent form, together with a signed and dated note documenting the name of the person who made the entry and the date of the entry (see Figure 4-3).

• The consenter should make her/his mark on the consenter’s signature line. • Unless other conventions that have been endorsed by DAIDS are specified in site SOPs, the

study staff member who completes the informed consent process should enter the date upon which the consenter made her/his mark on the informed consent form below the consenter’s signature date line, together with a signed and dated note documenting the name of the person who made the entry and the date of the entry (see Figure 4-3).

• For more information, see Section 4.8 of the ICH GCP guidance and the informed consent

section of the DAIDS policy on Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials.


Figure 4-3. Example of Completed Informed Consent Signature Blocks for Illiterate Consenters


Figure 4-4. Sample Informed Consent Comprehension Checklist for IMPAACT 2017 – Cohort 1

Participant’s Identifier

✓ 1. Please tell me what you understand about this study and why it is being done.

Testing two ARV medications (CAB and RPV) for adolescents when taken as pills and given as shots to see if it they are safe and are being given at the correct dose for adolescents.

RPV pills are approved by the FDA for adults and adolescents 12 years and older with HIV.

CAB pills, CAB shots and RPV shots are new ARVs that are being tested in adults in the United States and other countries. There is little information as of now about CAB pills, CAB shots and RPV shots in adolescents.

✓ 2. Please tell me about who will participate in this study.

Adolescents who are 12 years old to less than 18 years old who have HIV.

Adolescents can turn 18 years old or older after they enroll and continue in the study.

Cohort 1 participants will take either CAB pills followed by CAB shots or RPV pills followed by RPV shots. The pills are taken daily, and the shots are given four weeks apart.

Cohort 1 participants will keep taking their usual ARVs.

✓ 3. What are participants asked to do if they join this study

In Cohort 1-Phase 1, adolescent participants will start taking either CAB or RPV pills at the study entry visit (the first study visit) and will then come to the clinic for 2 study visits over 4-6 weeks.

If eligible for Cohort 1-Phase 2, at the fifth study visit, participants will take their last CAB or RPV pill and will receive their first CAB or RPV shot. Participants will have 5 more visits over 12 weeks. At one of these visits, participants will receive another shot of CAB or RPV.

Participants will keep taking their usual ARVs during both phases in Cohort 1.

Participants will answer questions about themselves, have blood collected for tests and have physical exams at each study visit. At two of the visits, the physical exam will include a genital exam to determine the stage of puberty.

At 3 visits, participants will have an electrocardiogram (ECG).

At 3 visits, participants will have an adherence assessment.

At one visit, participants will have an intensive pharmacokinetic test (PK).

Females will have blood or urine collected for pregnancy testing at 7 visits. Female participants who are able to get pregnant will also have to agree to use certain methods of birth control while on the study.

(U.S. sites only) Participants may be asked to complete one in-depth phone interview after their first shot of CAB or RPV.

Participants may have extra visits if their HIV is not controlled.

Participants who are not eligible to receive shots of CAB or RPV will stop taking CAB or RPV pills and have a final study visit about 4 weeks after the last oral dose.

During Cohort 1-Phase 1, participants who are not eligible for Cohort 2, if Cohort 2 is not open, or during Cohort 1-Phase 2 must stop getting CAB or RPV shots early, will stop getting shots of CAB or RPV and will enter into long-term follow-up. If eligible, participants may enter Cohort 2 when Cohort 2 is ready.

✓ 4. What are the possible risks for participants in this study?

Procedures may cause discomfort (must mention at least one; see sample ICF #20-21 for Cohort 1).

ARVs may cause side effects (must mention at least one; see sample ICF #22-25 for Cohort 1).

Others may treat participants unfairly for being in the study.

✓ 5. What are the possible benefits for participants in this study?

There may be a benefit to participants, but no guarantee can be made (may mention one or more possible benefits; see sample ICF #27 for Cohort 1).

✓ 6. What happens if adolescents choose not to join the study?


People are free to make their own choice about joining or not joining.

No matter what potential participants decide about joining, there will be no effect on access to medical care outside the study

No matter what potential participants decide about joining, it is important to take ARVs. Taking ARVs is the best known way for people with HIV to stay healthy.

✓ 7. How will information about participants be protected?

Every effort will be made to keep information private and confidential (must mention at least one method used by the site, see sample ICF #26 for Cohort 1).

✓ 8. What should participants do if they have questions or concerns about their health or what is happening in the study?

Must state how to contact study staff (see sample ICF #31 for Cohort 1)

Outcome (mark one)

Consenter demonstrated comprehension of all required points Consenter did not demonstrate comprehension of all required points

Study Staff Printed Name

Study Staff Signature and Date


Figure 4-5. Sample Informed Consent Comprehension Checklist for IMPAACT 2017 – Cohort 2

Participant’s Identifier

✓ 1. Please tell me what you understand about this study and why it is being done.

Testing two ARV medications (CAB and RPV) for adolescents when taken together as pills and given together as shots to see if it they are safe and are being given at the correct dose for adolescents.

RPV pills are approved by the FDA for adults and adolescents 12 years and older with HIV.

CAB pills, CAB shots and RPV shots are new ARVs that are being tested in adults in the United States and other countries. There is little information as of now about CAB pills, CAB shots and RPV shots in adolescents.

✓ 2. Please tell me about who will participate in this study.

Adolescents who are 12 years old to less than 18 years old who have HIV.

Adolescents can turn 18 years old or older after they enroll and continue in the study.

Cohort 2 participants will take CAB pills and RPV pills followed by CAB shots and RPV shots. The pills are taken daily, and the shots are given four weeks apart and then every eight weeks.

Cohort 2 participants will not keep taking their usual ARVs.

✓ 3. What are participants asked to do if they join this study

In Cohort 2-Phase 1, adolescent participants will start taking CAB and RPV pills at the study entry visit (the first study visit) and will then come to the clinic for 2 study visits over 4-6 weeks.

If eligible for Cohort 2-Phase 2, at the fifth study visit, participants will take their last CAB and RPV pills and will receive their first CAB and first RPV shots. Participants will have 14 more visits over 92 weeks or 2 years. At 12 of these visits, participants will receive a shot of CAB and RPV.

Participants will stop taking the ARVs they were taking before joining the study.

Participants will answer questions about themselves, have blood collected for tests and have physical exams at each study visit. At three of the visits, the physical exam will include a genital exam to determine the stage of puberty.

At 3 visits, participants will have an adherence assessment.

Females will have blood or urine collected for pregnancy testing at all Cohort 2-Phase 1 visits, and at each Cohort 2-Phase 2 visit prior to getting the CAB and RPV shots. Female participants who are able to get pregnant will also have to agree to use certain methods of birth control while on the study.

(U.S. sites only) Participants may be asked to complete one in-depth phone interview after their first shot of CAB and RPV.

Participants may have extra visits if their HIV is not controlled.

During Cohort 2-Phase 1, participants who are not eligible to receive shots of CAB and RPV will stop taking CAB and RPV pills and have a final study visit about 4 weeks after the last oral dose.

Participants who must stop getting CAB or RPV shots early during Cohort 2-Phase 2will enter into long-term follow-up.

✓ 4. What are the possible risks for participants in this study?

Procedures may cause discomfort (must mention at least one; see sample ICF #20-21 for Cohort 2).

ARVs may cause side effects (must mention at least one; see sample ICF #22-25 for Cohort 2).

Others may treat participants unfairly for being in the study.


✓ 5. What are the possible benefits for participants in this study?

There may be a benefit to participants, but no guarantee can be made (may mention one or more possible benefits; see sample ICF #27 for Cohort 2).

✓ 6. What happens if adolescents choose not to join the study?

People are free to make their own choice about joining or not joining.

No matter what potential participants decide about joining, there will be no effect on access to medical care outside the study

No matter what potential participants decide about joining, it is important to take ARVs. Taking ARVs is the best known way for people with HIV to stay healthy.

✓ 7. How will information about participants be protected?

Every effort will be made to keep information private and confidential (must mention at least one method used by the site, see sample ICF #26 for Cohort 2).

✓ 8. What should participants do if they have questions or concerns about their health or what is happening in the study?

Must state how to contact study staff (see sample ICF #31 for Cohort 2)

Outcome (mark one)

Consenter demonstrated comprehension of all required points Consenter did not demonstrate comprehension of all required points

Study Staff Printed Name

Study Staff Signature and Date

Figure 4-6. Guidance for using Sample Informed Consent Comprehension Checklists in IMPAACT 2017

For sites choosing to use informed consent comprehension checklists similar to the sample provided above, the text that follows provides guidance on its intended use. Please contact the IMPAACT Operations Center Clinical Trial Specialists with any questions. 1. The sample informed consent comprehension checklist may be adapted for use at each site. 2. The checklist should be administered after the consenter has completed the informed consent

discussion, i.e., after the consenter has read the informed consent form (ICF) or had it read to her/him and discussed any issues, questions, or concerns, but prior to the consenter being asked to sign or make her/his mark on the ICF. It is generally expected that the checklist will be administered by the same study staff member who conducted the informed consent discussion with the consenter. However, this is not required.

3. The checklist should not be presented to the consenter as a “test,” but rather as a way of double-

checking that study staff have fulfilled their responsibility to provide all information needed to make an informed decision about taking part in the study. Study staff members who administer the checklist must be sufficiently knowledgeable about the study to make good judgments about consenters’ comprehension of the informed consent information. They should be thoroughly familiar with the site-specific ICFs as well as with the content of the comprehension checklists. Role-playing is strongly recommended as part of preparation and training on use of the checklists.


4. Each checklist is structured around open-ended questions that correspond to the required elements of informed consent for research. For each question, at least one “required point of comprehension” is listed on the checklist; for some questions, several required points of comprehension are listed. Each open-ended question should be read to the consenter. Then, through discussion and dialogue, the intent is for the consenter to demonstrate comprehension of all required points of comprehension listed for each question. The consenter should not be expected to state each required point of comprehension using the exact same wording that appears on the checklist. Rather, the consenter should demonstrate in her/his own words that s/he understands each required point.

5. Because the open-ended questions are to be read to consenters, these questions should be translated

into local languages. Sites may also translate the required points of comprehension, but this is not as critical as translating the questions, because the required points of comprehension are not read to consenters.

6. For each question, the consenter should ideally demonstrate comprehension of all required points

before proceeding to the next question. When the consenter demonstrates comprehension of one of the required points, study staff should tick that point in the designated space. If the consenter does not spontaneously address one or more of the required points in her/his response, study staff should ask another open-ended question to elicit a response about that point. For example, one of the required points in Question 3 of the sample checklist is “At most of the visits the participants have a physical exam. At one of the visits, this includes a genital exam to determine the stage of puberty.” If the consenter does not mention this in her/his initial response to Question 3, study staff may say, “You mentioned the at most visits there will be a physical exam. Can you tell me what you understand will take place in this exam?”

7. The sample comprehension checklist has been designed to include points of comprehension that

address all information required to make an informed decision about study participation. As such, comprehension of all points should be demonstrated before proceeding to the final informed consent decision and signing or marking of the ICF. Sites may choose to modify the wording of the required points of comprehension to correspond with wording used in their site-specific ICFs. Sites may also add points of comprehension to the checklists. Deletions are not recommended.

8. When responding to the open-ended questions, consenters may report back more information than

is included on the checklist. This is acceptable, as long as the required information is reported back. However, if any misinformation is reported back, study staff should explain the correct information before proceeding to another question.

9. Once administration of the comprehension checklist begins, it is possible that the consenter may

spontaneously state many of the required points, without each open-ended question being asked. In such cases, study staff should tick the relevant points on the checklist and then ask the remaining questions or probe about the remaining points that the consenter has not yet mentioned. It is acceptable to ask a question that a consenter may have already answered in her/his response to a previous question. However, if study staff are confident that a previous response was adequate, the specific question or point does not need to be repeated.


10. It is possible that a consenter might state correct information, yet study staff may not be convinced that s/he truly understands a required point of comprehension. In such cases, the study staff member should decide if further explanation or discussion is needed before proceeding to the final informed consent decision and signing or marking of the ICF. Further explanation or discussion may take place at the same visit or at another visit. The assessment process may also take place over the course of multiple days if the consenter becomes fatigued and/or if more time is needed for any other reason.

11. Whenever additional information or explanation is needed to help ensure the consenter’s

comprehension, any informed consent support materials may be used (e.g., the ICF, other visual aids) to help provide the necessary information. After additional information or explanation is provided, open-ended questions should again be asked to confirm the consenter’s comprehension of the required points. Some consenters may be more comfortable interacting with the same study staff member throughout the informed consent process and comprehension assessment. However, another staff member may be consulted, if necessary or desired, to help explain difficult concepts and/or respond to specific questions or concerns.

12. The sample comprehension checklist has been designed as a source document, which should be

completed, handled, and retained in participant study records like any other source documents. Relevant consenter and participant identifiers should be recorded on the checklists and tick marks for required points of comprehension should be recorded as instructed above. The study staff member who administers the checklist should document the outcome of the assessment in the space provided and should sign and date the checklist on the date of administration. Additional comments may be recorded on the checklist or on an informed consent cover sheet or other site-specific source document per site SOPs; however, such comments are not required.

13. The study staff member who administers the checklist should carefully review it to verify that

comprehension of all required points was demonstrated and that this is documented on the checklist (i.e., all required points of comprehension should be ticked). It is recommended that a second study staff member also complete this verification because failure to document comprehension of all required points could be considered an informed consent and eligibility/enrollment violation.


Figure 4-7. Sample Informed Consent Coversheet for IMPAACT 2017

Participant identifier

Can the consenter read?

Yes

No A literate impartial witness should be present during the

entire IC process. Record name and relationship/role of

witness below.

Language of IC process [Language A]

[Language B]

Version number and version date of informed consent form used during IC process

Was the IC process conducted per site SOPs? Yes

No Record and explain departures from site SOPs below.

Was all information required to make an informed decision provided in a language understandable to the consenter?

Yes

No Explain below.

Were all of the consenter’s questions answered? Yes

No Explain below.

Did the consenter comprehend all information required to make an informed decision?

Yes

No Explain below.

Was the consenter given adequate time and opportunity to consider all options, in a setting free of coercion and undue influence, before making an informed decision?

Yes

No Explain below.

Did the consenter choose to provide IC? Yes

No STOP.

Date and time at which the consenter signed or marked the informed consent form

NA (consent declined, form not signed or marked)

Date:

Time:

Did the consenter accept a copy of the IC form? NA (consenter chose not to provide informed consent)

Yes

No Offer alternate form of study contact information.

Notes/Comments

Signature of study staff person completing IC process (and this coversheet)


Figure 4-8. Sample Informed Assent Coversheet for IMPAACT 2017

Participant identifier

Can the assenter read?

Yes

No A literate impartial witness should be present during the

entire informed assent process. Record name and

relationship/role of witness below.

Language of informed assent process [Language A]

[Language B]

Version number and version date of informed assent form used during process

Was the informed assent process conducted per site SOPs?

Yes

No Record and explain departures from site SOPs below.

Was all information required to make an informed decision provided in a language understandable to the assenter?

Yes

No Explain below.

Were all of the assenter’s questions answered? Yes

No Explain below.

Did the assenter comprehend all information required to make an informed decision?

Yes

No Explain below.

Was the assenter given adequate time and opportunity to consider all options, in a setting free of coercion and undue influence, before making an informed decision?

Yes

No Explain below.

Did the assenter choose to provide informed assent?

Yes

No STOP.

Date and time at which the assenter signed or marked the informed assent form

NA (assent declined, form not signed or marked)

Date:

Time:

Did the assenter accept a copy of the informed assent form?

NA (assenter chose not to provide informed assent)

Yes

No Offer alternate form of study contact information.

Notes/Comments

Signature of study staff person completing informed assent process (and this coversheet)


SECTION 5 STUDY VISITS, VISIT SCHEDULING, AND SELECT VISIT PROCEDURES

Table of Contents 5.1 Visit Scheduling and Considerations for Selected Study Visits ................................................... 1

5.1.1 Study Visit Target Dates and Windows ....................................................................................... 1

5.1.2 Cohort 1 and Cohort 2 Entry Visit Procedure Considerations .............................................. 3

5.1.3 Visit Scheduling and Procedure Considerations for Cohort 1 Participants Screening and Enrolling to Cohort 2 ............................................................................................................................ 3

5.1.4 Week 2 Visit Scheduling Considerations (Cohort 1 and Cohort 2) ...................................... 3

5.1.5 Week 4a and Week 4b Visit Timing and Procedures (for Cohort 1 and Cohort 2) .............. 4

5.1.6 Study Product Injection Visit Scheduling and Visit Spacing Requirements (Cohort 1 Step 2 and Cohort 2 Step 4) ............................................................................................................................. 5

5.1.7 Considerations for Short-Term Oral Bridging (Cohort 2 Step 4 only) ................................. 6

5.1.8 Off-site Visit Considerations (Non-injection Follow-Up Visits only) .................................. 7

5.1.9 Considerations for Conducting Study Visits During COVID-19 .......................................... 9

5.2 Select Study Procedures and Evaluations ................................................................................... 12

5.2.2 Pharmacokinetic Evaluations .............................................................................................. 13

5.2.3 Medical and Medications History ....................................................................................... 14

5.2.4 Physical Exams and Sexual Maturity Rating (Tanner Staging) .......................................... 14

5.2.5 Performing an ECG ............................................................................................................. 15

5.2.6 Adherence Assessments and Pill Counts ............................................................................ 15

Appendix 5-1: Target Visit Date and Window Tables ............................................................................... 16

Appendix 5-2: Example Order of Procedures for a Combined WeeK 4a/Week 4b visit ............................ 19

Appendix 5-3: Scheduling Scenario of Cohort 2 Step 4 Injections ............................................................ 20

Appendix 5-4: Example Off-site Visit Preparation Checklist..................................................................... 21

Appendix 5-5: Tanner Staging chart and Guidelines .................................................................................. 22

Appendix 5-6: Example Chart Note of IoR Determination of Adequate Oral Study Product Exposure ... 23

Protocol Section 6 and protocol Appendix I Schedule of Evaluations (SoE) provide comprehensive information on scheduling and procedural requirements for conducting study visits. This section of the manual provides additional guidance or explanation on select study visits and select study visit procedures. 5.1 Visit Scheduling and Considerations for Selected Study Visits 5.1.1 Study Visit Target Dates and Windows Protocol Section 6.1 provides the requirements and parameters regarding study visit target dates, visit windows, conducting split or interim visits, and conducting non-injection follow-up visits off-site. A target visit date and a target visit window (also referred to as a “target window”) for follow-up visits are


specified throughout protocol Sections 6.3-6.5. For select non-injection follow-up study visits, a broader allowable visit window is also specified. Visits not conducted within their respective protocol-specified window(s) are considered missed. Sites are expected to make every effort to schedule and conduct study visits on the target visit date. However, if this is not possible, study visits should be conducted within the target window. Target windows allow flexibility in participant scheduling and are set surrounding or extending from the relevant visit’s target visit date. The priority of timeframes in which a study visit is to be scheduled are as follows:

• Target visit date: Study visits should be scheduled to occur on the respective target visit date.

• Target window: If it is not possible to schedule or conduct a visit on the respective target visit date, the visit may be scheduled within the target window.

• Allowable window (if applicable): If it is not possible to schedule or conduct a visit within the respective target window, the visit may be scheduled within the allowable window, if an allowable window is specified for that study visit. The CMC must be notified if the Cohort 1 Week 2 visit occurs within the allowable window (and outside the target visit date and target window).

Per protocol Section 6.1.2, if a participant is unable to complete all required visit procedures on the same day, then the visit may be split within the target window, unless otherwise specified (e.g., the Entry and Week 4b visits). Protocol Sections 6.3 and 6.4 sub-sections require several visit procedures to be performed on the same day, per the respective visit. Additionally, protocol Section 6.9 describes required procedures prior to dispensing oral study product and prior to administering injectable study product. Sites should carefully review the protocol requirements for each visit when conducting split visits, as some procedures may need to be repeated to comply with the protocol requirements. See Section 5.1.8 below for non-injection follow-up visits conducted off-site. For all study visits, the target date, target window, and allowable window (if applicable) are calculated with the reference visit counted as day 0. For example, the Cohort 1 Week 12 visit has a target date of 28 days after the Cohort 1 Week 8 visit. The Cohort 1 Week 8 visit is the reference visit and is therefore counted as day 0. If the Cohort 1 Week 8 visit occurred on Tuesday, 18 January 2021, the target visit date for the Cohort 1 Week 12 visit is Monday, 15 February 2021. For both Cohort 1 and Cohort 2, target visit dates for study product injection visits are set relative to administration of the first study product injection occurring at the Week 4b visit, with the Week 4b visit counted as day 0. See Section 5.1.6 below for additional scheduling requirements for study product injection visits. Section Appendix 5-1 combines target visit dates and target windows for Cohort 1, Cohort 2, and LSFU study visits. The Visit Forecaster tool projects which participants are expected in the clinic for the protocol-defined visits according to standard Data Collection Forms Schedules with specific week intervals. Sites can use the Visit Forecaster tool available on the DMC website located on the Frontier Science Portal: www.frontierscience.org


5.1.2 Cohort 1 and Cohort 2 Entry Visit Procedure Considerations Cohort 1 and Cohort 2 Entry visits are detailed in protocol Sections 6.3.1 and 6.4.1, respectively. Select Entry visit procedures are specified to be conducted in a required sequence in relation to final determination of eligibility and enrollment of participants. Other visit procedures required at the Entry visit but not stated to be conducted in a specified sequence may be conducted at any timepoint during the visit. For example, pregnancy testing must be performed prior to enrollment as a negative pregnancy test result must be obtained as part of final determination of eligibility. Other laboratory samples (such as hematology and chemistries) may be collected at the same time as collecting blood for the pregnancy test, even though those other test results establish the participant’s baseline and are not required per protocol to be obtained prior to enrollment. However, any laboratory test results which become available prior to enrollment should be reviewed as part of final determination of eligibility. 5.1.3 Visit Scheduling and Procedure Considerations for Cohort 1 Participants Screening and Enrolling to

Cohort 2 Cohort 2 will open to accrual limited to participants who previously enrolled to Cohort 1. Eligibility criteria for Cohort 2 are provided in protocol Sections 4.1 and 4.2; some criteria include specified “Notes” of exemption or additional considerations for Cohort 1 participants screening for Cohort 2. Protocol Section 6.2 provides procedural details regarding Cohort 1 participants screening for Cohort 2. It is generally expected that most Cohort 1 participants will still be on-study when they screen for Cohort 2. For example, Cohort 1 participants screening for Cohort 2 may have recently completed their Cohort 1 Step 2 Week 16 visit, or one or more of their LSFU visits. There is no minimum length of time required to elapse between completion of the Cohort 1 Step 2 Week 16 visit and enrolling to Cohort 2 Step 3. Some Cohort 1 Step 2 participants may complete all scheduled LSFU study visits and exit the study (at the LSFU Week 48 visit) prior to Cohort 2 being opened to accrual. These former Cohort 1 Step 2 participants may resume study participation in Cohort 2 Step 3, if eligible. Upon successful enrollment to Cohort 2 Step 3, the off-study date entered on the ADM10008 eCRF will be removed to reflect that the participant is back on study. Clinical assessments, evaluations, and laboratory values obtained during Cohort 1 Step 2 or LSFU study visits may be used to screen for Cohort 2 eligibility, if obtained within 28 days of the Cohort 2 Entry Visit. Otherwise, all Cohort 2 Step 3 screening visit procedures must be completed for eligibility determination, with the exceptions noted in protocol Section 6.2 (e.g., a new PID should not be assigned). Informed consent (or assent, as applicable) for Cohort 2 must be obtained prior to study staff initiating Cohort 2 screening procedures (such as completing a Cohort 2 Step 3 screening checklist or entering participant information on a Cohort 2 Step 3 screening/enrollment log). Participant files should clearly source document the timing of obtaining consent/assent for Cohort 2 prior to initiating Cohort 2 screening procedures. 5.1.4 Week 2 Visit Scheduling Considerations (Cohort 1 and Cohort 2)

Cohort 1 and Cohort 2 Week 2 visits are detailed in protocol Sections 6.3.2 and 6.4.2, respectively. Safety evaluations and PK sampling will be conducted at the Week 2 visit (in both Cohort 1 and Cohort 2). To ensure a successful PK evaluation of exposure to the oral study product, sites should have close contact with participants (and/or parents/guardians) leading up to the Week 2 visit to facilitate study product adherence. The protocol provides detailed guidance relating to Week 2 visit preparatory considerations, including confirmed adherence to and timing of administration of the oral study product for the three days prior to the Week 2 visit:


• For the three days prior to the Week 2 visit, oral study product must be taken, and • For the three days prior to the Week 2 visit, oral study product must be taken at the same time of

day (morning or evening) as the Week 2 pre-dose PK sample, and • The oral study product dose due on the day of the Week 2 visit must be held for observation at the

site. If these conditions are not confirmed per participant-report, the full Week 2 visit must be rescheduled within the target window (or allowable window). Additionally, for participants who immediately prior to or on the day of the scheduled Week 2 PK sample collection report intercurrent illness that may have interfered with study product administration or resulted in malabsorption of study product (e.g., fever, vomiting, diarrhea), the Week 2 visit should be rescheduled. If the observed oral study product dose is not retained within 30 minutes (inclusive) of administration (e.g., vomiting), the Week 2 visit should be also rescheduled. To facilitate participant compliance with adhering to the oral study product administration requirements, sites are recommended to advise participants to align their oral study product dosing to the timing of the Week 2 pre-dose PK sample early in their oral study product regimen. For example, most sites will obtain the Week 2 pre-dose PK sample in the morning. During the Entry visit, sites should recommend participants to take their oral study product in the morning, beginning with the day following the Entry visit; and this timing of oral study product should then continue through the Week 2 visit. As the Week 4b visit also has a pre-dose PK sample collection, the timing of oral study product should ideally continue through that visit as well. Additional guidance regarding oral study product regimen, such as administration with a meal (for Cohort 1R and all Cohort 2 participants), is provided in protocol Section 5. Section 7 of this manual also provides guidance on prescribing and dispensing additional oral study product at the Week 2 visit to ensure daily coverage through the Week 4a and Week 4b visits. 5.1.5 Week 4a and Week 4b Visit Timing and Procedures (for Cohort 1 and Cohort 2) Protocol Sections 6.3.3 and 6.4.3 provide detailed requirements and visit procedures for the Cohort 1 Week 4a and Cohort 2 Week 4a visits, respectively. The purpose of the Week 4a visit is to obtain safety information for determination of participant eligibility to receive the injectable study products. Protocol Section 4.3 provides the inclusion and exclusion criteria for participants to progress from Cohort 1 Step 1 to Cohort 1 Step 2. Similarly, protocol Section 4.4 provides the inclusion and exclusion criteria for participants to progress from Cohort 2 Step 3 to Cohort 2 Step 4. Sites should review the laboratory test results obtained from the Week 4a visit as soon as they are available to determine whether to schedule the Week 4b visit. Interim visits (after obtaining the Week 4a laboratory test results and prior to scheduling the Week 4b visit) may be conducted if required to confirm the Week 4a results. The Week 4b visit should be scheduled to occur as soon as possible after the Week 4a visit, but no later than 42 days from the Entry visit (i.e. a maximum of 6 weeks on oral study product). The target dates of all subsequent study product injections are relative to the completion of the Week 4b visit. Therefore, the participant’s future schedule and availability (e.g., holidays, vacations, extracurricular activities, school exams), and those of the parent/guardian’s as applicable, should be considered to the extent possible when scheduling the Week 4b visit. See Section 5.1.6 below for injection visit requirements which may also be considered when scheduling the Week 4b visit.


The target windows of the Week 4a and Week 4b visits overlap, and combining these visits is allowed if the laboratory test results from the Week 4a visit blood collections (hematology and chemistries) are available within a reasonable timeframe. Protocol Sections 6.3.4 and 6.4.4 (Week 4b visits for Cohort 1 and Cohort 2, respectively) provide detailed requirements regarding whether oral study product should be administered (and observed) during the Week 4b visit. These requirements also include whether the pre-dose PK sample is collected in relation to the participant’s last oral study product dose or in relation to the participant’s first study product injection. These same requirements apply to a combined Week 4a/Week 4b visit. Additionally, the following considerations must also be taken into account for a combined Week 4a/Week 4b visit:

• For the three days prior to the combined Week 4a/Week 4b visit, participants should ideally take the oral study product at the same time of day (morning or evening) as the pre-dose PK collection time point and be fully adherent to their assigned daily oral study product regimen.

• Participants and their parents/guardians should be reminded to hold administration of the daily oral study product due on the day of the combined Week 4a/Week 4b visit, to allow for a pre-dose PK sample collection and for the dose to be observed at the site.

• Participants and their parents/guardians should also be reminded to return all oral study product at the combined Week 4a/Week 4b visit, such that the adherence assessment may be performed.

However, the combined Week 4a/Week 4b visit does not need to be rescheduled if these conditions are not met. An example order of visit procedures for a combined Week 4a/Week 4b visit is available in Section Appendix 5-2. During the Week 4b visit, the timing of PK sample collection relative to the oral dose administration is critical. In the event the participant vomits within 30 minutes of an observed oral dose, then the pre-dose PK sample should be redrawn (if already collected) followed by a second observed oral dose. If vomiting occurs more than 30 minutes of an observed oral dose during the Week 4b visit, then a second dose should not be administered, and the PK sampling may proceed as scheduled. Any vomiting episodes should be source documented. 5.1.6 Study Product Injection Visit Scheduling and Visit Spacing Requirements (Cohort 1 Step 2 and

Cohort 2 Step 4) To maintain the prescribed study product dosing regimen, study product injections must be administered within the visit’s respective target window and must be administered in accordance to the protocol-defined minimum and maximum number of weeks having elapsed since the previous injection (i.e., visit spacing requirements). If a study product injection is not able to be administered within both of these timeframes, it is considered missed. Should a participant miss a study product injection, the CMC must be consulted regarding clinical considerations and study product management. See Section 5.1.7 below for specific guidance regarding short-term oral bridging and resuming injections for Cohort 2 Step 4 participants. In Cohort 1 Step 2, study product injections are only administered during the Week 4b and the Week 8 study visits. In Cohort 2 Step 4, study product injections are initially administered four weeks apart: during the Week 4b and Week 8 study visits. The target visit date for the Week 8 visit is determined by the date of study product injection during the Week 4b visit, therefore visit spacing requirements will be maintained regardless of whether the injection was administered early or later in the target window. For Cohort 2 Step 4 visits, following completion of the Week 8 visit, all subsequent study product injections will be administered eight weeks apart. Of note, these subsequent Cohort 2 Step 4 injection visits may be more challenging to schedule, as the target visit date for each visit will be determined by the date of the Week 4b injection, but sites must also ensure the scheduled visit date aligns with injection spacing requirements based on the date of the previous injection, as further outlined below.


For Cohort 2 Step 4 Week 16 through Week 96 visits, the protocol requires a specified minimum and maximum number of weeks to elapse between injections:

• The Step 4 Week 16 injection must be administered a minimum of 7 weeks (49 days) and a maximum of 8 weeks and 3 days (59 days) from the Step 4 Week 8 injection, with the Step 4 Week 8 injection counted as day 0.

• The Step 4 Week 24 and all subsequent Step 4 injections must be administered a minimum of 7 weeks (49 days) and a maximum of 9 weeks (63 days) from the previous scheduled injection, with the date of the previous injection counted as day 0.

Sites should take extra care when scheduling any Cohort 2 Step 4 study product injection visit within the target window yet outside of the target visit date. If a study product injection is administered late or early in the target window, the subsequent visit’s target window will effectively be shortened with fewer days available to comply with the protocol-required elapsed time between injections. In some circumstances, it may no longer be possible to schedule the next injection visit on the target visit date while maintaining the required spacing between injections. In these circumstances, the visit should be scheduled on another day within the target window which aligns with the injection spacing requirements. Section Appendix 5-3 provides an example of a Cohort 2 Step 4 injection scheduling scenario.

5.1.7 Considerations for Short-Term Oral Bridging (Cohort 2 Step 4 only) Initiating Short-Term Oral Bridging Sites are expected to make every effort to ensure study product injections are scheduled on the target visit date (or within the target window). In the event a Cohort 2 Step 4 participant is unable to receive their scheduled study product injections within the target window and within the max allowed spacing requirement, the CMC may be consulted to provide the participant with short-term oral bridging to ensure study product coverage between injections. Sites should thoroughly explore and discuss with the participant (and parent/legal guardian as applicable) the reason(s) why the study product injection will be missed as well as the agreed-upon plan (date and any associated logistics) to resume study product injections. These discussions must be clearly documented in the participant’s file. When requesting to initiate short-term oral bridging for a participant, sites should provide the following information to the CMC (in addition to the information outlined in MOP Section 2):

• Injection visit that will be missed (e.g., Cohort 2 Week 32 visit), • Target visit date, and the target window open and close dates of the missed injection visit, • Reason for missing the injection, • Brief description of site efforts to retain the participant on the visit schedule, • Planned date to resume study product injections, and • IoR assessment of the participant’s future compliance with the study product injections

An affirmative response from the CMC must be received prior to initiating short-term oral bridging with the participant; this CMC response must be filed in participant’s file. As noted in protocol Section 6.1.2, an interim visit may be conducted (at the site or off-site) to dispense oral study product for short-term oral bridging. Protocol Section 5.1.4 provides details regarding the administration of short-term oral bridging doses, and additional guidance is provided in MOP Section 7.3.4. Resuming Study Product Injections Following Short-Term Oral Bridging


The CMC must be consulted prior to resuming study product injections following short-term oral bridging for details regarding clinical considerations, injectable study product management, and injection visit scheduling. Protocol Section 6.4.14 outlines the general expectations of the CMC instructions to sites regarding injection visit scheduling, however alternative instructions may be given depending on an individual participant’s circumstance. The length of time a Cohort 2 Step 4 participant received short-term oral bridging will impact the timing of when (and if) injectable study products are to be resumed. For some participants, the study product injections may be resumed during their next regularly scheduled injection visit with no alteration from the original injection schedule. For other participants, an interim visit may be required to resume the study product injections (i.e., an interim injection visit). Depending on the duration of the short-term oral bridging, re-initiation to the injectable study products may be required such that the participant will again receive the injections four weeks apart and thereafter 8 weeks apart. Some participants may also require a gradual realignment of the study product injections to their original visit schedule. Multiple interim injection visits may be required in these circumstances. An affirmative response from the CMC, including details regarding injectable study product management and injection visit scheduling, must be received prior to resuming injectable study products with the participant; this CMC response must be filed in participant’s file. 5.1.8 Off-site Visit Considerations (Non-injection Follow-Up Visits only) Sites are expected to make every effort to conduct each study visit at the clinical research site. However, if allowed per local law and regulations and/or institutional policies, protocol Section 6.1.3 allows off-site visits to be conducted for any non-injection follow-up visit if the participant is unable to attend their study visit in-person at the clinical research site. Off-sites visits are not permitted for Screening, Entry, or any visit in which an injection is administered. If an injection visit must be split, the partial visit in which the injection is not administered may be conducted off-site. All study product injections must be administered on-site. The potential to conduct off-site study visits is incorporated into the protocol sample informed consents and assents. Sites should follow IRB/EC requirements with regards to developing any additional phrasing or separate consents and assents further describing off-site visits. Site staff should use clinical judgment and discretion when determining that an off-site visit is needed for a participant. Protocol Section 6.1.3 describes several requirements for conducting an off-site study visit, and sites should carefully assess their capacity to comply with those requirements prior to offering an off-site visit to any participant. Notably, off-site visits may only be conducted if the required PK specimens can be appropriately collected at the off-site location and safely transported back to the site. Specimen handling and initial processing requirements as well as limitations from time of collection to time of centrifuge are provided in the LPC and must be followed. Sites should carefully review the time requirements for PK sample processing when considering an off-site visit. Sites with the ability to collect and transport PK specimens are generally expected to also have the ability to collect and transport specimens for safety evaluations. When specimen collection is required during an off-site visit, the procedures specified in Section 6.16 must be followed. Additional flexibilities are provided in protocol Appendix VII regarding the use of alternate assays or alternate laboratories for sites experiencing disruptions due to COVID-19. Oral study product may be provided to the participant during an off-site visit. Visit procedures specified in protocol Section 6.9 must be performed on the same day as and prior to dispensing oral study product to assess for any indication of study product hold or permanent discontinuation. For female participants


this includes obtaining a negative pregnancy test result on the same day as and prior to dispensing oral study product. Per protocol Section 6.16, protocol-required testing must be performed at local laboratories that are CLIA-certified or equivalent (for US sites) or VQA-certified (for non-US sites) for the tests performed, including pregnancy testing. The logistics of maintaining protocol requirements with regards to off-site pregnancy testing may be complicated, however the use of home pregnancy test kits is not consistent with protocol Section 6.16 or the LPC. Therefore, the use of home pregnancy test kits to provide oral study product to a female participant is considered a protocol deviation and should be documented accordingly. The below guidance should be followed for sites choosing to use home pregnancy test kits:

- Details of the test kit used must be clearly documented in the participant’s file and provided to the CMC if requested.

- Oral study product should only be provided to the participant if a negative result is obtained from the home test kit.

- Regardless of the result obtained from the home test kit, a specimen (urine or blood, per site SOPs) must be collected during the off-site visit for testing at the site’s testing laboratory, or in accordance with the site’s Protocol Analyte List, upon study staff returning to the site.

- If oral study product had been provided to the participant based on a negative home test kit result but the test result from the specimen is positive, then the participant must immediately be contacted and instructed to hold oral study product.

- Protocol Section 8.3 must be followed regarding participant and study product management in the event of a positive pregnancy test result. Confirmatory testing is required based on the result of testing completed at the site’s testing laboratory regardless of the home test kit result.

o For example, if the home test kit result is positive, a specimen (blood or urine) must be collected for testing at the site’s testing laboratory. If this specimen is also positive, confirmatory testing is required within 48 hours per protocol Section 8.3.

- All pregnancy test results must be documented on eCRF LBW10005: Pregnancy Test. If more than one pregnancy test result was obtained for a study visit (ie. result from home test kit followed by result from laboratory testing), additional log lines should be added to the eCRF to capture the additional test results.

MOP Section 7 provides details regarding dispensing additional study product at either the Week 2 or Week 4a study visits (for both Cohort 1 and Cohort 2). Sites should review the required study procedures for these visits in full to determine which visit may be more suitable to dispense more oral study product and whether conducting one or both of these study visits off-site is feasible. Injections must be administered at the site. In the event that an injection visit must be split, the part of the visit in which the study product injection is not administered may be conducted off-site. Prior to administering the injection, protocol Section 6.9 procedures must be completed. Any pre-dose PK sample required during an injection visit should ideally be obtained during the part of the visit in which the injection is administered. Other blood samples required for laboratory safety evaluations should ideally be collected at the same time as the pre-dose PK sample to avoid multiple blood draws from the participant. Due to these protocol requirements and operational guidelines, it is generally expected that very few injection visits will be split and, if an injection visit is split, only behavioral and counseling visit procedures would be conducted off-site. Clinical evaluations may be conducted off-site and per site SOPs. For Cohort 1 Week 9 and Week 16 study visits, an ECG is required. Sites which have the ability, processes, and SOPs in place to conduct an ECG off-site are permitted to do so. For sites in which conducting an ECG off-site is not possible and an off-site visit is still needed to ensure participant study compliance, these visits may be split with the ECG conducted on-site on a different date within the target or allowable windows. For sites conducting off-site


visits due to COVID-19 restrictions and without the capability to conduct the ECG off-site, a missed ECG should be documented accordingly; see MOP Section 5.1.9 below for additional details regarding prioritization of visit procedures due to COVID-19 restrictions. Off-site visits may require two staff members, including one who is able to provide clinical assistance in case of symptoms or AEs, perform phlebotomy, and assist with specimen processing. At a minimum, one of these staff members must be conversant in the language of choice of the participant. Off-site visits may only be conducted by designated study staff who are qualified to perform all protocol-specified procedures and have undergone study-specific and all other applicable training relevant to the procedures they will perform off-site (e.g., Human Subject Protection [HSP], Good Clinical Practices [GCP], International Air Transport Association [IATA]). These staff members should also be thoroughly versed in confidentiality and lab chain of custody issues (as well as pharmacy chain of custody issues when providing oral study product during an off-site visit). These staff should also be adequately trained and qualified to immediately manage any adverse events and/or social impacts that may occur during off-site visits (e.g., fainting during phlebotomy, family dispute in the home). If adverse events requiring further evaluation or management are identified during an off-site visit, study staff conducting the visit will arrange for the participant to return to the study site as soon as possible. When communicating with participants (and the parent/guardian as applicable) ahead of off-site visits, the rationale and the procedures to be conducted for the visit should be clearly explained to the participant as well as the approximate time that will be needed to complete the required procedures. Every effort should be made to ensure that the scheduled time and location of the off-site visit is convenient for the participant and confidentiality is maintained. Site-specific procedures for preparing for and conducting off-site visits and study-specific procedures should be described in site SOPs. Considerations and topics addressed in an off-site visit SOP may include, but are not limited to:

• Procedures for and documentation of verifying participant (and parent/legal guardian as applicable) agreement prior to conducting off-site visits. This agreement must be documented and available in the participant’s file, per protocol.

• The location, date, and time the off-site visit is scheduled. This information must be documented and available in the participant’s file, per protocol.

• Any special instructions for study staff. This information must be documented and available in the participant’s file, per protocol.

• Procedures to protect the safety of study staff, participants and any family members present during off-site visits, as well as confidentiality of participants.

• Identification of staff member roles and responsibilities for off-site visits. Site staff must document that a visit was conducted off-site in eCRF ADM10006 by choosing “Other” for Type of Visit/Contact and noting that the visit was conducted off-site and the reason. For example, “Visit conducted off-site due to COVID-19 restrictions.” Section Appendix 5-4 provides an example checklist for preparing for an off-site visit. Sites are encouraged to develop a checklist(s) to facilitate preparation, conducting, and completion of an off-site visit. 5.1.9 Considerations for Conducting Study Visits During COVID-19 At all times, in-person study visits at the clinical research site with all protocol-specified visit procedures conducted is preferred for ensuring study integrity and achieving the study objectives. Sites with the capability to fully conduct an in-person study visit at the clinical research site should do so.


Protocol Appendix VII provides detailed guidance regarding implementation of study visits at sites experiencing operational disruptions due to the COVID-19 pandemic and local outbreaks. As noted in the protocol, all sites should follow applicable government, health authority, and institutional policies with respect to conduct of study visits and procedures, with utmost importance placed on the health and well-being of study participants and study staff. Screening and Enrollment of Participants Participants should only be screened for and/or enrolled to the study if the site has the capacity to administer both oral and injectable study products, collect and store PK samples, and perform clinical and laboratory safety evaluations. Sites in locations that experience a resurgence of COVID-19 resulting in operational disruptions or restrictions which prevent any of these critical study activities from being conducted should suspend screening and enrollment and notify the CMC. Participant Management Considerations Figure 5-1 below further describes the guidance and requirements provided in protocol Appendix VII regarding study product and participant management. Figure 5-1: Study Product and Participant Management During the COVID-19 Pandemic

Cohort/Step COVID-19 Operational Guidance

• All Cohort 1 participants

• All LSFU participants (Cohort 1 and Cohort 2)

Adherence counseling and support should be provided at each study visit regarding the importance of correctly and consistently taking background cART regimens. For example, adherence counseling should be an added visit procedure to the LSFU Week 24 visit.

• Cohort 1 Step 1 participants

• Cohort 2 Step 3 participants

Oral study product may be dispensed off-site during the Week 2 or Week 4a visits (see protocol Section 6.1.3). This is allowable regardless of COVID-19 conditions in the local area.

• Cohort 2 Step 4 participants initiating short-term oral bridging

Oral study product may be dispensed off-site, in consultation with the CMC (see protocol Section 5.1.4 and Section 6.1.3). This is allowable regardless of COVID-19 conditions in the local area.

• Cohort 1 Step 2 participants with Week 4b and/or Week 8 injections pending

• Cohort 2 Step 4 participants with any injection pending

Injectable study products (CAB LA, RPV LA) must be administered on-site. Sites should carefully assess their ability to utilize alternative approaches (as provided below) for monitoring participant safety, in the event of disruptions or limitations to conducting on-site visits for non-injection follow-up visits.


Sites should only consider administering injectable study products if there is adequate assurance that participant safety monitoring can be conducted through one of the alternative approaches provided below. Injectable study products should only be administered if collection, processing, and storage of PK specimens, consistent with the Laboratory Processing Chart (LPC), remains possible for the injection visit and for the subsequent non-injection visits.

• Cohort 1 Step 2 participants who are unable to receive their Week 4b and/or Week 8 injection

At sites where the above conditions cannot be met, Cohort 1 Step 2 participants with study product injections remaining should be permanently discontinued from injectable study product and followed per the LSFU visit schedule.

• Cohort 2 Step 4 participants who are unable to receive an injection

The IMPAACT 2017 CMC should be consulted for guidance on short-term oral bridging options.

Conducting Off-site Visits and Split Visits Off-site visits are allowed per protocol Section 6.1.3 for any non-injection follow-up visit, regardless of local conditions due to the COVID-19 pandemic. Similarly, sites may split a study visit to ensure all visit procedures are completed within the target window. Protocol Appendix VII provides additional allowances and guidance regarding PK specimen collection, genotypic and phenotypic resistance sample collection, and performing laboratory tests when conducting an in-person visit (whether on-site or off-site) and during COVID-19 site restrictions or limitations:

• For visits at which PK specimen collection is expected per protocol, before any PK specimen is collected, sites should verify that they are able to process and store PK samples, as described in the LPC. If this cannot be verified, the samples should not be collected. Sites that are not able to collect, process, and store PK specimens consistent with the LPC should not administer injectable study products. For sites with limited capacity to ship PK or genotypic and phenotypic resistance samples to the designated testing laboratory, the ability to store the samples locally must be verified prior to sample collection.

• If laboratory tests (other than PK testing) cannot be performed consistent with a site’s Protocol Analyte List (non-US sites) or at a CAP/CLIA-certified laboratory, the tests may be performed in alternate laboratories using alternate assays (alternate laboratories must adhere to local regulations for clinical laboratory testing), in consultation with the CMC.

Conducting Remote Visits Procedures For sites with operational disruptions resulting in restrictions or limitations in conducting in-person study visits (on-site or off-site) due to COVID-19, protocol Appendix VII allows for conducting the following specified study visit procedures remotely using telephone, live video, text, or other IRB-approved methods:

• Obtaining informed consent/assent • Adherence and contraceptive counseling • Obtaining medical and medication histories


• Identify/review/update adverse events • Adherence assessments may also be performed remotely but only if observed by site staff • Administering acceptability/tolerability questionnaires

Prior to conducting remote study visits or visit procedures, site staff should communicate with participants/parents/guardians as applicable to determine in advance how and when such visits will take place, with adequate protections for safety, privacy, and confidentiality. Remote visit procedures should be conducted within the target window (or allowable window, if applicable) and by site staff who are adequately qualified and trained to conduct the procedures, as determined by the IoR, with attention paid to data chain of custody. These staff should also be adequately qualified and trained to immediately assess and/or manage any adverse events or social impacts that may occur during the visits. If adverse events requiring further evaluation or management are identified during a remote visit, staff conducting the visit should arrange for appropriate clinical management, in consultation with the IoR or designee as needed. Clinical signs or symptoms determined to be Grade 2 or lower may continue to be assessed remotely and per protocol Section 8. Participants should be assessed in-person within the target window (or allowable window, if applicable) to follow-up on any clinical sign or symptom if severity grading cannot be determined, determined to be Grade 3 or higher, or at the discretion of the IoR. Adherence assessments may also be performed remotely but only if visually observed in real-time by site staff. To observe an adherence assessment remotely, the participant and the site staff must be communicating in real time with a live video feed/stream for visual interaction. For participants without access to a platform or device allowing for live video interaction, remote adherence assessments are not permitted; adherence assessments may be conducted off-site (in-person) for these participants. Remote visit procedures may not be conducted at sites not experiencing restrictions or limitations in conducting in-person study visits at the site and sites experiencing such disruptions due to reasons other than COVID-19. Visit procedures other than those specified in protocol Appendix VII may not be conducted remotely. Additional Considerations in Prioritization of Study Visit Procedures Protocol Appendix VII also provides a prioritization of visit procedures in the event COVID-19 restrictions prevent a study visit from being completed in entirety (whether conducted in-person or remotely). At all times, ensuring participant safety is the highest priority and visit procedures may be prioritized as clinically necessary. Any visit procedure which is missed or skipped due to COVID-19 restrictions must be documented accordingly, even when following protocol Appendix VII prioritization guidance. Documentation Guidance regarding documenting COVID-19 contingency plans, operational plans, and participant management as well as the use of alternate laboratories or alternate assays are also provided in protocol Appendix VII. 5.2 Select Study Procedures and Evaluations The following sub-sections provide additional guidance and considerations on select visit procedures. Additional information relating to the acceptability/tolerability questionnaires is provided in Section 6, and counseling (including HIV, adherence, and contraceptive counseling) is provided in Section 8.


5.2.2 Pharmacokinetic Evaluations As a primary objective of the IMPAACT 2017 study, the collection of high quality pharmacokinetic (PK) data is of paramount importance. PK specimens will be collected for this study as indicated in protocol Sections 6.3, 6.4, Schedules of Evaluations (Appendices I-A, I-B, and I-C) and per guidance provided in the LPC. Sites should review protocol Sections 6.3 and 6.4 for a detailed description of visit-specific PK collection timepoints (e.g., multiple time points, pre-dose only, or single sample only) prior to conducting a visit. The date and time of each PK sample collection must be source documented and entered into eCRFs for all PK samples. Additionally, height and weight must be obtained on the same day as any PK sample collection is initiated, be source documented, and entered into eCRFs. Site staff collecting specimens for PK evaluations must prepare the workspace and supplies with regards to protecting all specimens from light, as specified in the LPC. All pre-dose PK sample collections should be performed prior to and on the same day as administration of the study product as specified in the protocol for the visit. Cohort 1 Considerations: The following visits require PK sampling for Cohort 1C and 1R:

• Weeks 2, 4b, 5, 8, 9, 12, and Week 16 visits • Confirmation of Virologic Failure visit (if conducted)

PK sample collection timepoints for Cohort 1C and 1R will only differ at the Week 2 visit (see table 5-1 below). During the Week 2 visit, PK samples will be collected over an 8-hour period. Scheduling considerations and rescheduling requirements which apply to the Cohort 1 Week 2 visit are described in Section 5.1.4 above, as well as in protocol Section 6.3.2. Table 5-1: Cohort 1 Week 2 PK samples collection timepoints for Cohort 1C and Cohort 1R

Collect Blood for: Cohort 1C Cohort 1R

Pre-dose X X

1 hour post-dose X

2 hours post-dose X

3 hours post-dose X

4 hours post-dose (+/- 30 min) X X

8 hours post-dose (+/- 1 hr) X X Cohort 2 Considerations: The following visits require PK sampling for Cohort 2:

• Weeks 2, 4b, 5, 8, 16, 24, 25, 32, 40, 48, 64, 80, 88, and Week 96 visits, • All Interim Injection Visits (if conducted, following short-term oral bridging) • Confirmation of Virologic Failure visit (if conducted)

LSFU Considerations: PK sampling is required at each visit during LSFU, with the required blood volumes provided in protocol Appendix I-C. The volume of blood collected for the PK evaluation will depend on whether the


participant is in Cohort 1 or Cohort 2. For example, the amount of blood required for the PK evaluation at the LSFU Week 8 visit of a Cohort 1 participant is 2 mL to allow for the analysis of one of the study products (either CAB or RPV). The amount of blood required for the PK evaluation at the LSFU Week 8 visit of a Cohort 2 participant is 4 mL to allow for the analysis of both study products (CAB and RPV). Cohort 1 Step 1 and Cohort 2 Step 3 participants completing an Early Termination visit will not have a PK evaluation performed and a PK sample will not be collected. 5.2.3 Medical and Medications History Protocol Section 6.10 provides details regarding obtaining medical and mediations history to establish baseline as well as obtaining interval history during study follow-up. For participants reporting depression at baseline (Screening and Entry visits), sites should use a validated screening assessment tool to establish a depression baseline score or value. Sites may use the validated screening assessment tool specified in site SOPs or, for sites without access to a validated tool, the Patient Health Questionnaire-9 (PHQ-9). A sample of the PHQ-9 screener tool with accompanying instructions is available on the IMPAACT 2017 website. Any questions administered to study participants should be translated into the preferred language of the participant. Sites should also use the same tool during clinical re-evaluation of depression throughout study follow-up, per site SOPs. Sites should clinically manage participants according to local standards of care and site SOPs, with consideration of the scoring from the screener tool. There is not a separate eCRF to specifically capture any assessments from screener tools used by sites. Medical conditions, including depression, ongoing at the Entry visit will be entered into the Medical History Log eCRF and any changes from baseline during study follow-up will be entered into the adverse event log eCRF. 5.2.4 Physical Exams and Sexual Maturity Rating (Tanner Staging) A physical examination is required at each scheduled visit, either as a complete physical exam or as a symptom-directed physical exam. Protocol Section 6.11 outlines the visits when a complete physical exam versus a symptom-directed exam is required, including the required elements for each. All exam findings should be source documented, with vital signs and any abnormal findings entered into eCRFs. Height and weight must be obtained on the same day as any PK sample collection is initiated, be source documented, and entered into eCRFs. Sexual maturity rating (SMR) should be conducted at the following study visits during the complete physical exam:

• Cohort 1: Screening, Week 16, and LSFU Week 48/Early Termination visits • Cohort 2: Screening, Week 24, Week 96, and LSFU Week 48/Early Termination visits

Sites will use the Tanner Staging method to perform the SMR and must use the chart and guidelines provided in Section Appendix 5-5. To perform the Tanner Stage assessment, study staff should visually assess the participant during the complete physical exam to determine the corresponding rating of development:

• For females, breast and pubic hair Tanner Stages • For males, genitalia and pubic hair Tanner Stage (testicular volume measurements are not

required for this study) All Tanner Staging data should be entered onto the Tanner Stage/Testicular Volume eCRF (EVW10027), and the Tanner Staging chart is also available in the help text on the EVW10027 eCRF. Note that menarche status will be collected separately on the EVW10042 eCRF.


5.2.5 Performing an ECG Protocol Section 6.12 provides details regarding performing an ECG, including when an ECG in triplicate is required. Additional information regarding participant management of QTc prolongation is provided in protocol Section 8.2. If automated QTc calculations are not available, an appropriately qualified ECG reader must interpret the results. This may be the IoR or designee, if appropriately qualified, and a cardiologist is not a study requirement. Sites without direct access to an ECG machine should refer participants to an appropriate facility, per site SOPs, such as a hospital or cardiology department. In these circumstances, the cardiologist is not required to be listed on the site’s delegation log; however, review of the cardiologist report for assessment of adverse events and QTc prolongation must be performed by delegated study staff. 5.2.6 Adherence Assessments and Pill Counts Protocol Section 6.14 provides details regarding performing study product adherence assessments. Per protocol Sections 4.3.4 and 4.4.4, the IoR or designee must assess whether each Cohort 1 Step 1 participant, or Cohort 2 Step 3 participant respectively, has had exposure to the oral study product to permit an adequate evaluation of safety and tolerability. While pill counts will be conducted at the Week 2, Week 4a and Week 4b visits, these will not be the sole basis for determination of sufficient exposure to oral study product. The IoR assessment should not attempt to reconcile discrepant information on study product use. Rather, the data from the pill count should be combined with information learned from participant self-report and adherence counseling discussions for the broader assessment of participant eligibility to receive injectable study product. The IoR, or designee, should source document all contributing information leading to the final determination with regards to this Step 2 or Step 4 eligibility criterion. In general, the following aspects are expected to be included in this source documentation:

• Study visits and visit procedures contributing information (e.g., Week 2, Week 4a, Week 4b, and any interim visits),

• Location in the participant’s file of the contributing information (e.g., previous chart notes, site-specific tools/worksheets, eCRFs may be listed but not required),

• Brief summary of the final assessment, • Statement of adequate or not adequate exposure (as assessed by the IoR or designee) to oral study

product • IoR or designee initial/signature and date.

An example chart note of IoR determination that adequate exposure was met is provided in Section Appendix 5-6.


APPENDIX 5-1: TARGET VISIT DATE AND WINDOW TABLES Appendix 5-1a: Target Visit Dates and Target Windows for Cohort 1 Follow-up Visits

Study Visit Name Target Visit Date Target Window Target Window (days

from reference visit)

Week 2* 14 days from Entry + 7 days from target date

14-21 days from Entry

Week 4a* 28 days from Entry 28-35 days from Entry

Week 4b As soon as lab results are available from the Week 4a visit 21-42 (maximum) days from Entry

Week 5* 3 days from Week 4b +4 days from the target date 3-7 days from Week 4b

Week 8 28 days from Week 4b -7 days/+3 days from the target date 21-31 days from Week 4b

Week 9* 3 days from Week 8 +7 days from the target date 3-10 days from Week 8


Week 16* 56 days from Week 8 ±7 days from the target date 49-63 days from Week 8

*A broader allowable visit window is defined per visit in the protocol.


Appendix 5-1b: Target Visit Dates and Target Windows for Cohort 2 Follow-up Visits

Study Visit Name Target Visit Date Target Visit Window Target Window (days

from reference visit)

Week 2* 14 days from Entry + 7 days from target date

14-21 days from entry

Week 4a* 28 days from Entry 28-35 days from entry

Week 4b As soon as lab results are available from the Week 4a visit

21-42 (maximum) days from Entry

Week 5* 3 days from Week 4b +4 days from the target date 3-7 days from Week 4b

Week 8 28 days from Week 4b -7 days/+3 days from the target date

21-31 days from Week 4b

Week 16 84 days from Week 4b 77-87 days from Week 4b

Week 24 140 days from Week 4b ±7 days from the target date 133-147 days from Week 4b


Week 32 196 days from Week 4b

±7 days from the target date

189-203 days from Week 4b








Week 96 644 days from Week 4b 637-651 days from Week 4b *A broader allowable visit window is defined per visit in the protocol.


Appendix 5-1c: Target Visit Dates and Target Windows for LSFU Follow-up Visits (for Cohort 1 and Cohort 2)

Study Visit Name Target Visit Date* Target Visit Window Target Window (days

from reference visit)*

LSFU Week 8 56 days from the last administration of injectable study product

-14 days/+28 days from the target visit date

42-84 days from last administration of injectable study product


±42 days from the target visit date






*For participants who become pregnant during Steps 1-4, the LSFU target date and window is from the confirmatory positive pregnancy test result.


APPENDIX 5-2: EXAMPLE ORDER OF PROCEDURES FOR A COMBINED WEEK 4A/WEEK 4B VISIT

EXAMPLE Order of Procedures for a COMBINED Week 4a/Week 4b Visit Protocol Sections 6.3.3 and 6.3.4 must be followed for Cohort 1 participants. Protocol Sections 6.4.3 and 6.4.4 must be followed for Cohort 2 participants.

Prior to final Step 2 (or Step 4) eligibility determination [The following procedures may be ordered differently as best for visit flow. For example, blood collection may be performed early in the visit and other procedures may be conducted while waiting for the laboratory test results.] • Update medical and medications history since last visit • Perform complete physical exam • Identify/review/update adverse events • Collect blood for:

o Hematology: Complete blood count with platelets and hemoglobin o Chemistries: Creatinine, CrCl, creatine kinase, total bilirubin, ALT, lipase, BUN o HIV-1 RNA o Store plasma for genotypic and phenotypic resistance testing o Pre-dose PK sample

• For females, collect blood or urine for pregnancy test • Perform adherence assessment • Provide contraceptive counseling • Provide adherence counseling

Prior to enrollment into Step 2 (or Step 4)

• Complete final eligibility confirmation for Step 2 (or Step 4) • Complete paper-based eligibility checklist for Step 2 (or Step 4)

Enrollment into Step 2 (or Step 4)

• Enter checklist data into SES to enroll the participant and generate SID for Step 2 (or Step 4); print and file a copy of the confirmation file

After enrollment into Step 2 (or Step 4)

• Provide a meal to the participant [Refer to protocol Section 5] • Observe participant’s last oral study product dose [Refer to protocol Section 6.3.4 (or Section 6.4.4) on whether an oral study product dose is to be observed at the visit. If taken at the visit, the oral study product dose may be observed prior to enrollment into Step 2 (or Step 4), but must be observed as follows:

o after the PK pre-dose sample collection, and o after protocol Section 6.9 requirements are met, and o before the first study product injection, and o before the post-dose PK sample collection.]

• Prescribe, prepare, and administer injectable study product

After first study product injection • Perform acceptability/tolerability assessment questionnaires • Conduct qualitative phone interview, if indicated • Collect blood for 2 hours post-dose PK sample (must be after administration of injectable study

product; ± 30 minutes window is allowed) • Perform ECG: 2 hours post-injection dose, ± 1 hour window is allowed (for Step 4 participants only)


APPENDIX 5-3: SCHEDULING SCENARIO OF COHORT 2 STEP 4 INJECTIONS A Cohort 2 Week 4b visit occurs on Tuesday, 12 January 2021. The target visit dates and target windows for the remaining Cohort 2 Step 4 visits may be calculated; Week 8 and Week 16 visits are shown below: Target Window

Visit Name Target Visit Date Opens Closes

Week 8 09/Feb/2021 02/Feb/2021 12/Feb/2021

Week 16 06/April/2021 30/March/2021 09/April/2021

Due to participant availability, the Week 8 visit occurs on the first day of the target window, Tuesday, February 2nd. The Week 16 target visit date is Tuesday, April 6th (i.e., 84 days as counted from the Week 4b visit). However, due to the early administration of the Week 8 injection, the Week 16 visit must be administered within the dates of March 30th and April 2nd (inclusive) to comply with both the required spacing from the previous injection as well as the visit’s target window. This results in the Week 16 target visit date no longer being available as well as fewer total days available in which to administer the injection.


APPENDIX 5-4: EXAMPLE OFF-SITE VISIT PREPARATION CHECKLIST

EXAMPLE Off-site Visit Preparation Checklist This checklist may be adapted or modified per site SOPs and operational plans for conducting

off-site visits, including the addition of tasks required upon return to the site (e.g., source documentation and data management, QA/QC reviews, specimen chain of custody, etc.).

☐ Confirm the visit is a non-injection visit during study follow-up. ☐

Confirm whether any laboratory specimens are required per protocol. If yes, confirm site ability to collect and safely transport the specimens to the site as specified in protocol Section 6.16 and the IMPAACT 2017 LPC.

☐

Confirm whether oral study product will be provided. If yes, confirm site ability to comply with protocol Section 6.9 requirements.

☐ Determine participant availability: • Confirm the participant is unable to complete the visit in full at the site within the target

window. • Discuss the rationale for conducting an off-site visit and approximate time needed to complete

the visit procedures. • Verify participant (and parent/legal guardian as applicable) agreement to conduct an off-site

visit. This agreement must be documented and available in the participant’s file. • Determine the date, time, and location for the off-site visit. This information must be

documented and available in the participant’s file. • Any special instructions for study staff. This information must be documented and available in

the participant’s file. • Confirm communication plan with participant should scheduling complications arise.

☐

Determine study staff availability: study staff designated and trained to perform the required study visit procedures are available, and at least one is conversant in the language of choice of the participant.

☐

Review protocol and MOP sections applicable to the visit.

☐ Review applicable site policies, procedures, and operational plans such as maintaining participant confidentiality, specimen chain of custody SOP, study product chain of custody SOP, source documentation SOP, data Management SOP, off-site visit SOP.

☐ Confirm all materials and supplies required to conduct the visit are available and secure. Such items may include clinical or laboratory supplies for specimen collection, blank paper CRFs or tablet/laptop, blank chart note pages, all appropriate staff identification tags, participant contact information, etc.


APPENDIX 5-5: TANNER STAGING CHART AND GUIDELINES

Tanner Staging Guidelines

Tanner Stage Male and Female Pubic Hair

Female Breast Male Genitalia

1 Pre-pubertal (can see velus hair similar to abdominal wall)

Pre-pubertal Pre-pubertal

2 Sparse growth of long, slightly pigmented hair, straight or curled, at base of penis or along labia

Breast bud stage with elevation of breast and papilla; enlargement of areola

Enlargement of scrotum and testes; scrotum skin reddens and changes in texture

3 Darker, coarser and more curled hair, spreading sparsely over junction of pubes

Further enlargement of breast and areola; no separation of their contour

Enlargement of penis (length at first); further growth of testes

4

Hair adult in type, but covering smaller area than in adult; no spread to medial surface of thighs

Areola and papilla form a secondary mound above level of breast

Increased size of penis with growth in breadth and development of glans; testes and scrotum larger, scrotum skin darker

5 Adult in type and quantity, with horizontal distribution ("feminine")

Projection of papilla only, related to recession of areola

Adult genitalia


APPENDIX 5-6: EXAMPLE CHART NOTE OF IOR DETERMINATION OF ADEQUATE ORAL STUDY PRODUCT EXPOSURE The participant’s file was reviewed for the following: adherence assessment (pill count data) from the Week 2, Week 4a, and Week 4b visits; counseling notes occurring at the Week 2, Week 4a, and Week 4b visits; and chart notes on discussions with the participant and parent about study participation and the study product regimen during the medical/medications history and adverse event assessments at Week 2, Week 4a, and Week 4b visits. No significant issues regarding oral study product use were noted. The participant has been sufficiently adherent to permit an adequate evaluation of safety and tolerability of prescribed oral study product. [IoR or designee initial and date.]


SECTION 6 ACCEPTABILITY AND TOLERABILITY ASSESSMENTS

Table of Contents 6.1 Acceptability and Tolerability Assessment Overview .................................................................. 1

6.2 General Guidance for Interviewer-Administered Questionnaires ................................................. 2

6.2.1 Welcoming the Participant .................................................................................................... 2

6.2.2 Asking Sensitive Questions .................................................................................................. 3

6.2.3 Pacing the Questions ............................................................................................................. 3

6.2.4 Reading Items Aloud ............................................................................................................ 3

6.2.5 Recording Participant Responses Verbatim .......................................................................... 4

6.2.6 Probing .................................................................................................................................. 4

6.2.7 Watching for Non-Verbal Cues ............................................................................................ 5

6.2.8 Accuracy and Completeness of Questionnaires .................................................................... 5

6.3 Specific Guidance for Individual Questionnaires ......................................................................... 5

6.3.1 Study Medication Satisfaction Questionnaire Status- Teen (SMSQs-T) (QLW10032) ....... 5

6.3.2 Revised Perceptions of Injection Questionnaire (QLW10033)............................................. 6

6.3.3 Study Medication Satisfaction Questionnaire Change- Teen (SMSQc-T) (QLW10034) ..... 6

6.3.4 Reason for Switch Questionnaire - Cohort 1 (QLW10035) .................................................. 7

6.3.5 Reason for Switch Questionnaire – Cohort 2 (QLW10036) ................................................. 7

6.3.6 Preferences Questionnaire- Adolescent Version (QLW10037) ............................................ 7

6.3.7 PedsQL - Pediatric Quality of Life Inventory - Child Report (Ages 8-12 years) (QLW10040) ......................................................................................................................................... 7

6.3.8 PedsQL - Pediatric Quality of Life Inventory - Teen Report (Ages 13-18 years) (QLW10041) ......................................................................................................................................... 8

6.3.9 Post-Injection Phase Questionnaire (QLW10045) ................................................................ 8

6.3.10 Reason for Study Termination Questionnaire (QLW10047) ................................................ 8

6.3.11 Pain During Injections - Cohort 1 (SSW10002) ................................................................... 9

6.3.12 Pain During Injections - Cohort 2 (SSW10003) ................................................................... 9

Appendix 6-1: Acceptability and Tolerability Data Collection Schedule ................................................... 10

6.1 Acceptability and Tolerability Assessment Overview Acceptability and tolerability of the study products will be assessed at specified study visits and following permanent study product discontinuation through the administration of up to eleven study specific questionnaires (see protocol Section 6.15). These questionnaires will cover topics related to participant perceptions of the study product injections, reasons for switching from daily oral cART to long-acting study products, satisfaction with treatment, quality of life, and treatment preferences. The visits during which each questionnaire is to be administered are outlined in Section Appendix 6-1 (Table 6-1 for Cohort 1 questionnaires, and Table 6-2 for Cohort 2 questionnaires). All questionnaires will be completed as paper-based forms, and then entered into the database by the site staff. Forms will not be directly entered into the database in real-time. The Preferences Questionnaire


(QLW10037) and the Pain During Injections Questionnaires (SSW10002, and SSW10003) are interviewer-administered by site staff to the participant. The other acceptability and tolerability questionnaires are designed to be self-administered by the participant. Study teams should confirm whether each participant has the necessary literacy level and is comfortable completing these forms without assistance as self-administration is preferred. However, recognizing that some participants may have limited literacy, site staff may read the questions to the participant if the participant prefers or the site staff has concerns about the participant’s ability to complete the questions without assistance. Study staff should indicate on each questionnaire whether the participant answered the questions alone or with assistance. When the questionnaires are completed without assistance, site staff should check them for completion (but should avoid asking participants about their answers except in cases where questions were left blank). While most acceptability and tolerability questionnaires will be administered to all participants enrolled in this study, the following three study medication satisfaction questionnaires will only be administered to participants who speak English or Spanish: QLW10032, QLW10033, QLW10034. Questionnaires must be administered in the preferred language of each participant. As a condition for site-specific study activation, each site will be required to translate the questionnaires into all applicable local languages and to submit their translations and back-translations (into English) for review and approval by the Protocol Data Managers. Please contact the Data Managers with any questions related to this process. If the study staff member administering the questionnaire is not fluent in the participant’s preferred language, a translator (third party) may be used to facilitate the administrator’s understanding of the translated questionnaires and the participant’s responses, such as translating questions and responses in real time. However, every effort should be made to have a staff member who is fluent in the participant’s preferred language administer the questionnaire, and paper-based questionnaires in the participants preferred language should be made available to the participant for reference. Participants reporting pain or discomfort on acceptability/tolerability questionnaires should be clinically assessed prior to the leaving the clinic for a potential adverse event, if not already noted and documented during the clinical evaluation. See Section 9 of this manual for further guidance regarding participant management, specifically assessment of injection site reactions. Participants who are prematurely discontinued from the injectable study product or are terminating the study early will complete the Reasons for Study Termination Questionnaire (QLW10047) and the Pediatric Quality of Life Inventory (QLW10040/QLW10041) in addition to any other questionnaires still indicated for that visit. For example, if premature permanent study product discontinuation is initiated during a participant’s Cohort 1 Week 4b visit, then the Reasons for Switch Questionnaire and Pain During Injections Questionnaire would not be administered because the participant would not be receiving the study product injection 6.2 General Guidance for Interviewer-Administered Questionnaires To standardize interviewer-administered data collection from site to site, and to maximize data quality, study staff should work to establish rapport with participants and ask all questions in a non-biased, non-judgmental, consistent manner across participants. Interviewers should use both verbal and non-verbal techniques to obtain the most honest, accurate, and thorough responses from participants. These techniques are discussed in more detail below.

6.2.1 Welcoming the Participant From the first study visit until the last study visit, it is important for participants to feel physically comfortable, understood, and connected with study staff. This ensures participants know they are


welcome to ask any questions they may have related to the study and facilitates more honest responses from participants on the acceptability and tolerability questionnaires. Suggestions for study staff are provided below on how to help participants feel more comfortable prior to and when completing the acceptability and tolerability questionnaires:

• Consider offering the participant a glass of water or other refreshment. • Introduce yourself and try to create rapport (connection) between yourself and the participant to help

them feel comfortable during administration of the questionnaire. • If considered helpful, offer the participant a blank copy of the form (in the preferred language) to read

along as the questionnaire is administered. It is also acceptable for the participant to see the copy of the questionnaire being completed by the interviewer, as responses are being recorded, because this can reduce anxiety and increase collaboration.

• Some questionnaires include introductory statements to help prepare the participant for sensitive

questions. Read these introductions as they appear on the forms.

6.2.2 Asking Sensitive Questions This study addresses sensitive issues, such as HIV treatment. Your level of comfort with asking sensitive questions will affect the participant's comfort and answers to the questions. If you ask the questions in a confident and supportive manner, the participant will feel more confident and comfortable answering the questions. Make eye contact with the participant to let them know that you are listening to them. Avoid apologizing for questions or displaying facial expressions or gestures that might show you feel any way but neutral about a question or the participant's response. If the participant feels judged, they will be less likely to respond honestly.

6.2.3 Pacing the Questions Every participant is different. Some will answer questions quickly. Others may take longer to answer or may change their answers after giving more thought to the question. Always account for these participant preferences when administering questionnaires. Read questions slowly and let the participant finish thinking before you record the participant’s answer and go on to the next question.

6.2.4 Reading Items Aloud Read all items to the participant word-for-word and speak clearly. Avoid re-phrasing questions because this can change the meaning of the question, making it inconsistent with questions administered to other participants. Provide explanation or interpretation if necessary only after reading the item word-for-word. Avoid counseling or educating the participant during data collection. Counseling and instruction may unintentionally influence the way the participant answers questions. When applicable, acknowledge questions and concerns raised by the participant during the questionnaire and state that these can be discussed after the questionnaire is completed. Read the questions with interest and variability, so you do not sound automated. Emphasize the important words in a question, so that the meaning of the question comes through. For questions with multiple sub-parts, read all sub-parts to the participant and mark the appropriate response for each, based on the participant’s answers.


6.2.5 Recording Participant Responses Verbatim

Often, questions will have a list of response categories to capture the participant’s response. Sometimes, an “other, specify” option is included for responses that do not fit into one of the categories already listed. When “other, specify” must be used, record the participant’s verbatim response, word-for-word, in the language spoken by the participant. Once the questionnaire is completed, go back and translate the local language text into English, for entry into eCRF screens. Do not translate in real-time during administration of the questionnaire.

6.2.6 Probing One of the objectives of the study questionnaires is to obtain accurate information on participant behaviors (e.g., adherence), feelings, and opinions. The questionnaires ask participants to recall information that participants may not have thought about or may have difficulty remembering. The technique for helping a participant remember an answer, clarify a response, decide between two similar but different answers, or report something more precisely is called probing. Effective probing helps a participant think more about a question or refine an answer that is too general. However, probing can also bias or otherwise direct participant answers. As the interviewer, you should not offer answers to the participant. Therefore, all probes must be neutral. The following are some probing strategies to use when a participant initially answers “I don't know” to a question or cannot remember or refine their response enough to answer the question. • Repeat Probe: The repeat probe is used by repeating the item or response categories. Although the

participant might hear you the first time you ask a question, he or she may need to hear the question more than once to provide an answer. Instead of rephrasing a question, always first repeat the question as written. Sometimes hearing the question a second time is all that is needed.

• Echo Probe: The echo probe involves repeating the participant’s exact response. Sometimes hearing

the answer with a different voice will help the participant be more precise. The echo should always be repeated in a neutral, non-judgmental style.

• Silent Probe: The silent probe is used by pausing briefly after a participant gives what seems to be an

uncertain answer. Although silence can feel awkward, sometimes it is helpful when a participant is trying to determine the most accurate answer to a question. Use a silent probe when the participant sounds unsure of their answer and may need some extra time to think more carefully about the question.

• Non-verbal Probe: The non-verbal probe is used by giving hand or facial gestures that may help the

participant to come up with an answer. All such gestures must be neutral and non-judgmental. • Specification Probe: The specification probe is used by asking the participant to give a more precise

answer. Although a participant may give an answer that he or she considers accurate, it may not be specific enough. For example, if a participant answers with a range instead of exact number you may need them to specify a number within the range provided. If a more precise answer is needed for the question, the probe, “Can you be more specific?” is often enough to help the participant choose the most accurate response.


• Historical Probe: The historical probe is used by asking whether the event in question occurred anytime around major holidays or personal events such as a birthday or other life event. Some items require the participant to recall dates, and initially the participant may be unable to recall a date. Referencing a calendar can also help the participant remember dates.

6.2.7 Watching for Non-Verbal Cues

A participant may give you one answer verbally but express something else using body language or facial expressions. Although you should not question a participant so as to make them feel like you don't trust their answers, be aware of whether they are giving you non-verbal cues that indicate they are not feeling comfortable, not taking the questionnaire seriously, or not answering honestly.

6.2.8 Accuracy and Completeness of Questionnaires While administering a questionnaire, follow any written form instructions and guidance. Also, make sure the participant is understanding and responding to you, and that you record all reported information on the questionnaire form. After the questionnaire is completed, and while the participant is still at the study site, review the questionnaire form for accuracy and completeness. This review step is not intended as an active review with the participant to confirm all of his/her responses; rather, it is a check to help ensure that any items that might have accidentally been missed or miss-marked can be completed or corrected before the participant leaves the study site. Thereafter, questionnaire forms may undergo additional reviews, following site SOPs for QC/QA. For questionnaires that are completed by the participant alone, review the questionnaire for unanswered questions before the participant leaves the study site. Avoid asking about questions that they completed because this may make the participant feel less comfortable answering questions honestly at later visits. If questions were left blank, ask the participant if they can complete them or if they would like you to help them to complete them. Do not leave questions blank unless the participant refuses to answer them. 6.3 Specific Guidance for Individual Questionnaires The following sections describe the key study-specific questionnaires that will be used in this study and provide administration instructions for each questionnaire. See Appendix 6-1 below for the questionnaire study schedule for Cohort 1, Cohort 2, and the LSFU visits.

6.3.1 Study Medication Satisfaction Questionnaire Status- Teen (SMSQs-T) (QLW10032) Purpose: The Study Medication Satisfaction Questionnaire Status -Teen (SMSQs-T) is designed to measure satisfaction with study medications. This is a revised version of the HIV Treatment Satisfaction Questionnaire (HIVTSQ) used for adults. This version for teens is simplified and avoids use of the term “HIV” due to the possibility that younger adolescents might not know their HIV status. Along with total treatment satisfaction, SMSQs-T subscales measure general treatment satisfaction and ease of treatment. This questionnaire is asking participants to rate their satisfaction with the study product injections administered at their previous injection visit. Questions or items requiring additional guidance: Likert scale (choices) vary from question to question. Assistance with completion should be provided when participants are not fully comfortable with the scales.


Instructions specific to administration: This questionnaire is only administered to Cohort 2 participants, at the visits specified in Table 6-2. The questionnaire should be administered prior to administration of the injection so that the participant’s responses are reflective of their prior experiences and not overly influenced by discomfort from an injection given that day. The site staff assisting with questionnaire completion should not be the same staff who administer the injections since it may be harder for participants to admit difficulties with the injections to the person administering them.

6.3.2 Revised Perceptions of Injection Questionnaire (QLW10033) Purpose: The Perceptions of Injection Questionnaire is designed to assess pain and other sensations and changes in function resulting from receipt of the study injections administered at a previous study visit. Questions or items requiring additional guidance: All questions use Likert scales and assistance with completion should be provided when participants are not fully comfortable with the scales. Some questions are similar to other questions. For example, one question asks how bothered the participant was by redness at the injection site and another asks how bothered the participant was by swelling at the injection site. Site staff may clarify the difference between these questions when needed. Instructions specific to administration: This questionnaire is administered to both Cohort 1 and Cohort 2 participants receiving injections at the visits specified in Tables 6-1 and 6-2. This questionnaire assesses the participant’s experience since a previous injection. Therefore, the questionnaire must be administered after the participant has received their first injection and ideally prior to the participant receiving an injection at the current study visit (if an injection is scheduled to be administered). The site staff should take into account the fact that some questions are similar (as noted above) and may be confusing to some participants when making this determination. The site staff assisting with questionnaire completion should not be the same staff who administer the injections since it may be harder for participants to admit difficulties with the injections to the person administering them. This form has been adapted from the Vaccinees' Perception of Injection (VAPI) from the Mapi Research trust. These instructions and items have been reframed to focus on injections in the buttocks instead of a vaccination in the arm. This revised version is a derivative, trial-specific form, and should not be reused unless written permission from the developers Sanofi and MRT is obtained prior to use. Please visit https://eprovide.mapi-trust.org/ for more information.

6.3.3 Study Medication Satisfaction Questionnaire Change- Teen (SMSQc-T) (QLW10034)

Purpose: The Study Medication Satisfaction Questionnaire Change- Teen (SMSQc-T) is designed to measure satisfaction with injectable study medications compared to their past medications taken for HIV. This is a revised version of the HIV Treatment Satisfaction Questionnaire (HIVTSQ) used for adults. The version for teens is simplified and avoids use of the term “HIV” due to the possibility that younger adolescents might not know their HIV status. Along with total treatment satisfaction, SMSQc-T subscales measure general treatment satisfaction and ease of treatment in relation to their past treatments. Questions or items requiring additional guidance: Likert scale (choices) vary from question to question. Assistance with completion should be provided when participants are not fully comfortable with the scales. Instructions specific to administration: This questionnaire is only administered to Cohort 2 participants and only at their Week 24 visit. The SMSQc-T should be administered immediately after the Study Medication Satisfaction Questionnaire Status Teen (SMSQs-T) (QWL10032), and prior to the Week 24 injection. The flow of questioning will therefore ask participants to first express their satisfaction with

https://eprovide.mapi-trust.org/


their current study treatment (per QWL10032), and then ask them to compare their current satisfaction with their satisfaction with the medicines they took prior to starting the study (per QWL10034). The site staff assisting with questionnaire completion should not be the same staff who administer the injections since it may be harder for participants to admit difficulties with the injections to the person administering them.

6.3.4 Reason for Switch Questionnaire - Cohort 1 (QLW10035) Purpose: The purpose of this questionnaire is to elicit Cohort 1 participant’s reasons for wanting to try a long-acting injectable medication. Questions or items requiring additional guidance: This questionnaire is a “select all that apply” including an “other” choice with the ability to free-text a response. Instructions specific to administration: This questionnaire must be administered prior to the participant’s study product injection at the Cohort 1 Week 4b visit. After site staff read the instructions aloud to the participant, this questionnaire may be self-administered.

6.3.5 Reason for Switch Questionnaire – Cohort 2 (QLW10036) Purpose: The purpose of this questionnaire is to elicit Cohort 2 participant’s reasons for wanting to try a long-acting injectable medication. Questions or items requiring additional guidance: This questionnaire is a “select all that apply” including an “other” choice with the ability to free-text a response. Instructions specific to administration: This questionnaire must be administered prior to the participant’s study product injection at the Cohort 2 Week 4b visit. After site staff read the instructions aloud to the participant, this questionnaire may be self-administered. If the participant is more comfortable (e.g. if they have limited literacy) the site staff can read each question and record the participant’s responses.

6.3.6 Preferences Questionnaire- Adolescent Version (QLW10037) Purpose: The purpose of this questionnaire is to elicit Cohort 2 participant’s preferred choice of medication (bimonthly LA-injectable v/s daily oral) and reason for this choice. Questions or items requiring additional guidance: After selection of preferred choice (monthly LA v/s daily oral) the primary reason for this choice should be entered (via free-text). Instructions specific to administration: This questionnaire is administered only to Cohort 2 participants at the visits specified in Table 6-2 and is read aloud to the participant by site staff.

6.3.7 PedsQL - Pediatric Quality of Life Inventory - Child Report (Ages 8-12 years) (QLW10040) Purpose: The 23-item PedsQL Measurement Model is a modular approach to measuring health-related quality of life (HRQOL) in children and adolescents. The 23-item PedsQL Generic Core Scales were designed to measure the core dimensions of health (Physical, Emotional and Social) as delineated by the World Health Organization, as well as role (school) functioning.


Questions or items requiring additional guidance: If the child has a question about what an item means or how they should answer it, do not interpret the question for them. Repeat the item to them verbatim. Ask them to answer the item according to what they think the question means. If they have trouble deciding on an answer, ask them to choose the response that comes closest to how they feel. With this questionnaire, the child has the option of not answering a question if they truly do not understand the question. Instructions specific to administration: This questionnaire is administered to only 12-year-old participants in both Cohort 1 and Cohort 2 at the visits specified in Tables 6-1 and 6-2. Participants may self-administer the PedsQL™ after introductory instructions from the administrator. If the administrator determines that the child is unable to self-administer the PedsQL (e.g., due to illness, fatigue, reading difficulties), the PedsQL should be read aloud to the child.

6.3.8 PedsQL - Pediatric Quality of Life Inventory - Teen Report (Ages 13-18 years) (QLW10041)

Purpose: The 23-item PedsQL Measurement Model is a modular approach to measuring health-related quality of life (HRQOL) in children and adolescents. The 23-item PedsQL Generic Core Scales were designed to measure the core dimensions of health (Physical, Emotional and Social) as delineated by the World Health Organization, as well as role (school) functioning. Questions or items requiring additional guidance: If the teen has a question about what an item means or how they should answer it, do not interpret the question for them. Repeat the item to them verbatim. Ask them to answer the item according to what they think the question means. If they have trouble deciding on an answer, ask them to choose the response that comes closest to how they feel. The teen has the option of not answering a question if they truly do not understand the question Instructions specific to administration: This questionnaire is administered to participants in both Cohort 1 and Cohort 2 aged 13-18 years, at the visits specified in Tables 12-1 and 12-2. Participants who age beyond 18 years and are still on study should continue to be administered this questionnaire. Teens may self-administer the PedsQL™ after introductory instructions from the administrator. If the administrator determines that the teen is unable to self-administer the PedsQL (e.g., due to illness, fatigue, reading difficulties), the PedsQL should be read aloud to the teen.

6.3.9 Post-Injection Phase Questionnaire (QLW10045) Purpose: This questionnaire will elicit preference and acceptability of daily oral medication vs monthly LA-injections by asking about ease/difficulty of taking daily medication (now and before the study) and if the participant would prefer to go back to receiving monthly LA-injections. Questions or items requiring additional guidance: Likert scale (choices) vary from question to question. For Question 2 (“Think about how easy or difficult…”) the reason for answering “easier” or “more difficult” should be entered (via free-text). If the site staff are writing the text, the staff should transcribe the participants words verbatim. Instructions specific to administration: This questionnaire is only administered to Cohort 2 participants during their LSFU Week 8 visit. After site staff read the instructions aloud to the participant, this questionnaire may be self-administered.

6.3.10 Reason for Study Termination Questionnaire (QLW10047)


Purpose: The purpose of this questionnaire is to elicit participant’s reasons for premature permanent study product discontinuation or early termination from the study. Questions or items requiring additional guidance: This questionnaire is a “select all that apply” including an “other” choice with the ability to free-text a response. Instructions specific to administration: This questionnaire is administered to both Cohort 1 and Cohort 2 participants at the study visit during which premature permanent study product discontinuation is initiated, or during which premature study termination is determined. After site staff read the instructions aloud to the participant, this questionnaire may be self-administered.

6.3.11 Pain During Injections - Cohort 1 (SSW10002) Purpose: To measure perceived pain of study product injections. Questions or items requiring additional guidance: The Wong-Baker FACES Pain Rating Scale will be shown with the questions. Instructions specific to administration: This questionnaire is administered to Cohort 1 participants at the visits specified in Table 6-1, and must be administered after the injection of study product. The questionnaire is administered by site staff and should not be the same staff who administer the injection. The questionnaire, including an explanation of the faces responses, should be read out loud by site staff. Staff should record the participant’s response. Explain to the participant that each face represents a person who has no pain (hurt), or some, or a lot of pain. For example: “Face 0 does not hurt at all. Face 2 hurts just a little bit. Face 4 hurts a little bit more. Face 6 hurts even more. Face 8 hurts a whole lot. Face 10 hurts as much as you can imagine, although you don’t have to be crying to have this worst pain.” Ask the participant to choose the face that best depicts the pain they are experiencing.

6.3.12 Pain During Injections - Cohort 2 (SSW10003)

Purpose: To measure perceived pain of study drug injections. Questions or items requiring additional guidance: The Wong-Baker FACES Pain Rating Scale will be shown with the questions. Instructions specific to administration: This questionnaire is administered to Cohort 2 participants at the visits specified in Table 6-2, and must be administered after the injections of study product. The questionnaire is administered by site staff and should not be the same staff who administer the injections. The questionnaire, including an explanation of the faces responses, should be read out loud by site staff. Staff should record the participant’s response. Explain to the participant that each face represents a person who has no pain (hurt), or some, or a lot of pain. For example: “Face 0 does not hurt at all. Face 2 hurts just a little bit. Face 4 hurts a little bit more. Face 6 hurts even more. Face 8 hurts a whole lot. Face 10 hurts as much as you can imagine, although you don’t have to be crying to have this worst pain.” Ask the participant to choose the face that best depicts the pain they are experiencing.


APPENDIX 6-1: ACCEPTABILITY AND TOLERABILITY DATA COLLECTION SCHEDULE Table 6-1: Acceptability and Tolerability Data Collection Schedule: Cohort 1

Cohort 1

Timepoint of Administration

Form Number Title Entry

Week 4B (Step 2 Entry)

Week 8 Week 16 LSFU Week 8

LSFU Week 48

Early Study Product/ Study Participation

Discontinuation (Step 1 or 2)*

QLW10033 Revised Perceptions of Injection Questionnaire

X X X

QLW10035 Reasons for Switch Questionnaire – Cohort 1

X

QLW10040/ QLW10041

Pediatric Quality of Life Inventory (Child Report: 8-12; Adolescent Report: 13-18)

X X X X

QLW10047 Reason for Study Termination Questionnaire

X

SSW10002 Pain During Injections – Cohort 1

X X

*These acceptability and tolerability questionnaires are to be administered at the study visit during which premature permanent study product discontinuation is initiated, or during which premature study termination is determined, in addition to any other questionnaires indicated for that visit.


Table 6-2: Acceptability and Tolerability Data Collection Schedule: Cohort 2 Cohort 2

Timepoint of Administration

Form Number Title Entry

Week 4B

(Step 4 Entry)

Week 8 Week 24

Week 48

Week 96

LSFU Week

8

LSFU Week

48

Early Study Product/ Study Participation

Discontinuation (Step 3 or 4)*

QLW10032 Study Medication Satisfaction Questionnaire Status-Teen

X X X

QLW10033 Revised Perceptions of Injection Questionnaire X X X X X

QLW10034 Study Medication Satisfaction Questionnaire Change-Teen

X

QLW10036 Reason for Switch Questionnaire – Cohort 2 X

QLW10037 Preferences Questionnaire – Adolescent Version X X X X X (Step 4 only)

QLW10040/ QLW10041

Pediatric Quality of Life Inventory (Child Report: 8-12; Adolescent Report: 13-18)

X X X X X X X X (Step 4 only)

QLW10045 Post-Injection Phase Questionnaire X

QLW10047 Reason for Study Termination Questionnaire

X

SSW10003 Pain During Injections – Cohort 2

X X X X X

*These acceptability and tolerability questionnaires are to be administered at the study visit during which premature permanent study product discontinuation is initiated, or during which premature study termination is determined, in addition to any other questionnaires indicated for that visit.


SECTION 7 STUDY PRODUCT AND PHARMACY CONSIDERATIONS

Table of Contents 7.1 Ordering Study Products ............................................................................................................... 1

7.2 General Prescribing and Dispensing Guidance ............................................................................. 2

7.3 Oral Study Product Considerations ............................................................................................... 2

7.3.1 Prescribing and Dispensing During Cohort 1 Step 1 and Cohort 2 Step 3 ........................... 2

7.3.2 Returning Unused Oral Study Product .................................................................................. 3

7.3.3 Oral Study Product Storage and Administration: Oral CAB and/or Oral RPV .................... 3

7.3.4 Short-Term Oral Bridging During Cohort 2 Step 4 .............................................................. 4

7.3.5 Short-Term Storage of Participant-Specific Oral Study Product in the Clinic ..................... 4

7.4 Injectable Study Product Considerations ...................................................................................... 5

7.4.1 CAB LA ................................................................................................................................ 5

7.4.2 RPV LA ................................................................................................................................ 5

7.4.3 Injectable Study Product Administration .............................................................................. 5

7.4.4 Short-Term Storage of Participant-Specific Injectable Study Product in the Clinic ............. 6

7.4.5 Unused Syringe Containing Study Product (i.e. Wasted Doses) .......................................... 6

7.5 Additional Considerations for Concomitant Medications ............................................................. 6

Appendix 7-1: Oral CAB and Oral RPV Example Labels ............................................................................ 8

Appendix 7-2: CAB LA and RPV LA Example Labels ............................................................................... 9

Refer to protocol Section 5 for detailed information regarding study product regimens, study product supply, study product storage, and study product accountability. Protocol Section 5 also provides information on concomitant medications; listings of precautionary and prohibited medications can be found on the study-specific web page:


7.1 Ordering Study Products Clinical research site (CRS) pharmacists may order study products from the Clinical Research Products Management Center (CRPMC) by following the instructions in the Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks. Products may be ordered as soon as the site has registered the protocol to DAIDS PRO. As study products must be shipped at different temperatures, the study product will be shipped in separate packaging. Pharmacy staff are to open the boxes immediately upon receipt and follow the instructions included in the respective package/box.



7.2 General Prescribing and Dispensing Guidance Cohort 1 participants will be assigned to receive either CAB (oral CAB during Step 1, followed by CAB LA during Step 2), or RPV (oral RPV during Step 1, followed by RPV LA during Step 2). Cohort 2 participants will all be assigned to receive both oral CAB and oral RPV during Step 3, followed by CAB LA and RPV LA in Step 4.

The Pharmacist of Record (PoR) must receive a prescription signed by an authorized prescriber prior to dispensing study product. Please refer to the Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks for information which should be included on a prescription, and for additional guidance. The PoR must place a participant-specific label on the prepared study product in accordance with the local regulations and by following instructions provided in the manual, Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks. All sites must establish SOPs for prescribing and dispensing study product – including both oral as well as injectable study products – in this study. Sites must develop one SOP to address communication between pharmacy and clinic staff, and chain of custody of study products. Detailed guidance on the elements that must be included in this SOP will be provided to site PoRs by DAIDS PAB. Clinic and pharmacy staff should work together to specify (in advance of study initiation) the most appropriate site-specific procedures to be followed. After study initiation, SOPs may be updated as needed to reflect actual experiences and lessons learned throughout study implementation. The Communication/Chain of Custody SOP must be provided to the DAIDS Protocol Pharmacist for review prior to study activation and may only be modified after consultation with the DAIDS Protocol Pharmacist. 7.3 Oral Study Product Considerations 7.3.1 Prescribing and Dispensing During Cohort 1 Step 1 and Cohort 2 Step 3 For both Cohort 1 and Cohort 2 participants, the first dose of oral study product is to be administered at the Entry visit and the last oral dose is expected to be administered during the Week 4b visit (which is to occur no later than 42 days from the Entry visit). Therefore, participants may take up to a maximum of 43 doses of oral study product. Cohort 1 participants will receive a single 30-day supply of their assigned oral study product (oral CAB or oral RPV) at their Step 1 Entry visit. Cohort 2 participants will receive a single 30-day supply of each oral study products (one 30-day supply of oral CAB and one 30-day supply of oral RPV) at their Step 3 Entry visit. It is expected that this initial supply of oral study product should be sufficient to provide daily oral administration through the participant’s Week 2 visit. It is anticipated that a second 30-day supply of oral study product will be needed to ensure sufficient coverage through the participant’s scheduled Week 4a and/or anticipated Week 4b visit. This second supply may be dispensed at either the Week 2 visit, or the Week 4a visit. The decision to dispense additional oral study product may be determined collaboratively by the site clinician and pharmacist. A maximum of two dispensations of each prescribed oral study product is anticipated for each participant in Cohort 1 Step 1 or Cohort 2 Step 3. If the second 30-day supply of oral study product is dispensed at the Week 2 visit, it is expected that a third 30-day supply will not be required to be dispensed at the Week 4a visit.


7.3.2 Returning Unused Oral Study Product Sites should counsel participants to return unused oral study product to the clinic at their scheduled Week 2, Week 4a and Week 4b visits to allow for the adherence assessment (pill count). All unused oral study product should be returned to the study participant after the pill count has been performed during the Week 2 and Week 4a visits, and in consideration of guidance provided in Section 7.3.1 above. After the pill count during the Week 4b visit, unused oral study product should be kept by the pharmacy and returned to the CRPMC per the Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks. Additionally, all unused oral study product should be returned to the site as soon as possible after a temporary product hold or permanent discontinuation of oral study product and should also be specified in site SOPs. 7.3.3 Oral Study Product Storage and Administration: Oral CAB and/or Oral RPV Study participants must be advised to keep their prescribed oral study product in the respective original bottle, and under the storage conditions specified in the protocol (see protocol Section 5.1). Participants should be advised to not combine the oral tablets into a single bottle, noting that RPV tablets must also be protected from light. CAB oral tablets should be kept in their original CAB bottle, whereas RPV oral tablets should be kept in their original RPV bottle. See Section Appendix 7-1 for example labels of CAB oral tablets and RPV oral tablets. During Cohort 1 Step 1, participants will be prescribed either oral CAB (Cohort 1C) or oral RPV (Cohort 1R). Therefore, the oral study product administration instructions provided to the Cohort 1C participants will differ from those provided to the Cohort 1R participants:

• Oral CAB tablet must be taken once daily with or without food, at approximately the same time each day.

• Oral RPV tablet must be taken once daily with a meal, at approximately the same time each day During Cohort 2 Step 3, participants will be prescribed both oral CAB and oral RPV. The oral CAB and oral RPV tablets must be taken together once daily with a meal, at approximately the same time each day. As stated above, a meal must be taken with any administration of oral RPV. While there are no specific caloric or fat requirements of the meal, a moderate to full meal is recommended and a snack or appetizer is not sufficient. Site staff providing oral study product administration instructions should work with participants, and parents/guardians, to identify examples of a typical meal. Per protocol Sections 6.3.2 and 6.4.2, study staff should counsel participants (both Cohort 1 and Cohort 2 participants) to take the oral study product at the same time of day (morning or evening) as the pre-dose PK collection timepoint of their respective Cohort 1 or Cohort 2 Week 2 visit. Per protocol, a participant must be fully adherent to their assigned daily oral study product regimen (i.e. have not missed a dose) and take their assigned daily oral study product regimen at the same time of day (morning or evening) as the scheduled pre-dose PK collection timepoint for the three days preceding their Week 2 visit. Otherwise, the entire visit must be rescheduled. Study staff may emphasize this study design aspect to participants and parents/legal guardians as deemed appropriate.


Re-dosing following vomiting In general, if the participant vomits within 30 minutes of an oral dose, then another oral dose may be administered (i.e. re-dose). If the participant vomits more than 30 minutes after an oral dose, then a second dose should not be administered. Any vomiting episodes should be source documented. See MOP Section 5 for guidance regarding rescheduling PK visits or PK samples due to vomiting following the oral study product dose (such as during the Week 2 or Week 4b visits). 7.3.4 Short-Term Oral Bridging During Cohort 2 Step 4 Protocol Section 5.1.4 provides guidance regarding short-term oral bridging for Cohort 2 Step 4 participants who will miss a subsequent injection visit. CMC consultation should be documented in the participant’s file prior to prescribing oral bridging study product. Supply of oral study products for short-term oral bridging should ensure sufficient coverage for daily use until the participant can resume study product injections, noting that the resumption of the injections will vary per participant’s circumstances. Additionally, oral study product may be dispensed to study staff to provide to a participant at an off-site location. Close communications between the clinical staff, scheduling staff, and the study pharmacist are expected when determining the supply and, as needed, off-site logistics regarding oral study product for short-term oral bridging; see Section 7.2 above regarding the communication and chain of custody SOP. Participants initiating short-term oral bridging will ideally take their first dose of each oral CAB + RPV on the target visit date of the missed injection. The final dose of each oral CAB + RPV is ideally to be taken on the same day and prior to the administration of the resumed study product injections. During the oral bridging period, the oral CAB + RPV tablets must be taken together once daily with a meal, at approximately the same time each day. Sites should counsel participants to return all unused oral study product to the clinic at the visit in which they are resuming the study product injections. See additional Section 7.3.2 above for additional guidance regarding returning unused oral study product to the CRPMC. Per protocol Section 5.1.4, the CMC must be consulted prior to resuming injectable study product after oral bridging. See MOP Section 5 for detailed guidance on scheduling a study product injection visit following short-term oral bridging. 7.3.5 Short-Term Storage of Participant-Specific Oral Study Product in the Clinic If the PoR does not dispense directly to participants and participant-specific study product is stored in the clinic for a short period of time (e.g., while the participant is undergoing the study visit procedures for a particular visit), study product must be stored at the conditions described in the protocol in an area that is always locked and is accessible only to pharmacists and authorized study staff as specified in the site’s SOP and Pharmacy Establishment Plan. If the site staff believes that the study product has been exposed to temperatures outside of the temperatures specified in the protocol, the PoR must be contacted immediately so that she/he can dispense a replacement participant-specific study product as needed. In addition, the IMPAACT 2017 DAIDS Protocol Pharmacist must be notified by email of the temperature excursion. The temperature in the clinic storage area must be reviewed and recorded daily. These temperature records must be reviewed by the PoR on a monthly basis and must be provided to the PoR to be maintained in the pharmacy. These records must be available for review by site monitors.


7.4 Injectable Study Product Considerations The participant will receive their first injection of study product at the Week 4b visit. For all participants completing a Week 4b visit, their last dose of prescribed oral study product must be administered prior to the first dose of injectable study product. Cohort 1 participants will receive a single injection of their assigned study product, whereas Cohort 2 participants will receive a single injection of each study product for a total of two injections. The Pharmacist of Record must be proficient in the preparation of products requiring aseptic technique under a pharmacy biological safety cabinet/isolator. Local regulations and site institutional policies and procedures for use of protective equipment, such as gloves, gowns, and masks, and safety glasses, must be followed. 7.4.1 CAB LA See Section Appendix 7-2a for an example label and packaging of CAB LA. CAB LA is supplied in vials as a suspension which needs no further dilution or reconstitution. However, the directions provided in protocol Appendix VI-A Injectable Study Product Preparation must be followed for the preparation of CAB LA injection. 7.4.2 RPV LA See Section Appendix 7-2b for an example label and packaging of RPV LA. RPV LA is supplied in vials as a suspension which needs no further dilution or reconstitution. However, the directions provided in protocol Appendix VI-B Injectable Study Product Preparation must be followed for the preparation of RPV LA injection. 7.4.3 Injectable Study Product Administration Injectable study products will be prepared in the pharmacy and delivered to the study clinic for clinic staff to administer to participants and must be administered as soon as possible and within two hours of preparation by the site pharmacist. The products must remain at the storage temperatures specified in the protocol, from the time they are prepared to the time they are administered. As noted above, the process and procedures by which to maintain the required temperatures as the study products are transferred from the pharmacy to the clinic, and prior to administration, should be described in the site’s Chain of Custody SOP. Prior to administering injectable study product, all requirements listed in protocol Section 6.9 must be met and source documented to confirm continued study product use is appropriate. Additionally, all local regulations and site institutional policies and procedures for use of protective equipment, such as gloves, gowns, and masks, and safety glasses, must be followed.

Suggested supplies for CAB LA and RPV LA Needle for IM injection: 23G x 1½ inch SurGuard Safety Hypodermic Needle, CE MARKED Manufacture Catalog Number: SG3-2338, or equivalent. For all IM injections, the needle should be long enough to reach the muscle mass and prevent study product from seeping into subcutaneous tissue, but not so long as to involve underlying nerves, blood vessels, or bone. The recommended gauge of needle is 1½ inch 23 gauge needle for CAB LA and RPV LA for the average sized adult. Variable needle lengths and/or needles with different gauge (1½ inch, 2


inch; CAB LA: 21 to 25 gauge; RPV LA: 21 to 23 gauge) are permitted if needed to accommodate individual body types. Note that 25 gauge needle is not permitted for administration of RPV LA. Longer needle lengths may be required for participants with higher body mass indexes (BMIs, example > 30), to ensure that injections are administered intramuscularly as opposed to subcutaneously. A participant's BMI can be used as a guide for determining length of needle to be used, with the final decision to be made by the IoR or designee. Once a needle length is decided for a participant, all subsequent injections should be made with the same length needle unless there is a significant change in body composition.

Intramuscular Injection Administration Technique (Z-Track Method) Injectable study products will be administered by designated site staff by intramuscular injection in the gluteus medius muscle. For administration of injectable study product, standard IM injection techniques will be used. The below listing provides the minimum procedures for administering the IM injections; however, sites must follow institutional policies regarding injection techniques, safety precautions, and needle/syringe disposal.

• Remove the needle cap and inject the entire content intramuscularly (gluteus medius muscle, upper-outer quadrant of the buttock). Ensure the compound is not injected in vein. The Z-track method is a commonly used IM injection method and recommended for this study.

• After the injection is complete, immediately dispose of the needle and syringe in a designated sharps container.

• Record the time of injection, location (right or left side of the buttock) of the IM injection administered, the needle length and gauge used, and the volume of injection administered in source documents. Sites may consider the use of an "injection map" to keep track of each injection, and where it was given in the gluteus medius muscle.

7.4.4 Short-Term Storage of Participant-Specific Injectable Study Product in the Clinic The products must remain at the storage temperatures specified in the protocol, from the time they are prepared to the time they are administered. If an injectable study product is unable to be administered within two hours from the time it was prepared, the PoR must be contacted immediately so that she/he can prepare and dispense a replacement participant-specific study product as needed. 7.4.5 Unused Syringe Containing Study Product (i.e. Wasted Doses) In the event a dose is prepared but not administered, the unused syringe(s) should be returned to the pharmacy for accountability with a reason attached (e.g., injectable study product is temporarily held or permanently discontinued). A replacement dose may be required if a dose is unable to be administered (e.g., dose is drawn up and syringe is accidentally dropped and stepped on). A new prescription should be requested for the replacement dose. 7.5 Additional Considerations for Concomitant Medications For this study, the term concomitant medications refers to medications other than the study products listed in protocol Section 5.1. cART medications, other than CAB and RPV, will not be provided through the study. Protocol Section 5.6 provides further information related to concomitant medications, and protocol


Sections 5.7 and 5.8 provide information related to prohibited and precautionary medications, respectively.


Appendix 7-1: Oral CAB and Oral RPV Example Labels

Appendix 7-1a: Oral CAB example label - CAB 30 mg Oral Tablets

Appendix 7-1b: Oral RPV example label - RPV 25mg Oral Tablets


Appendix 7-2: CAB LA and RPV LA Example Labels

Appendix 7-2a: CAB LA example label - CAB LA 400mg/2 mL vial

Appendix 7-2b: RPV LA example label - RPV LA 600mg/2 mL vial


SECTION 8 COUNSELING CONSIDERATIONS

Table of Contents 8.1 Counseling Overview .................................................................................................................... 1

8.2 HIV-Related Counseling ............................................................................................................... 1

8.3 Contraception Counseling ............................................................................................................. 2

8.4 Adherence Counseling .................................................................................................................. 3

8.1 Counseling Overview All counseling provided in this study should be provided per site standard operating procedures (SOPs), which should reflect all national and local policies and guidelines that are applicable at each site. Site SOPs should reflect counseling expectations consistent with the fact that participants are HIV-infected with documentation of viral suppression. Additionally, all adolescents may not be aware of their HIV status. As such, study staff should confer with the participant’s parent/legal guardian before providing HIV counseling. As appropriate and per site SOPs, parents and guardians can also be included in counseling sessions. All study staff who provide counseling should be trained to do so in accordance with local standards of care and site training policies. Site supervisory staff are responsible for ensuring the quality of counseling provided through on-site monitoring, mentoring, and refresher training throughout the course of the study. Participation in this study may identify counseling and other needs that are beyond the scope of the study to address. When such needs are identified, participants should be referred to appropriate, non-study service providers and other organizations that may be able to assist them. Each site should maintain current lists of referral organizations and make these lists available to all counselors for use during all counseling sessions. At each counseling session after a referral is made, the counselor should actively follow-up on the referral to determine whether the participant sought the services to which he or she was referred, determine the outcome of the referral, and determine whether additional referrals are needed. Additional counseling may also be needed to help ensure that participants access services that may be beneficial to them. All counseling must be documented in participant study records. Documentation should include the content of each counseling session, participant responses to the counseling provided, any concerns raised by the participant, action planned to be taken by the participant prior to the next counseling session, action to be taken by the counselor (or other study staff) prior to the next session, and issues to be reviewed or addressed at the next session. Specific to referrals, all follow-up actions, outcomes, counseling, and plans for next steps should also be documented. Study sites may choose to use checklists to document counseling sessions — particularly to document the content of each session — but it is expected that narrative notes will also be required to fully document each session. Careful attention should be paid to clearly identify counseling issues to be addressed at the next session, given that different counselors may provide counseling at different visits. 8.2 HIV-Related Counseling Sites may need to provide HIV-related counseling to adolescent participants in relation to confirmatory HIV testing.


• Counseling in relation to HIV testing: Some participants enrolled in this study may undergo HIV testing as a study procedure, to confirm their eligibility for study participation. HIV testing must be performed in the context of pre-test and post-test counseling. Pre-test and post-test counseling should be provided per site SOPs in a client-centered manner, i.e., in a manner that is responsive to the information and counseling needs of the participant at the time of the session. Counseling should also include the rationale for the confirmatory testing.

• Counseling in relation to risk reduction: For this study, the term risk reduction counseling refers to

counseling provided to support participants in reducing their risk of re-infection and their risk of transmitting HIV to others (e.g., to sexual partners). Counseling should include HIV/AIDS education, discussion of disclosure issues and emotional support, discussion of healthy living strategies, discussion of stressors and potential strategies to address these, and provision of referrals, as applicable to each participant. Counseling should include information on suppression of HIV viral load as an effective strategy to minimize the risk of transmission to others. Risk reduction counseling should be provided as part of the pre-test and post-testing counseling described above and at any time in response to client-centered needs, per site SOPs.

8.3 Contraception Counseling All sites will provide contraceptive counseling to both male and female participants, regardless of self-reported sexual activity or childbearing potential at all study visits. Counseling should begin during the screening visit and continue for each participant throughout their participation in the study. As stated in protocol Section 4.1.15 females of childbearing potential are required to use at least one allowable effective method of contraception to enroll to the study. For any female participant who becomes of childbearing potential during the study, use of an allowable effective contraceptive method must be confirmed (per participant report) on the same day and prior to administration of study product (oral or injectable study product). The effective methods of contraception allowed for this study are listed in protocol Section 6.13 and includes abstinence from intercourse of reproductive potential. Protocol Section 6.13 also provides additional details on contraceptive counseling. Contraceptive counseling should be age-appropriate and should be provided in a client-centered manner consistent with local standards of care and site SOPs. When applicable, participants should be offered the option of having their parent, legal guardian, or partners attend counseling sessions with them. At each session, issues requiring follow-up from the prior session should be reviewed and updated, and plans should be made for actions to be taken between the current session and the next session. Contraceptive counseling will include maintaining contraceptive use for 30 days after the last oral study product use and for 48 weeks after the last injection of study product (even if only a single injection). Female participants should also be encouraged to delay pregnancy for at least 30 days following oral study product use, or 48 weeks following the last injection of study product (even if only a single injection). At any point during study participation, additional counseling on correct use of chosen contraceptive methods should also be offered according to site SOPs; this will include information on correct use of barrier methods. For Cohort 1 and all LSFU participants, contraceptive counseling will also reflect the ARVs which participants are currently taking for the potential interactions between these ARVs and available contraceptive methods. Study sites should ideally integrate provision of contraceptive methods with other services offered to study participants and should provide referrals to non-study sources of methods that cannot be provided at the study site. Study staff should confirm (per participant report) effective contraception with one of the study required contraceptive methods at each visit in which study product is administered.


Pregnancy test results will be disclosed to participants and their parent/guardians consistent with local standards of care; local standard procedures will be noted in site-specific informed consent and assent forms. Protocol Section 8.3 provides the requirements for participant and study product management in relation to contraception use as well as in the event of a pregnancy, with additional guidance provided in Section 9 of this manual. 8.4 Adherence Counseling The purpose of adherence counseling is to provide information, skills building, and other guidance to support participants in completing study requirements as correctly and consistently as possible. Protocol Section 6.14 provides details regarding adherence counseling for various aspects of the study, including adherence to study product, cART regimen, and attending study visits. All sites will provide adherence counseling to all study participants and parents/guardians throughout study participation at specified study visits, and as needed based on IoR discretion.

Adherence counseling should be provided in a client-centered manner per site SOPs. Site SOPs should designate roles and responsibilities for adherence assessment, counseling, and support and specify how clinic and pharmacy staff will share information and coordinate efforts while fulfilling their respective roles and responsibilities. Topics discussed during adherence counseling will vary depending on the Cohort, Step and whether participants are also taking a (non-study provided) cART regimen.

Adherence Counseling Topic Timepoints for Discussion

Adhering to the (non-study provided) cART regimen and instructions on cART administration

• Throughout Cohort 1 participation • Prior to participants transitioning to the LSFU

visit schedule • During specified LSFU visits • At Early Termination visits

Adhering to the oral study product in relation to the purpose of the oral lead-in phase and allowing for sufficient evaluations of safety and tolerability

• Cohort 1 Step 1 • Cohort 2 Step 3

Adhering to the oral study products in relation to maintaining viral suppression

• Cohort 2 Step 3 • Cohort 2 Step 4 participants on short-term oral

bridging Importance of adhering to the study visit schedule • All participants

• Throughout Cohort 2 participation (no longer receiving a non-study provided cART regimen)

Importance of adhering to the intended injectable study product dosing regimen and adhering to the study visit schedule

• Cohort 1 Step 2 • Cohort 2 Step 4

Counseling will include the importance of adhering to the intended injectable dosing regimen and schedule

• For participants exiting the study at the Cohort 2 Week 96 visit (to continue injectable CAB LA + RPV LA external to the protocol)


For discussions regarding adhering to a participant’s non-study provided cART regimen or to the oral study product, information on correct use of each ARV should be provided. Once this knowledge is established, the emphasis of adherence counseling should be on supporting the participant in consistent use over time. Adherence counseling should acknowledge that consistent use of oral ARVs and, for participants in Cohort 1 Step 2 or Cohort 2 Step 4, attending injectable study visits over time are challenging and should encourage participants to openly discuss any challenges they may face, so that study staff can assist with identifying strategies to address the challenges. Counseling should also acknowledge that adherence challenges may change over time; therefore, adherence strategies may also need to change over time. The role of the counselor is to support the participant in identifying strategies that are most likely to work for him/her. Additional tips and guidance for providing adherence counseling are as follows, where adherence refers to oral study product, cART regimen, and to the visit schedule, as applicable: • In preparation for each counseling session, review study records to:

– Identify how long the participant has been taking ARVs; whether s/he has experienced ARV side effects; and whether adherence challenges have been encountered to date.

– Review the adherence strategies that have been identified for the participant to date and which of

these have been perceived as successful or unsuccessful by the participant; pay particular attention to adherence strategies identified at the last counseling session.

• Prepare any materials that may be needed for the session. • Greet the participant by name, establish rapport, and foster open dialogue. Reinforce confidentiality

and explain that the purpose of the session.

• Invite the participant to ask any questions and express any concerns s/he may have. • As needed, address any knowledge gaps or misinformation with regard to use of ARVs. Use

information sheets and/or other visual aids to help ensure the participant’s understanding of instructions for correct use of each ARV, paying particular attention to these issues as participants enter the study and begin the oral study product regimen.

• As needed, provide skills building support to the participant (e.g., on proper storage of ARVs; on

disclosure of HIV status and/or study participation to others). • Use open-ended questions and actively listen to the participant’s responses to assess her/his

experience with adherence since her/his last visit.

Note: Adherence assessments (pill counts) to the oral study product regimen during Cohort 1 Step 1 and Cohort 2 Step 3 may not be used as a basis for adherence counseling in this study. Rather, client-centered dialog should guide all counseling. See Section 5 of this manual for further information regarding the adherence assessment by pill count.

• Incorporate discussion of HIV viral load test results and trends in these results over time. If results

and trends are not as expected, ask the participant for her/his thoughts on why this may be the case and build from the participant’s perceptions to guide additional counseling.


• Provide positive reinforcement for adherence successes. Ask the participant to share more information on successful strategies so that her/his approaches can be shared with other study participants. Continue successful strategies as part of the participant’s ongoing adherence plan.

• Review the adherence strategies discussed at the previous session and probe as needed to identify

ongoing or new barriers to adherence. With continued dialog, assess whether the reminder and adherence strategies discussed at the previous session were perceived by the participant as useful/successful. As needed, assist the participant with identifying new strategies to try to address new or ongoing barriers.

• At each session, clearly articulate the adherence plans and strategies identified by the participant for

the time period between the current session and the next session. All plans and strategies should be practical and feasible for the participant. For participants with significant adherence barriers, plans and strategies may need to be incremental. For participants whose adherence barriers change over time, plans and strategies may also need to change over time. All plans and strategies should be documented in study records with written copies given to the participant, if desired.

• Thank the participant for her/his participation in the study. Acknowledge the contributions they are

making toward finding new treatments for people with HIV and improving the health of such people worldwide.


SECTION 9 PARTICIPANT MANAGEMENT CONSIDERATIONS AND EXPEDITED ADVERSE EVENT REPORTING

Table of Contents 9.1 Participant Management Considerations for Selected Events ...................................................... 1

9.1.1 Injection Site Reaction (ISR) ................................................................................................ 1

9.1.2 Elevations in ALT, Bilirubin ................................................................................................ 2

9.1.3 Depression ............................................................................................................................. 3

9.1.4 Management of Pregnancy .................................................................................................... 3

9.2 Expedited Adverse Event Reporting ............................................................................................. 4

Appendix 9-1: Study Product Use Management for Elevations in ALT ..................................................... 5

Protocol Section 7.2 provides a listing of which adverse events, pre-existing conditions, and laboratory test results are to be entered into eCRFs. Protocol Section 8 describes management of adverse events (AE); monitoring and management of QTc prolongation; monitoring and management of contraception and pregnancy; and monitoring and management of HIV viral load. Protocol Sections 8.1.2-8.1.9 provide detailed participant and study product management on specified adverse events and abnormal laboratory test result values. If an observed adverse event or abnormal laboratory test result value is not listed in those sections, the guidance in protocol Section 8.1.1 General Management of Adverse Events should be followed. This section of the manual provides additional guidance on selected aspects already described in protocol Section 8. 9.1 Participant Management Considerations for Selected Events 9.1.1 Injection Site Reaction (ISR) Participant and study product management requirements due to an ISR adverse event is described in protocol Section 8.1.2. An ISR is defined as an adverse event which, in the opinion of the IoR or designee, results in one or more of the following and which is out of proportion to that which could reasonably be expected following an IM injection, regardless of when it occurs after administration of an injection:

• Pain, • Tenderness, • Erythema, • Redness, • Induration or swelling, or • Pruritis

It is expected that all study participants receiving an intramuscular injection will feel the needle and feel pressure from the study product as it is injected into the tissue. In the adult studies to date, some participants have reported discomfort as the study product is injected into the tissue, and the ISRs reported have largely been injection site pain occurring one to two days after administration. For both of these scenarios, topical anesthetic is not anticipated to be helpful. Topical anesthetics (e.g. EMLA) prior to administration of the injectable study product may be used at the discretion of the site staff. Any topical anesthetic should be documented on the Concomitant Medications Log eCRF (CMW10000). Procedural


pain and/or discomfort from the needle or from the volume of the suspension entering the tissue at the time of injection that is normal and expected with an IM injection, in the opinion of the investigator, is NOT considered an adverse event or an ISR. These expected procedural events should not be reported as an AE. However, injection site pain or pressure that is extreme or unanticipated, regardless of when it occurs, should be assessed and reported per the Site Reactions to Injections and Infusions section of the DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. Participants reporting pain or discomfort on acceptability/tolerability questionnaires should be clinically assessed prior to the leaving the clinic for a potential ISR occurrence. See Section 6 of this manual for the timing of administration of all acceptability and tolerability questionnaires. Notably, the Pain During Injections questionnaire (SSW10002 for Cohort 1, and SSW10003 for Cohort 2) will be administered immediately following the study product injection at specified visits. It is generally not expected that pain reported during administration of this questionnaire be considered an ISR, but rather more likely as expected procedure pain. However, the Revised Perceptions of Injection Questionnaire (QLW10033) will be administered at specified study visits with responses relating to a previously administered injection. Ongoing pain or discomfort from a previous injection reported via this questionnaire may qualify as an ISR. Clinical examinations of a potential ISR, and supporting source documentation, should include an assessment of each of the following:

• Pain, • Tenderness, • Pruritis, • Warmth, • Purulence, • Rash, • Erythema, • Swelling, • Induration, and • Nodules (granulomas or cysts)

For participants reporting either expected procedural pain or an ISR, management of symptoms may include:

• For pain, acetaminophen, ibuprofen/other NSAIDS, cold/hot compress should be administered. • For swelling, ibuprofen/other NSAIDS should be administered. • If any drainage, fever, chills, fatigue, weakness, the site should be contacted immediately. • Do not attempt to squeeze or drain any fluid from injection site. • Cover with a sterile bandage and contact clinic immediately if drainage occurs. • If the participant is unable to see or access the injection site, a parent or legal guardian may look

at the injection site noting color, tenderness, any drainage. All ISRs will be recorded into the AE Log eCRF (ADE10003). Sites should clearly document the start date and end date of each ISR to avoid multiple ISRs over the course of study participation as being reflected in the database as one very long-lasting ISR event. 9.1.2 Elevations in ALT, Bilirubin Participant and study product management requirements due to elevations in ALT, including considerations of accompanying bilirubin test results, are described in protocol Section 8.1.5.


Participants with an abnormal total bilirubin test result should have serum bilirubin fractionation (i.e. direct bilirubin) testing requested. If the abnormal total bilirubin is elevated, then ideally direct bilirubin is requested from the same sample (i.e. automatic fractionation). Confirmatory repeat testing should be performed at the timepoints indicated in protocol Section 8.1.5 (if ALT is also elevated) or per CMC consultation (if ALT is normal). In all cases of elevated ALT and/or elevated bilirubin (total or direct), possible alternative etiology should be assessed, and the underlying illness treated, or the likely causative agent removed. Direct bilirubin is required for Cohort 1 participants with hyperbilirubinemia and on an atazanavir-containing regimen. As noted in protocol Section 8.1.5, direct bilirubin test results are required prior to assessment of atazanavir as a likely causative agent of the event. CMC notification timeframes specified in protocol Section 7.1.1 apply while fractionation results are pending. Schematics of participant and study product management corresponding with protocol Section 8.1.5 are provided in Section Appendix 9-1 below. Repeat testing within 72 hours is required for a Grade 2 ALT test result obtained from the Week 4a visit (for either Cohort 1 or Cohort 2 participants). Participants should not progress to the study product injection phase (Step 2 or Step 4) until this Grade 2 ALT returns to baseline, or per CMC guidance. 9.1.3 Depression Participant and study product management requirements due to depression are described in protocol Section 8.1.9. Participants with HIV infection may occasionally present with symptoms of depression and/or suicidal ideation or behavior. The Patient Health Questionnaire-9 (PHQ-9) will be used to establish a screening assessment for participants reporting depression at baseline (Screening and Entry visits). See the IMPAACT 2017 website for a sample of the PHQ-9 screener tool to be used, and accompanying instructions. Sites should clinically manage participants according to local standards of care and site SOPs, with consideration of the scoring from the PHQ-9 screener tool. Sites have the option to also use this screener tool during clinical re-evaluation of depression throughout study follow-up, per site SOPs. 9.1.4 Management of Pregnancy Participant and study product management requirements due to pregnancy are described in protocol Section 8.3. As described in protocol Section 1.2.1, findings from the Botswana NICHD-funded Tsepamo Birth Outcomes Surveillance Study indicate a potential increased risk of neural tube defects associated with exposure to dolutegravir, an integrase strand transfer inhibitor, at the time of conception. Cabotegravir is not dolutegravir. While these medications share a common molecular backbone, and have a similar mechanism of activity, they are separate chemical compounds and have differences in antiviral activity, pharmacokinetics, metabolism and drug-drug interactions. It is not known if the safety signal identified with dolutegravir will be confirmed in other studies and/or settings where dolutegravir is being used or whether these will be observed with cabotegravir. Per protocol Section 8.3, sites should actively refer pregnant participants to antenatal standard of care upon obtaining a positive confirmatory pregnancy test result. However, sites may begin the referral process upon obtaining the initial positive pregnancy test result per site SOPs. For all pregnant participants, sites should actively encourage engagement with antenatal care as early in the pregnancy as possible.


9.2 Expedited Adverse Event Reporting Refer to protocol Section 7.3 for detailed information on expedited adverse event (EAE) reporting requirements for this study. Other important references and resources related to EAE reporting include:

• Manual for Expedited Reporting of Adverse Events to DAIDS (Version 2.0) • DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version

2.1, dated July 2017 • Study product package insert for Rilpivirine (oral) • Study product Investigator’s Brochures for:

Cabotegravir (oral and long-acting injectable) Rilpivirine (long-acting injectable)

• DAERS Site User Instructional Guide for EAE Reporting • DAERS Reference Guide for Site Reporters and Study Physicians • DAIDS safety training resources

The DAERS and DAIDS resources listed above are available at:

https://rsc.niaid.nih.gov/clinical-research-sites/safety


APPENDIX 9-1: STUDY PRODUCT USE MANAGEMENT FOR ELEVATIONS IN ALT Figure 9-1a: Grade 1 ALT and/or Grade 1 bilirubin

Figure 9-1b: Grade 2 ALT with Grade <1 bilirubin


Figure 9-1c: Grade 2 ALT with Grade >2 bilirubin

Figure 9-1d: Grade 2 ALT + symptomatic + baseline ALT < ULN (regardless of bilirubin)


Figure 9-1e: Grade 3 ALT regardless of bilirubin

Figure 9-1f: Grade 4 ALT regardless of bilirubin


SECTION 10 LABORATORY CONSIDERATIONS

Table of Contents Section 10 Laboratory Considerations ................................................................................................... 1

10.1 Laboratory Considerations ............................................................................................................ 1

10.1 Laboratory Considerations Protocol Section 6, protocol Appendices (Appendices I-A through I-C), and Laboratory Processing Chart (LPC) are the primary sources of information on specimen collection, processing, testing, storage, and shipping for this study; both clinic and laboratory staff should routinely refer to these resources as needed. Sites continuing to implement protocol Version 2.0 should refer to the most recent LPC corresponding to protocol Version 2.0. Likewise, sites implementing protocol Version 3.0 should refer to the most recent LPC corresponding to protocol Version 3.0.


SECTION 11 DATA MANAGEMENT CONSIDERATIONS

Table of Contents Section 11 Data Management Considerations ....................................................................................... 1

Refer to protocol Section 12 and the study-specific eCRF completion guide, developed by the Data Management Center (DMC), for detailed guidance and step-by-step instructions regarding the eCRFs used for this study. eLearning modules and other operational guidance on use of the Medidata Rave system for this study are available on the DMC portal. Table 11-1 below maps the participant medical and medication history elements specified in protocol Section 6.10 (protocol Table 7) to the relevant eCRFs forms to be completed for each element. Note that additional eCRFs may be required for completion at any given study visit beyond those listed below. Table 11-1: Mapping of Required History Elements to eCRFs

Medical and Medication History Element eCRF

Baseline Medical and Medication History Elements Age and other socio-demographics Eligibility checklist

HIV diagnosis, mode of transmission, and ARV treatment history (including all prior ARV use)

CMW10000: Concomitant Medications Log HXW10012: IMPAACT 2017 Mode of HIV Transmission

History of allergy and/or hypersensitivity (including to ARVs)

MHW10000: Medical History Log

Medical conditions (including malignancies) occurring during the 28 days prior to entry, ongoing at entry, as well as all prior significant central nervous system disorders (including seizures and migraines/headaches), mood disorders (such as depression), and significant liver disease resulting in hospitalization or interfering with daily activities.

MHW10000: Medical History Log

Medications, (other than ARVs, see above) taken within the 28 days prior to enrollment and/or ongoing at enrollment

CMW10000: Concomitant Medications Log

Assessment of sexual activity Eligibility checklist

Contraceptives ongoing at enrollment, including start date and most recent date of administration of current contraceptive method. Note: Hormonal-based contraceptives must have been initiated within the prescribed time, per the respective contraceptive method, to be considered effective at the time of Entry. The site IoR or designee is responsible for ensuring that the contraceptive is used in accordance with the approved product label


Any other information needed to determine eligibility for the study

Eligibility checklist

Interval Medical and Medication History Elements

Current status of conditions that were ongoing at the previous visit

ADE10003: Adverse Events Log (Multi) MHW10000: Medical History Log

Occurrence of any new conditions since the last visit ADE10003: Adverse Events Log (Multi)


Medical and Medication History Element eCRF Current status of medications (including contraceptives) that were ongoing at the previous visit

CMW10000: Concomitant Medications Log EVW10054: IMPAACT 2017 Contraceptive Use

Use of any new medications since the last visit (see protocol Section 5.6 for more information on concomitant medications) Note: For participants in Cohort 1 and LSFU, ARVs would be considered concomitant medications.


Oral Study Product since the last visit (for Cohort 1 Step 1, Cohort 2 Step 3 participants, and any Cohort 1 or Cohort 2 participants on oral bridging) Note: Injectable study product information is not considered as part of medical and medications history since last visit, and will be collected as per protocol Section 5. See protocol Section 6 for details regarding study product dosing documentation requirements for PK evaluations.

TXW10004: IMPAACT 2017 Oral Study Treatment Log

Assessment of sexual activity since the last visit Not documented on an eCRF


SECTION 12 QUALITATIVE INTERVIEW CONSIDERATIONS

Table of Contents 12.1 Overview ....................................................................................................................................... 1

12.2 Adolescent Participants: Selection for a Qualitative In-depth Phone Interview ........................... 2

12.3 Parent/Caregiver Participants ........................................................................................................ 2

12.3.1 Parent/Caregiver Recruitment and Consenting ..................................................................... 3

12.3.2 Parent/Caregiver Eligibility Confirmation and Enrollment .................................................. 4

12.4 Scheduling the Interview .............................................................................................................. 5

12.4.1 Interview Procedural Windows ............................................................................................. 5

12.4.2 Scheduling Considerations .................................................................................................... 5

12.5 Prior to the Interview .................................................................................................................... 7

12.6 Conducting the Interview .............................................................................................................. 7

12.6.1 Interview Guides ................................................................................................................... 7

12.6.2 Audio-Recording ................................................................................................................... 7

12.6.3 Accessing the Interview ........................................................................................................ 8

12.7 Missed Interviews ......................................................................................................................... 8

12.8 Tracking Interview Completion .................................................................................................... 9

12.9 General Communications and Disclosure of Harm ...................................................................... 9

12.10 Site-Specific Qualitative Interview SOP ................................................................................. 10

12.11 Data Security ........................................................................................................................... 10

Appendix 12-1: Sample email Notifications ............................................................................................... 12

Appendix 12-2: Suggested Source Documentation of Parent/Caregiver eligibility criteria ....................... 16

Appendix 12-3: Interview Procedural Windows......................................................................................... 17

Appendix 12-4: Sample pre-interview communication .............................................................................. 19

12.1 Overview

A single in-depth qualitative phone interview will be conducted to identify acceptability and tolerability concerns unique to the participant population, and to evaluate adolescent participants’ experience of CAB LA and/or RPV LA. The qualitative phone interview will be conducted only at U.S. sites with a sub-set of adolescent participants and, separately, with parent/caregivers of a sub-set of adolescent participants. Participants may complete the interview from the clinic or at a quiet location outside the clinic. Each interview will take between 20 minutes and one hour to complete.

Protocol Section 11 provides qualitative interview requirements for adolescent participants, and protocol Appendix V outlines key qualitative interview requirements for the parents/caregivers.


Protocol Appendices II-IV provide the sample informed consents and assents for adolescent participation in this study. Consent (or assent, as applicable) for the possibility of being selected for a phone interview will be obtained for adolescent participants as part of the initial informed consent process (or informed assent process, as applicable) for the IMPAACT 2017 study. There is not a separate sample informed consent/assent form specific to the qualitative interview for adolescent participants, however sites may develop separate consents/assents as needed.

For all adolescent participants, at the entry visit as part of data collection, site staff will ask if the participant is willing to participate in a qualitative interview by phone and in English. Site staff will also ask if the adolescent has a parent/caregiver with whom they have regular, supportive contact, and if this parent/caregiver is potentially willing to participate in a qualitative interview in English. This information will be entered into eCRFs (QLW10031). Using the information obtained from the QLW10031, participant demographics (collected at the screening and entry visits), and other eCRFs indicating permanent discontinuation of injectable study products (collected during Step 2 or Step 4), the DMC will generate weekly reports.

12.2 Adolescent Participants: Selection for a Qualitative In-depth Phone Interview

The protocol interview team at the Children’s Hospital of Philadelphia (CHOP) are members of the study protocol team and will select individual adolescent participants to take part in an interview based on the DMC-generated reports. The aim of selection will be to ensure a balance of completed interviews from both males and females, older and younger participants, and across multiple research sites, but restricted to those willing and able to conduct the interview by phone in English. Additionally, participants who permanently discontinue injectable study product will be purposefully selected to ensure reasons for discontinuing the injections are also reflected in the final analysis. Selection will occur at one of two timepoints for each cohort:

• For Cohort 1, participants may be selected for an interview either prior to their scheduled Week 4b visit, or during their Long-term Safety and Washout PK Follow-Up (LSFU) visit schedule if permanently discontinued of injectable study product.

• For Cohort 2, participants may be selected for an interview either prior to their scheduled Week 24 visit, or during their LSFU visit schedule if permanently discontinued of injectable study product.

The protocol interview team will notify the site via email of the selected participant’s PID; this notification should be printed and maintained in the participant’s files. An example of this email notification is provided in Section Appendix 12-1a.

Site staff will then contact the participant to confirm their willingness and, if willingness is confirmed, to schedule the interview. Confirmation of willingness must be source documented in the participant’s research record. Details regarding scheduling the interviews are described in Section 12.4 below.

12.3 Parent/Caregiver Participants

Selected parents/caregivers of adolescent participants will take part in a separate in-depth phone interview. The protocol interview team will select parents/caregivers of adolescents based on the Data Management Center (DMC)-generated reports and the QLW10031 eCRFs as referenced above. initially, the parent/caregiver and the associated adolescent participant will be intentionally selected as a pair to each complete their applicable qualitative interview. For example, if an adolescent participant is already selected for an interview and indicates on the QLW10031 to have a parent/caregiver potentially willing to


interview in English, then the protocol interview team will preferentially select both this adolescent and their parent/caregiver to participate in the qualitative interviews. However, neither adolescents nor parents/caregivers will be excluded from interviews if the other is unwilling or unable to take part in an interview. While selection of pairs is desired because it allows for a more comprehensive look at the adolescent’s experience, it is not required.

Furthermore, the protocol interview team may purposefully select either adolescent or parent/caregiver participants who are not paired if needed to achieve thematic saturation. For example, the protocol interview team may select parent/caregivers of adolescents who themselves were not selected for an interview if new themes were arising in parent/caregiver interviews that require clarification through the interviewing of additional parents/caregivers.

The protocol interview team will email the site a request to initiate recruitment of the participant’s parent/caregiver either when the adolescent is selected for an interview or separately if needed. The notification by the protocol interview team will refer to the participant by the adolescent’s PID only and should be printed and maintained in the participant’s files. An example of this email notification is provided in Section Appendix 12-1b

Parents/caregivers will be selected across multiple U.S. sites but restricted to those willing and able to conduct the interview by phone in English.

12.3.1 Parent/Caregiver Recruitment and Consenting

Per protocol Appendix V, sites have the option of obtaining informed consent either in writing in-person, verbally in-person, or verbally over the phone from the parent/caregiver. All site IRB/EC policies must be followed concerning any consenting approach taken. Protocol Appendix V-A provides details on additional requirements and considerations when obtaining consent over the phone. As noted in the protocol and Section 4 of this manual, a parent or legal guardian will be required to provide consent for adolescent participants who are only able to provide assent (e.g. unable to provide independent informed consent). It is recommended in these situations that the parent or legal guardian of the adolescent participant is approached and consented to take part in the parent/caregiver qualitative interview at the time of providing consent for the adolescent to the overall study, even if this parent or legal guardian is not ultimately selected or does not ultimately meet the eligibility criteria to take part in the interview.

It is generally expected that parents/caregivers will be identified and recruited when either:

1. The adolescent participant is asked to provide a referral of an individual who fits this description of a potentially eligible parent/caregiver, or when

2. Site staff already know that a parent or legal guardian (or caregiver) of the adolescent participant is highly likely to fit this description, and site staff may approach that individual first.

Sites must follow their IRB/EC-approved recruitment methods for approaching a potential parent/caregiver participant. The adolescent can indicate multiple parents/caregivers who could be eligible to participate in an interview. However, only a single parent/caregiver can complete an interview for each adolescent. Should an adolescent participant indicate on the QLW10031 to have a potentially eligible parent/caregiver, but recruitment efforts of that parent/caregiver are not successful, site staff should continue to request the adolescent to refer another parent/caregiver who may be potentially eligible and willing to take part in the phone interview until a parent/caregiver is successfully recruited or all


options are exhausted. Site staff should notify the protocol interview team regarding instances in which no parent/caregiver is ultimately successfully recruited. After recruitment of a potentially eligible parent/caregiver, for those who have not already provided consent to take part in the qualitative phone interview, study staff will proceed with the informed consent process for the qualitative phone interview. Table 12-1 below provides the expected order of flow of parent/caregiver recruitment, consenting, eligibility determination/confirmation, and study procedures.

Table 12-1: Parent/Caregiver Order of Recruitment and Study Procedures

Selection/ Recruitment

1) Notification from protocol interview team of adolescent PID### to initiate parent/caregiver recruitment.

2) Site staff work to identify a potentially eligible parent/caregiver:

a) Staff request referral from the adolescent participant according to IRB-approved recruitment methods, OR

b) Staff already know an individual of the adolescent participant is highly likely to fit this description, and site staff may approach that individual.

3) The site recruits identified parent/caregiver per IRB-approved recruitment methods.*

*The interview may be scheduled at any point upon identifying the parent/caregiver for potential enrollment.

Screening

4) If not previously done (e.g., during the initial consent process for the adolescent participant), obtain consent from the parent/caregiver.

5) After consent is obtained, final eligibility is determined, confirmed and source documented in the parent/caregiver file.

a) Adolescent must (re)confirm that the consented parent/caregiver meets eligibility criteria 4.5.3.

Enrollment 6) Site enters the completed eligibility checklist into the Subject Enrollment

System (SES) and enrolls the parent/caregiver into the study.

Study Procedures

7) The site notifies the protocol interview team of parent/caregiver enrollment, provides them with the parent/caregiver PID, and preferred pronouns of parent/caregiver and adolescent participant.

8) The interview may be conducted.

12.3.2 Parent/Caregiver Eligibility Confirmation

Per protocol Section 4.5, a parent/caregiver is only eligible for an interview if both the adolescent participant and the parent/caregiver independently report that the parent/caregiver:

• has knowledge of how the adolescent participant tolerated the study product, and • lives with or has regular supportive contact with the adolescent participant.


Having knowledge of how the adolescent participant tolerated the study product is broadly defined and includes being present for study visits in which the injections were given or observing any ways in which participation in the study impacted the adolescent’s daily life. Individuals with regular supportive contact are expected to have daily or near daily interaction with the adolescent that allows them to be aware of the adolescent’s situation, routine, and changes in routine. All eligibility criteria for parents/caregivers must be determined, confirmed and source documented after obtaining consent and prior to enrollment. As noted above and per protocol Section 4.5, some of the parent/caregiver inclusion criteria require reporting from separate individuals. Adolescent participant referral of a potentially eligible parent/caregiver is considered a pre-screening/ recruitment process if provided prior to obtaining consent from the identified parent/caregiver (as will likely be the case for most of adolescent referrals). Therefore, after obtaining parent/caregiver consent, study staff must then reconfirm adolescent participant report of the identified parent/caregiver meeting eligibility criteria (i.e. per protocol Section 4.5.3). Thus, as mentioned above, it is recommended that the parent or legal guardian of the adolescent participant is consented to take part in the parent/caregiver qualitative interview at the time of providing consent for the adolescent to the overall study, even if this parent or legal guardian is not ultimately selected or does not ultimately meet the eligibility criteria to take part in the interview. See Section Appendix 12-2 for suggested source documentation of each parent/caregiver eligibility criteria.

12.3.3 Parent/Caregiver Enrollment and Participant Identification Number Following parent/caregiver consent and once parent/caregiver eligibility has been confirmed, sites should enter the completed eligibility criteria into the SES and the parent/caregiver will be enrolled in the study. Parents/caregivers who have been selected to take part in the qualitative interviews will be assigned a caregiver PID, which is separate from the adolescent PID; the screening and enrollment logs should be updated accordingly. The site should maintain documentation to link the caregiver PID to the corresponding adolescent participant(s) PID.

12.4 Scheduling the Interview

12.4.1 Interview Procedural Windows The qualitative phone interviews will be conducted (separately) with selected adolescent participants and selected parent/caregivers of adolescent participants within the following interview procedural window:

Cohort 1: Between the adolescent participant’s Week 4b and Week 12 visits (inclusive), or during LSFU visits.

Cohort 2: Between the adolescent participant’s Week 24 and Week 96 visits (inclusive), or during LSFU visits.

See Section Appendix 12-3 for both adolescent and parent/caregiver interview windows.

12.4.2 Scheduling Considerations

Upon notification of a participant’s selection, the protocol interview team will work with the site to find appropriate options for the interview within the interview procedural window and ideally based on the


adolescent participant’s in-clinic visit schedule. While interviews may occur from any quiet location, it is preferred that the interview take place while the participant is at the clinic to help ensure privacy, minimal background noise, and a stable phone connection. The participant’s in-clinic scheduled visits must be provided to the protocol interview team, if requested. Other scheduling considerations may include convenience for the adolescent and/or parent/caregiver. Adolescent and parent/caregiver interviewers may be conducted on separate days and in separate locations. Phone interviews scheduled to occur during a study visit should allow sufficient time for the interview and all visit procedures to be completed. If during the Week 4b visit, then the phone interview must be scheduled to occur after administration of the first study product injection. Otherwise, the interview may be scheduled to occur at any timepoint during a visit within the procedural window. Once options for the phone interview are available, the site will contact the participant to:

• Notify the participant of the phone interview selection • Re-confirm the participant’s willingness to take part in the phone interview • Confirm a scheduled date and time for the phone interview to be conducted

All contacts with the participant will be source documented in the participant’s chart, including the re-confirmation of willingness to take part in the phone interview. Site staff will notify the protocol interview team as soon as possible upon scheduling an interview with a study participant. Scheduling Considerations for Parent/Caregiver Interviews Sites will work with the protocol interview team to schedule the phone interview with a selected parent/caregiver throughout the recruitment, consenting and enrollment process to minimize the number of scheduled but uncompleted interviews. Ideally, sites will begin scheduling efforts either after the parent/caregiver has confirmed their intent to provide consent or after consent is obtained. The timing of when scheduling efforts begin with parents/caregivers should consider avoiding the following situations:

• Parents/caregivers enrolling to the study for the qualitative interview but scheduling the interview with the parent/caregiver takes several weeks and the interview is ultimately never conducted. This would lead to enrollments without interview data.

• Spending the time to schedule the interview but the parent/caregiver is ultimately not eligible. This would be a lot of staff effort and time but no interview data.

All parents/caregivers must be enrolled as study participants prior to conducting the interview. Parents/caregivers will be enrolled at sites, but the interview will be conducted by the protocol interview team at CHOP (external to any participating study site), as described above. Sites must notify the protocol interview team when each selected parent/caregiver has been enrolled to the study by providing the parent/caregiver’s PID. Enrollment may occur prior to or after the interview is scheduled but must occur prior to the qualitative interview. An example of this notification is provided in Section Appendix 12-1c. The protocol interview team cannot conduct the interview with the parent/caregiver until this notification has been received. Site staff will also provide the protocol interview team with the adolescent participant’s preferred pronouns (e.g. him/he, her/she, them/they, etc.) to facilitate conducting the interview.


12.5 Prior to the Interview

The protocol interview team will provide the site with the dialing details for the participant to dial into the interview. For interviews scheduled to take place at the site, the site will facilitate the participant dialing into the interview, in a private location with minimal background noise and free from distractions. Sites are encouraged to place a sign on the door for the duration of the interview asking that the participant not be disturbed. Additionally, site staff may offer to keep their cell phone in a safe place for them so that it will not distract them during the interview. In these situations, the participant does not need to receive the dialing details since the site staff will assist with the initial connection before excusing themselves from the private space.

For interviews that are scheduled outside of a study visit and/or not taking place at the research site, the site will provide the dialing details to the participant prior to the scheduled interview. To reduce the possibility of the participant dialing into the phone interview outside of the scheduled interview timeframe, the dialing details will ideally be provided to the participant close to when the interview is scheduled to begin.

Sites will provide additional instructions and guidance to participants after the interview is scheduled and prior to the interview occurring. These instructions include a general description of who is conducting the interview, what information about the participant is already known by the interviewer, and what the participant may expect during the interview. An example script containing all suggested information to be communicated to the participant (either by phone or in person), is provided in Section Appendix 12-4. 12.6 Conducting the Interview All phone interviews will be conducted by a protocol interview team member external to participating clinical research sites. The interview will follow an interview guide which allows for iteration, probing and digression on relevant themes.

12.6.1 Interview Guides The purpose of these guides is to conduct semi-structured individual phone interviews using qualitative data collection techniques. As such, the interviewers may not ask the questions verbatim, all of the questions may not be asked, and probing may be used to collect additional information depending on the responses provided by the study participant during the interview. The goal of the interview is to collect information on the acceptability and tolerability of the long-acting injectable CAB and RPV in adolescents, from the perspective of both the adolescent participants and their parent/caregivers.

Interview guides are available from the Clinical Trials Specialist (CTSs) for submission to site IRBs/ECs. When submitting the guides to IRBs/ECs, sites may find it helpful to include an explanation on the purpose of the guides and how they will be used, as described above. IRB approval of the interview guides is required. IRB approval will also be required should any modifications be made to the content of the guide, such as the addition of different questions. However, IRB approval is not expected or required for any further refinement of the format or instructions to the qualitative interviewers in the guide.

12.6.2 Audio-Recording


All interviews will be audio-recorded and transcribed by an outsourced/external transcription agency. See Section 12.9 below for additional information on management of audio recordings, transcripts, and data security.

12.6.3 Accessing the Interview

The participant or site staff will dial into a toll-free number unique to the IMPAACT 2017 study, which will be provided by the protocol interview team as described above. The interviewer will dial into the toll-free number prior to the start of the scheduled interview to prepare the audio recording. To avoid confusion regarding these administrative tasks and to ensure that the interview phone line is open, participants should ideally dial into the interview as soon as possible at or after the start of the scheduled interview time.

When the participant dials into the toll-free number, the interviewer will provide a brief introduction as stated on the interview guide. After this introduction, and after the participant’s questions are answered, the audio recording will be initiated and the remaining of the interview guide administered.

Site staff designated to receive interview-related communications from the interview team (for scheduling and disclosure of harm purposes) should plan to be available, either at the clinic or immediately reachable by phone, just prior to and for the duration of the scheduled interview time. The protocol interview team will also provide site staff with direct contact information, so the site and the protocol interview team may work together and with the participant if necessary, to address any connectivity issues that may occur during the interview. Participants may be directed to contact the site regarding any connectivity issues, as the protocol interview team will only have contact with participants during the interviews and through the dedicated conference line.

12.7 Missed Interviews Sites and the protocol interview team will communicate as soon as possible after a scheduled interview is missed. All reasonable attempts should be made to ensure interviews occur as scheduled, including reminder calls, following site’s standard procedures for visit-no shows. For those interviews planned to occur at the clinic, site staff will notify the protocol interview team as soon as possible after the participant would have been expected to arrive (after following any standard procedures for handling no-shows or rescheduled visits). For those interviews planned to occur by phone, the protocol interview team should allow participants approximately 10 minutes after the scheduled start time to join, and then should contact the designated site staff to ask that they call the participant to assess if they are able to join the interview. If sites are unable to reach the participant, they should notify the protocol interview team. The protocol interview team must be informed of a missed interview to quickly reschedule within the allowable interview window. Sites must be informed of a missed interview to maintain oversight of study visit procedures being conducted with study participants. The scheduling process described in Section 12.4 above will be repeated to reschedule a missed interview within the allowable interview window. If a participant changes his/her willingness to partake in the interview (i.e. if the participant declines the interview after the interview is scheduled), sites are expected to make every effort to ascertain and document the reason in the participant’s file. Similar to any other study procedure which is declined, sites are expected to counsel the participant on the purpose of the procedure, as appropriate, and answer any questions about the interview the participant may have. If the allowable interview window closes and the interview was unable to be completed, then the interview will be skipped as the participant is no longer eligible for an interview.


12.8 Tracking Interview Completion The protocol interview team will maintain a process of tracking the selection, scheduling, and completion of interviews. The protocol interview team will notify the site of the completed interview, and sites should maintain this notification in participant files. An example of this notification is provided in Section Appendix 12-1d. Sites will then indicate on the Adolescent Study Event Tracking eCRF (SVW10011) that the participant completed the interview. For parent/caregiver interviews, sites will also complete the Parent/Caregiver Student Event Tracking eCRF (SVW10012) to indicate that the interview was completed, and indicate exit from the study using the Discontinuation Log eCRF (ADM10008). 12.9 General Communications and Disclosure of Harm Prior to study activation, sites are required to provide key contact information to the Clinical Trials Specialist(s) regarding:

- Staff designated as the recipient of disclosure of harm communications from the protocol interview team, and immediate contact information, should such disclosure occur during an interview (see below).

- Staff designated as the main point of contact for all qualitative interview activities at the site, including recipient of interview selection and completion notifications, and scheduling communications.

The Clinical Trials Specialist(s) will in turn provide this information to the protocol interview team. Should staff contact information change while qualitative interviews continue to be scheduled and completed with the site’s participants, the updated information must be communicated to the Clinical Trials Specialist(s) as soon as possible. As noted in Section 12.5 above, site staff members designated for contact for disclosure of harm communications and all other qualitative interview activities should be immediately reachable during all scheduled interview times. In general, all PID-specific communications regarding participant selection for an interview and the subsequent scheduling of the interview, as well as the completion notification, will be handled between the site and the protocol interview team. Additionally, any logistical questions pertaining to the interviews may also be directed to the protocol interview team. For questions or guidance relating to protocol requirements, sites should send a query to the IMPAACT 2017 Qualitative Management Team ([email protected]), which consists of the protocol interview team, CTSs, Protocol Data Managers (PDMs), Protocol Statisticians, Protocol Chairs, and Medical Officers. Disclosure of Harm As stated in protocol Section 11.5, participating in the interviews is not expected to increase the likelihood or risk of self-harm or harm to others. During the consent (or assent, as applicable) process, participants will be informed that the information that they provide in the interview will be kept confidential, with the exception of disclosures of significant risk for harm, including being abused or experiencing violence, suicidal ideation, or homicidal ideation.


If at any time during a qualitative phone interview, a participant divulges that s/he is at risk for harm, including but not limited to being abused or experiencing violence, if harm is suspected or likely, or if the participant states s/he is suicidal or homicidal, the following will occur to ensure his or her safety:

• The interviewer will immediately contact the site designee and share any time-sensitive, potentially life-threatening information received from the study participant as part of the phone interview discussions.

• The site designee will follow local policies for management of such situations including engaging immediate/first responders as applicable.

• The site designee will also follow local reporting policies and legal statutes, including reporting to child protection or other appropriate agencies, as well as arranging referrals to appropriate support, counseling or treatment resources.

After the safety of the participant is addressed according to the steps above, the IoR or designee will notify the Clinical Management Committee (CMC) and thoroughly document the event in the participant’s file, and as applicable per Protocol Section 7. In the unlikely event that disclosure of harm as described above should occur, sites should also contact their OCSO Program Officer for guidance on Critical Event reporting.

The site is responsible for CMC notification (see Section 2 of this manual), however the protocol interview team will also contact the CMC as soon as possible to allow for cross-checking of required notifications and reporting. 12.10 Site-Specific Qualitative Interview SOP A sample Qualitative Interview SOP will be provided. At a minimum, each U.S. site’s SOP should include:

• Specification of the site designee responsible for each of the following: o Facilitating the scheduling of interviews with participants o Providing updates to site contact information to the IMPAACT 2017 CTSs, to be

communicated to the protocol interview team o Receiving and managing disclosures of harm that occur during an interview, as

communicated by the protocol interview team • Procedures for confirming parent/caregiver eligibility for interviews • Procedures for consenting parent/caregivers for interviews (if not included in other site

SOPs) • Procedures for enrolling parent/caregivers into the Subject Enrollment System (SES)

prior to the interview, including notification to the protocol interview team • Procedures for communicating with participants prior to the interview, including

specification of what information will be provided • Procedures for participants completing the phone interview in the clinic, including

specification of locations within the clinic where participants will complete the interview • Procedures for missed interviews

12.11 Data Security The transcription company will initially handle the management of the audio recordings to facilitate a rapid turnaround time for the interview transcripts. Names or other identifying information accidentally divulged during the interview will be redacted from the transcripts. The protocol interview team will


ensure accurate transcription of the interviews, including conducting the QA/QC process of the transcripts and the finalized transcripts will and will be linked to the participant only by their PID. The audio files and transcripts will be password protected throughout the management and QA/QC processing. After each transcript is finalized by the protocol interview team, the audio recording and finalized transcript will be securely transferred to the protocol interview team and securely stored and password protected on the CHOP servers. The audio recording and transcript with the external transcription company will be deleted (from primary and back-up servers). The finalized transcriptions of interviews will be uploaded and managed by the protocol interview team at CHOP using a qualitative software package (e.g. NVivo). The DMC will ultimately serve as a repository for the following data, which will be securely transferred by the protocol interview team at CHOP: finalized transcripts, codebook, and output data.


APPENDIX 12-1: SAMPLE EMAIL NOTIFICATIONS Sample 12-1a: Sample email notification of selected adolescent participant

Dear [Designated Site Staff] This email is to let you know that the study participant listed below has been selected to participate in a qualitative telephone interview for IMPAACT 2017. The next steps will be for you to confirm with the participant (1) that he/she remains willing to participate in a telephone interview and (2) that he/she is comfortable with the interview being conducted in English.

PID: Date Enrolled: CRS Number: Cohort: Interview Window Open (date)* Interview Window Closed (date)* *per protocol, the interview must be completed within a specified window of time

If the participant is no longer interested please respond to this email and let us know.

If the participant remains interested, using the dates/times listed below, please schedule a time for the participant to call in for the telephone interview and respond to this email with the selected date/time.

DATE/TIME OF ADOLESCENT INTERVIEW: to be completed by site staff for adolescent participant based on interviewer availability

DATE: _________________________

TIME: _________________________

[INTERVIEWER AVAILABILITY…insert table of dates/times available for interview]

Within __ hours of the scheduled interview, someone from the Qualitative Team will contact you to let you know the disposition of the call (e.g. interview completed, or interview not completed (with additional details)) and any additional follow-up needed from your end. Please print and keep this email with the participant’s files. Feel free to email or call if you have any questions. Sincerely,


Sample 12-1b: Sample email notification of selected parent/caregiver participant

Dear [Designated Site Staff] This email is to let you know that the parent/caregiver of the study participant listed below has been selected to participate in a qualitative telephone interview for IMPAACT 2017. The next steps will be for you to confirm with this parent/caregiver (1) that he/she is willing to participate in a telephone interview and (2) that he/she is comfortable with the interview being conducted in English. If the parent/caregiver is unwilling to participate or unable to complete the interview in English, you may inquire about another eligible/appropriate-for-interview parent/caregiver.

Adolescent PID: Adolescent also selected for interview: Adolescent CRS Number: Interview Window Open (date)* Interview Window Closed (date)*

*per protocol, the interview must be completed within a specified window of time If the parent/caregiver remains interested, please respond to this email embed responses to the questions listed in the green table below.

DATE PARENT/CAREGIVER ENROLLED: DATE: _____________________

PARENT/CAREGIVER PID: PID: _____________________

DATE/TIME OF PARENT/CAREGIVER INTERVIEW: please choose from the dates/times listed below in scheduling the parent/caregiver telephone interview

DATE: _____________________

TIME: _____________________

ADOLESCENT PARTICIPANT’S PREFERRED PRONOUNS: in order for the interview team to appropriately refer to the adolescent during the conversation with the parent/caregiver

she & her he & him they & them other ___________

[INTERVIEWER AVAILABILITY…insert table of dates/times available for interview]

Within __ hours of the scheduled interview, someone from the Qualitative Team will contact you to let you know the disposition of the call (e.g. interview completed, or interview not completed (with additional details)) and any additional follow-up needed from your end. Please print and keep this email with the participant’s files. Feel free to email or call if you have any questions.


Sample 12-1c: Example email notification of parent/caregiver enrollment from site staff to protocol interview team


Sample 12-1d: Example email notification for qualitative interview completion

Dear [Designated Site Staff]

PID: Date Enrolled: CRS Number: Cohort: Sex: Interview Window Open (date)* Interview Window Closed (date)* Date Interview Completed: Time Interview Completed:

*per protocol, the interview must be completed within a specified window of time This email is to let you know that the study participant listed above has

COMPLETED NOT COMPLETED

[add’l details if needed] _________________________________________________

their qualitative telephone interview for the IMPAACT 2017 Study. Thank you for your assistance in coordinating this [adolescent/parent/caregiver’s] participation! Please print and keep this email with the participant’s files. Feel free to email or call if you have any questions. Sincerely,

This info will be filled in from earlier

“PARTICIPANT SELECTED FOR

INTERVIEW” email


APPENDIX 12-2: SUGGESTED SOURCE DOCUMENTATION OF PARENT/CAREGIVER ELIGIBILITY CRITERIA

Eligibility Criteria Suggested Source documentation (after obtaining consent)

4.5.1 Selected by the protocol team for participation in the study

Printed email notification from protocol interview team placed in parent/caregiver file

4.5.2 Willing and able to provide informed (verbal or written) consent for study participation

The consent documentation serves as source

4.5.3 Per the adolescent participant, has knowledge of how the adolescent participant tolerated the study product, and lives with or has regular supportive contact with the adolescent participant

Source documented directly in the parent/caregiver file

4.5.4 Per parent/caregiver self-report, has knowledge of how the participant tolerated the study product, and lives with or has regular supportive contact with the adolescent participant 4.5.5 Willing and able to complete interview in English by phone 4.5.6 (Exclusion criteria) Any condition or social circumstance that, in the opinion of the IoR or designee, would make study participation unsafe for either the parent/caregiver or the adolescent participant, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives


APPENDIX 12-3: INTERVIEW PROCEDURAL WINDOWS

Cohort 1 Adolescent Participant’s Interview Procedural Window

Opens on the day of the adolescent participant’s Week 4b visit (date the adolescent received their first study product injection) Closes on the day of the adolescent participant’s Week 12 visit Opens on the day of the adolescent participant’s LSFU Week 8 visit Closes on the day of the adolescent participant’s LSFU Week 48 visit

Cohort 2 Adolescent Participant’s Interview Procedural Window

Opens on the day of the adolescent participant’s Week 24 visit (date the adolescent received their fourth study product injection) Closes on the day of the adolescent participant’s Week 96 visit (date the adolescent received their 13th study product injection) Opens on the day of the adolescent participant’s LSFU Week 8 visit Closes on the day of the adolescent participant’s LSFU Week 48 visit


Adolescent Participant’s Study Visit Schedule Parent/Caregiver Interview Procedural Window

If a parent/caregiver is selected for a qualitative phone interview during the adolescent’s Cohort 1 Step 2 study visits.

Opens on the day of the adolescent participant’s Week 4b visit (date the adolescent received their first study product injection) Closes on the day of the adolescent participant’s Week 12 visit

If a parent/caregiver is selected for a qualitative phone interview during the adolescent’s Cohort 1 LSFU study visits.

Opens on the day of the adolescent participant’s LSFU Week 8 visit Closes on the day of the adolescent participant’s LSFU Week 48 visit

If a parent/caregiver is selected for a qualitative phone interview during the adolescent’s Cohort 2 Step 4 study visits.

Opens on the day of the adolescent participant’s Week 24 visit (date the adolescent received their fourth study product injection) Closes on the day of the adolescent participant’s Week 96 visit (date the adolescent received their 13th study product injection)

If a parent/caregiver is selected for a qualitative phone interview during the adolescent’s Cohort 2 LSFU study visits.

Opens on the day of the adolescent participant’s LSFU Week 8 visit Closes on the day of the adolescent participant’s LSFU Week 48 visit


APPENDIX 12-4: SAMPLE PRE-INTERVIEW COMMUNICATION

You have been selected to participate in a telephone interview to talk about what it is like for you (your child) to be in this study, how you feel (how your child feels) about getting the medicine shots, your opinions about which adolescents should/should not receive these types of shots in the future, and about the best ways to support adolescents in the future. Here are some important things you should know about your telephone interview:

• You should call in from a private/quiet location. If you want to take the call from the clinic, study staff will help you connect and then will leave you to complete the call in private. We encourage you to take the call from the clinic if you can so that we can help. However, if you want to take the call from home or another location, the call-in details will be provided to you. You can take the call from wherever you want, as long as it is a quiet and private place.

• During the interview, please refrain from texting on your cell phone, or using a computer or other devices, that will distract you from the interview.

• The interview will likely take at least 20 minutes & last no more than 60 minutes

o NOTE: it could take longer if you would like to talk longer about your (your child’s) experience in this study.

• You will speak to one of two interviewers: Liz Lowenthal or Jennifer Chapman. Liz and Jennifer are part of the study team and work at The Children’s Hospital of Philadelphia.

• The interviewers want to hear your honest opinions about your (your child’s) experiences in this study. They do not know who you are and will not need to know your name.

o NOTE: If it makes you more comfortable, you may ask the interviewer to refer to you by a made up name. You may also make up a name for your child to protect your child’s privacy.

• The interview will be recorded and the information will be put into a report about the study.

• No identifying information (including any names you use during the interview) will be included in the interview transcript.

o NOTE: even if you accidentally mention your name or any other identifying information (like the name of a nearby clinic or landmark) during the interview, that information will be removed from the reports.

• Everything that you say during the interview will be kept confidential. That means that the interviewers will not tell anything that you say to anyone at your clinic or to your parents (child) or to anyone else.

o NOTE: There is one important exception to this. If you tell the interviewer that you plan to hurt yourself or someone else or if you tell her that you are being hurt or are at high risk of being hurt by someone else, the interviewer would have to tell someone who could help to keep you safe.

THANK YOU for your participation in this very important study!