neurosurgery-research.redcap.louisville.edu · web viewthe primary objective of this trial is to...

$: neurosurgery-research.redcap.louisville.edu · Web viewThe primary objective of this trial is to demonstrate the safety and clinical effect of a continuous low-dose intravenous unfractionated$
ASTROH Monitoring Plan Data Management and Coordinating Center: University of LouisvilleVersion 1.023 November 2015

DATA MONITORING PLAN

ASTROH

Aneurysmal Subarachnoid Hemorrhage Trial

RandOmizing Heparin

Continuous Low-dose Intravenous Heparin Therapy in Coiled Low-grade Aneurysmal Subarachnoid Hemorrhage patients with Significant Hemorrhage Burden

Version: 1.0

23 November 2015

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Table of Contents

1. INTRODUCTION1.1 Purpose of the Study1.2 Description of the Study Protocol1.3 Purpose of Monitoring Plan

2. Role2.1 Coordinating Center (CC)2.2 Data Monitoring Center (DMC)2.3 Site Principal Investigator2.4 Site Study Coordinator2.5 Blinded Team Members2.6 Biostatistics Team2.7 Core Imaging Lab 2.8 Biomarker Core Lab2.9 Steering Committee

3. Study Database: Electronic Data Capture (EDC) REDCap3.1 Description of REDCap3.2 ASTROH Trial Regulatory Database3.3 ASTROH Subject Database

4. Databases4.1 Regulatory Database4.2 Subject Database

5. Site Initiation

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5.1 Site Start-Up 5.2 Site Training5.3 Patient Enrollment and Randomization5.4 Randomization 24 hour Hotline---

6. Trial Monitoring6.1 Remote, Risk based Monitoring6.2 Data Monitoring 6.3 Source verification6.4 Locking and E-Signing eCRF's6.5 Quarterly Monitoring Reports6.6 Annual Monitoring Reports6.7 On-Site Monitoring

7. Safety7.1 Medical Safety Monitor (MSM)7.2 Clinical Events Committee (CEC)7.3 Data Safety Monitoring Board (DSMB)7.4 Adverse Event (AE) and Serious Adverse Event (SAE) Reporting

8. Compliance8.1 Protocol Deviations (PD)8.2 Management of Non-Compliance

9. Amendments to the Monitoring Plan

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1. Introduction

1.1 Purpose of the Study

The primary objective of this trial is to demonstrate the safety and clinical effect of a continuous low-dose intravenous unfractionated heparin (LDIVH) infusion for the prevention of aneurysmal subarachnoid hemorrhage (aSAH) induced neurocognitive dysfunction. Positive clinical effect will be demonstrated by comparing the mean Montreal Cognitive Assessment (MoCA) obtained at a 90 day follow-up visit between LDIVH treated patients and those patients in the Control arm

1.2 Description of the Study

The ASTROH Study is an Investigator initiated and sponsored, multicenter, prospective, randomized, open-labeled, blinded adjudication phase II study. Study patients randomized to

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the LDIVH arm will receive normal standard of care (SOC) plus continuous low-dose intravenous infusion of UFH for up to 14 days.

The study population will consist of patients with a supratentorial aSAH secondary to a ruptured cerebral aneurysm that has been secured by endovascular coil embolization. Study subjects must score as a WFNS SAH grade < 2 post-coiling with no significant aphasia at the time of enrollment and have a significant hemorrhage burden on the initial head CT scan that demonstrates a modified-Fisher grade = 3.

Subjects will be randomized, 1:1, using a stratified randomized process in an attempt to evenly distribute sex, and the presence of ruptured anterior communicating artery (ACoA) aneurysms among both the LDIVH and control groups. Subject participation in the trial will last approximately 1 year. Data will be collected at various time points throughout subjects' hospitalization, at hospital discharge, day 90 and 1 year follow-up.

Each site will designate a member of their research team to serve as the blinded rater for the day 90 and 1 year follow-up assessments. The blinded rater must not be involved in the subjects care during the initial hospitalization, and must not have knowledge of subjects assigned treatment arm.

1.3 Purpose of Monitoring Plan

The purpose of the monitoring plan is to describe the monitoring method, expectations and requirements for data collection throughout the trial as well as establish guidelines to ensure protocol adherence and trial integrity. The monitoring plan will establish guidelines to ensure compliance with good clinical practice, FDA regulations, Health Insurance Portability and Accountability Act (HIPPA) requirements, and all pertinent government regulations.

2. Roles

2.1 Coordinating Center

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The responsibilities Coordinating Center include, but is not limited to the following:

● Maintain files for each participating site, to include qualifications for their study team members. This file will include, but is not limited to, CV's of key personnel (PI), Good Clinical Practice training and compliance, professional license (if applicable), and other protocol required certifications and/or training certificates, such as NIHSS and modified Rankin certifications.

● Maintain a regulatory file to verify compliance of individual sites regarding Federal Wide Assurance (FWA), CAP and local IRB approvals, continuing review and amendment submission through approval letters and IRB documentation, and laboratory documents (CAP,CLIA).

● Verify proper training of team members as specified by sites' Delegation of Authority Log.● Ensure frequent communication with sites through emails, newsletters, quarterly monitoring

reports, and phone communication as needed.● Develop training documents/videos to ensure proper training for sites participating in the trial.

Training for the ASTROH trial will include, database (REDCap) training, protocol training, and neurological scales training, including MoCA training.

● Supervise protocol development and design, and well as submission and approval.● Submit and obtain approval of protocol amendments and ensure site acknowledge and

compliance.● Communicate DSMB and CEC recommendations/reports/findings to sites on a routine basis.● Maintain accurate and current roster of participating sites, investigators, and study team

members.2.2 Data Monitoring Center (DMC)

The responsibilities of the Data Management Center include, but are not limited to:

● Verify proper EDC (REDCap) training for all trial team members that are assigned the role of data entry on Delegation of Authority Log.

● Collect and manage data collected from all sites to ensure compliance with the protocol. this will include laboratory specimens which will be collected, processed and shipped according to the provided Laboratory Manual.

● Ensure proper specimen collection, processing, storage and shipment. Provide laboratory supplies and instructional material to individual sites. Monitor freezer temperatures of all enrolling site, on a regular basis to ensure proper storage of specimens.

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● Verify adverse events, serious adverse events and protocol deviations are captured and reported in accordance with protocol requirements.

● Verify proper informed consent process.● Monitor Adverse Event reporting and ensure information is disseminated to Clinical Events

Committee and Data Safety Monitoring Board and IRB, as outlined in protocol. ● Monitor and compare uploaded source data with data entered into EDC system. Monitor

submitted subject data for incompleteness and clarity of information. Submit queries for incomplete, missing or inconsistencies between source documentation and eCRF’s.

● Conduct statistical analysis at the completion of the trial.● Communicate DSMB and CEC recommendations/reports/findings to sites on a routine basis, and

per the CEC/DSMB Charters.● Communicate applicable study progress and safety information with the FDA as defined in

21CRF312.32(a)● Submit all final collected subject data for statistical analysis at the completion of the trial.

2.3 Site Principal Investigator

The responsibilities of the Site Principal Investigator include, but are not limited to:

● Ensure the trial is conducted according to the signed Statement of the Investigator (FDA 1572), the protocol, and applicable regulation, as described in 21CRF312.60.

● Supervise the overall conduct of activities at his/her site, including IRB submissions and approvals (21CRF56), protocol adherence, choice of study team members, and regulatory compliance.

● Ensure informed consent is properly obtained in accordance with 21CRF50.● Ensure compliance with Good Clinical Practice Guidelines from everyone delegated to

participate in this trial.● Assign appropriate duties to study team members and ensure they are properly trained for

these duties.● Ensure all adverse events, serious events and protocol deviations are reported to Data

Monitoring Center in accordance with the study protocol, and to local/central IRB per agencies per their respective policies.

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● Ensure study participant safety and protection through appropriate subject selection, and proper informed consent process.

● Oversee the preparation and maintenance of subject documentation and study-related procedures and events, to ensure accuracy of reported data.

2.4 Site Study Coordinator

The responsibilities of the Site Study Coordinator include, but are not limited to:

● Ensure submission of protocol and all subsequent amendments to local/central IRB as well as all reportable AE's, SAE's and PD's according to IRB policies.

● Submit all protocol specified AE's, SAE's and PD to Data Management Center as outlined in the protocol.

● Submit monthly screening log to DMC to include all spontaneous, non-traumatic aSAH presenting to site institution with 24 hours of symptom onset.

● Ensure all data for study timepoints are collected and entered into EDC within 5 days of visit and original source documents are submitted/uploaded for review.

● Ensure proper collection, processing, storage and shipment of subject's plasma and CFS specimens as outlined in the protocol and Laboratory Manual.

● Assist the Principal Investigator with the overall conduct on the study and maintain all required regulatory and study specific documents, such as Delegation of Authority and Screening Logs.

2.5 Blinded Study Member

The responsibilities of the Blinded Study Team Member include, but are not limited to:

● Maintain no involvement with subject or subjects' care/treatment during initial hospitalization.● Conduct 90 day and 1 year follow-up visit and perform all required clinical assessments for the

timepoint.● Complete proper training for MoCA assessment, NIHSS, mRS and ensure familiarity with the

other protocol specified neurological assessments. 2.6 Biostatistics Team

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The responsibilities of the Blinded Study Team Member include, but are not limited to:

● Work with University of Louisville Principle Investigator for data analysis per study protocol.● Descriptive statistics related to the participant characteristics, treatment, and prognostic factors

will be reported. For the continuous variables mean (95% confidence interval), median (minimum and maximum) will be reported and for discrete variables frequency and percentages will be reported.

● For continuous variables a two sample t-test/rank sum test will be used to compare between groups.

● A Chi-square test will be used for establishing association between categorical variables

2.7 Core Imaging Lab

The responsibility of the Core Imaging Lab is as follows, but is not limited to:

● Receive images in DICOM format, for each study subject to verify proper inclusion criteria is met prior to randomization of subjects.

● Maintain DICOM digital copies of study subjects’ images for a minimum of 10 years after study completion

● Communicate with Trial Principal Investigator for any safety concerns or issues with study protocol adherence.

2.8 Biomarker Core Lab

The responsibilities of the Biomarker Core Lab include, but is not limited to:

● Receive and store subject plasma and CSF specimens from sites for up to 10 years after study completion

● Conduct biomarker analysis as outlined in the protocol.● Communicate results of biomarker analysis to ASTROH Trial Principal Investigator and Data

Management and Coordinating Center.

3. Study Database

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3.1 Description of Database (REDCap)

REDCap is a secure web application for building and managing databases and is accessible from any device with internet connectivity. REDCap offers an array of tools including but not limited to: audit trails for tracking data, automated export procedures, customizable data entry forms. More information can be found at www.project-redcap.org.

3.2 Security Information

REDCap has many built-in security features, including authentication of end-users, automatic user logout after periods of inactivity, time-stamped audit trail, and encrypted web-based information transmission.

REDCaps’ auto-logout setting is customizable, the default is 30 minutes. It will log the user out for set periods without activity including clicking, typing, moving the mouse, etc. Another customizable feature is setting the amount of failed login attempts before locking a user out of the system for a set period of time.

REDCap has a built-in audit trail that automatically logs all user activity and logs all pages viewed by every user. Users with proper privileges have access to the audit trails logging record and can view and export the entire audit trail for a project.

3.3 Login Information

REDCap uses a table-based authentication method to validate the identity of end-users that log into the system. The assigned username is unique to each study team member. Each username will have an associated password that is stored in the database table as an encrypted one-way hash of the password. The username and password that is assigned should not be shared among team member or with those outside of the team.

3.4 Data Access

User access within the database will be managed and maintained by the Data Management and Coordinating Center. The user will have access to only the functions granted to them. The functions or rights of users will be managed on three levels:

1. Access to a database

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2. Record access within the database3. User permitted functions within the database

Once logged into REDCap, a site team member will only be given access to their sites information, and in varying levels of access, including no access, view-only access, or edit access.

4. Databases

4.1 ASTROH Trial Regulatory Database

The ASTROH Trial Regulatory Database will contain all site specific documents required for regulatory compliance, including but not limited to the following :

● Delegation of Authority Log● Laboratory Documents● IRB Protocol Approvals● General IRB Approvals● Approved Informed Consents● Approved Partial Waivers

The ASTROH Trial Regulatory Database will also contain the required documents and certifications for each person participating in the ASTROH study at each study site. The training requirements for each member of the site personnel will be dictated by his/her assigned role on the Delegation of Authority Log. These documents include, but are not limited to the following:

● CV● Medical License● CITI Human Subjects Training● CITI GCP Training● HIPPA Research Training● NIHSS certification● mRS training certification● MoCA training certification● RDC training certificate● Protocol training

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The Coordinating Center will maintain the ASTROH Trial Regulatory Database in order to ensure current status of documents and also to gain information that will be included in monitoring reports.

4.2 ASTROH Subject Database

The ASTROH Subject Database is the location where each individual subject's records will be stored. Each subject will be assigned a subject ID, and all records pertaining to that subject will be entered into the corresponding eCRF. Also, all supporting source documents will be uploaded to the subjects file in order for documents to be remotely monitored for source verification and comparison to eCRF's. Queries will be issued for any inconsistent or missing data noted in eCRF's. Queries are to be address within 15 days of being issued.

4.3 ASTROH Training Database

The ASTROH Training Database is the location where specific training for the ASTROH study will be located. The type of training provided includes, but is not limited to the following:

● Protocol Training● MoCA Training● EDC Training

5. Site Initiation

5.1 Site Start-Up Overview

Study start-up will entail everything listed below. The first three can occur in any order, with the following generally happen in the sequence set forth. The Data Management and Coordinating Center will:

1. Negotiate the budget, subcontract, etc. with the site.2. Provide the site with regulatory package which will include the protocol, informed consent

template, etc. to assist with IRB submission.3. Collect required regulatory documents for all study team members.

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4. Provide specified training and collect training certificates for all study team member according to the duties listed on the Delegation of Authority Log.

5. Conduct a Site Initiation Call with sites to review ASTROH study specifics, address areas of concern, and answer questions regarding the ASTROH protocol

6. Issue a letter of release to enroll, once all documents, both regulatory and study specific, are collected and approved

7. Grant access to the ASTROH Subject Database to the study team members who will be entering data, and have completed the proper training

5.2 Site Training and Database Access

After the site has received the regulatory package, and study start-up procedures have begun, the Data Management and Coordinating Center will contact the Lead Coordinator to inquire which study team members will need access to the database. Access to the ASTROH database should be limited to those that will randomize subjects, and those that will be responsible for data entry.

Limited information, such as name and email addresses will be collected for those requiring database access. Database training materials will be sent to appropriate study team member, such as Database Training, Subject Database Training and Protocol training. Documentation of training will occur with a signed certificate of completion, a completed online test, or an uploaded completed from, depending on the specified duties on the Delegation of Authority Log. Training certification will be uploaded and stored on the ASTROH Trial Regulatory Database and a copy should also be kept at local site.

5.3 Patient Enrollment and Randomization

Patient is considered enrolled in the ASTROH study after informed consent has been obtained and the patient has met all enrollment criteria AND has been randomized to a treatment allocation arm. To satisfy inclusion criteria #3 for the ASTROH protocol, uploading images to Core Imaging Lab may be required. Once all required enrollment criteria has been met, the site will enter specific subject inform for baseline data. After answering all inclusion and exclusion data into the ASTROH Subject Database, study personnel will “click” the randomization tab at the bottom of the page. Randomization assignment will then be revealed. If EDC system is not functioning at the time randomization, contact the randomization hotline for manual randomization will be performed by the Data Monitoring Center

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(DMC). DMC will keep a manual randomization table for such occurrence in attempt to keep stratification consistent throughout the trial.

5.4 Randomization Hotline---502-438-8787

6. Trial Monitoring

6.1 Remote/ Risk Based Monitoring

The ASTROH Trial will employ a remote, risk based monitoring approach throughout the trial. This approach allows for subject data to be monitored on a consistent basis, allowing for more efficient and timely review of data. The FDA has encouraged this type of monitoring approach for years, and in August 2013, issued the document Oversight of Clinical Investigations--A Risked-Based Approach to Monitoring, which further clarifies the benefits of risked based,or centralized monitoring. The document points out the FDA’s recommendations as well as encourages sponsors to employ centralized monitoring as it “could improve sponsor oversight of clinical investigations”. Using this approach, it is believed that issues with protocol adherence, GCP and possible patient safety will be readily identified. Data will be reviewed in a frequent and consistent basis throughout the trial sites participating in the ASTROH trial. In the event frequent deviations, missing or inconsistent data are noticed, On-Site monitoring may be employed, which would entail a member of the Data Management and/or Coordinating Team to travel to the site in an effort to clarify data, conduct a thorough review of sites protocol adherence and recommend suggestions to avoid issues in the future. These recommendations may include additional trail for site study team personnel.

Throughout the subject's participation in the ASTROH Trial, all study data will be entered, stored and verified in the ASTROH Subject Database. In order for electronically enter data to be verified remotely, source data must also be uploaded into the ASTROH Subject Database. Source data will be in the form of surveys, electronic medical records, ASTROH bedside worksheets, etc. and will need to be an exact copy of the sites source data. Data will not be redacted or altered in anyway, and may contain subject's personal health information. The use and disclosure of health information is permitted when the covered entity obtains a signed valid Authorization form for the patient or patient's representative that is 45CFR164.508 compliant.

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6.2 Data Monitoring and Querying

Data entry for each subject should be entered within 14 days of subject randomization or study visit, except for rate of LDIVH dose and corresponding aPTT level which should be entered daily. Once data is entered, it will be monitored for accuracy and compared to the corresponding uploaded original source data. If the data entered into the eCRF is verified and found to be complete and accurate, a green check mark will be generated and placed next to the data point, indicating the data for the field is verified. If data entry errors, missing data, or inconsistencies are found, the monitor will issues a query.

Once a query is issued, the site user is expected to respond to the query within 15 working days. To respond to a query, the site user must open the query, and respond with a correction or a confirmation that the information is correct and provide an explanation. The site user will also have the option of uploading/attaching a document to assist with query resolution. Using the Resolve Issues Application in the ASTROH Subject Database, the site use will have the ability to sort through queries. This function will enable the site to view all queries, responded queries, or only outstanding queries.

Once a site has responded to a query, the Data Manager will review the response and either issues a second query to request additional information, or close the query. If query is close, a green check mark will be place next to the data point to signify the data has been verified. Any change to the data, once verified, will generate a red exclamation point next to the altered data. The Data Quality Application will notify the Data Manager of any modification made to the data, once verified. The data revision will then be monitored using the same process, and will need to be verified for accuracy. All data modifications and query communications are tracked in an audit trail which can be retrieved for reference.

The first 2 patients enrolled at each site will be monitored for 100% source verification. If no major findings are found regarding missing data or frequent inconsistencies, monitoring will focus on data points that support the primary and secondary endpoint. Certain data, such as informed consent, inclusion/exclusion criteria and randomization will continue to be monitored for 100% source verification. Thereafter, approximately 20-100% of all additional data points will be monitored for accuracy.

The University of Louisville is the Data Management Center as well as the Coordinating Center for the ASTROH Trial, and will also serve as a clinical site to enroll subjects into the ASTROH study. Subject data

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for those enrolled at the Louisville site will be monitored and if necessary, queried, by a member of the Data Management Center that is not involved in clinical care of patients.

All Identifiable patient data will be stored on REDCap for a period of up to 5 years after study completion. At 5 years or sooner, all patient identifiers will be deleted from the database. Study subjects ID numbers will be maintained. Additionally, at the 5 year point, any upload source documents that are intended to be kept beyond 5 years will have identifiers manually masked.

6.3 Source Verification

All data entered into the ASTROH Subject Database must also have corresponding source data uploaded in the database. This will enable the Data Management Center to verify data is accurate and complete. Source data may originate from various sources, such as electronic medical records, surveys, bedside worksheets, progress notes, etc.,but must include documentation of date and time source was obtained. Electronic source data can be captured by various means, including but not limited to, direct entry of data into the eCRF, transcription of data from paper or electronic source to eCRF, direct transmission from eMR to ECRF, as stated in Guidance to Industry--Electronic Source Data in Clinical Investigation, issued September 2013. Also, if source is a documentation of a conversation or an order, the creator of the source must also sign the written/typed document, as well as include all applicable dates and times.

An exact copy of the subject’s source data should be uploaded. It is extremely important the original source be scanned and uploaded to the ASTROH Subject Database in its entirety, without removal of personal health information.

6.4 Locking and E-Signing eCRFs’

Once the Data Manager has verified data entered into the Subject database, the source associated with the specific eCRF, and discrepancies have been resolved, the corresponding eCRF will be locked. WHen the eCRF’s are lock, they will become”read-only”. Site users will not be able to alter the data at this time, but will be able to view it throughout the trial.

The site Principal Investigator will now be able to e-sign the eCRF’s to confirm that, to the best of his/her knowledge, the information contained in the eCRF is complete and accurate. The e-signature will be 21CFR11 Subpart C compliant and considered the equivalent of an ink signature, for the purpose of the study.

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In the event that the locked eCRF must be modified in any way, the Data Manager will unlock the eCRF and one the data is changed, query will be issued, and once query is addressed, the eCRF will once again be locked and PI will need to again e-sign to signify data accuracy.

6.5 Quarterly Monitoring Report

The Data Monitoring and Coordinating Centers will complete a quarterly monitoring report that will include all site specific activity for the given quarter, including site enrollment, eCRF completion, queries, action items, etc. This report will also address any adverse events and protocol deviation recorded by the site during this period. A copy of this report will be uploaded to the ASTROH Trial Regulatory Database. A copy should also be filed in the sites’ regulatory file for the ASTROH study.

6.6 Annual Monitoring Report

After the sites have been issued four quarterly monitoring reports, an annual monitoring report will be generated. This report will summarize the site activity over the course of the year. Unresolved issues or action items will be listed in this report which will be sent to the Primary Coordinator and the site PI.

6.7 On-Site Monitoring

It is expected that an on-site visit will not routinely be conducted in the course of this trial. In the event of study non-compliance or protocol adherence issues, a member of the Data Management and/or Coordinating Centers will travel to the site and granted permission to view all study and subject records. During this visit, the monitor will attempt to resolve issues and determine the source of the issues, while recommending a plan of improvement.

7. Safety

7.1 Medical Safety Monitor (MSM)

An independent neurocritical care physician will serve as a medical safety monitor for this study. The MSM responsibilities will include reviewing the first 5 patients enrolled and evaluating for any safety issues. The MSM will also provide the immediate evaluation and potential management recommendations for any patient safety concerns as they are raised and as they and as they relate to the study procedures and this protocol. ASTRoH Data Management or Coordinating Center may request the MSM to review any situation for advice on the best approach to maximize patient safety.

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Additionally, individual sites may obtain patient management advice from the MSM for patients enrolled in this study by contacting the MSM directly.

7.2 Clinical events Committee (CEC)

The Clinical Events Committee is comprised of three members, not participating in the trial. The responsibilities of the CEC include, but are not limited to:

● Remain familiar with current study protocol and clinical risk benefit analysis of the study.● Establish (in conjunction with the Sponsor) adverse event adjudication criteria and refine

definitions as necessary during the conduct of the study.● Review and adjudicate relevant events as the occur over the course of the study.● Provide opinions/recommendations concerning aspects of the study that may impact patient

safety if identified.7.3 Data Safety Monitoring Board (DSMB)

The DSMB will meet, periodically, but at least once a year, either in person or virtual, to review the progress of this study as well as the data on the safety of both treatment arms. The responsibility of the DSMB include, but is not limited to:

● Evaluated the progress of the trial, including periodic assessments of the data quality and timelines, participant recruitment, accrual and retention, participate risk versus benefit, performance of the trial sites, and other factors that can affect study outcome.

● Review the research protocol, informed consent documents and plans for data safety and monitoring.

● Consider factors external to the study when relevant information becomes available, such as scientific or therapeutic developments that may have an impact on the safety of the participants or the ethics of the trial.

● Make recommendations to the PI about continuation, termination, or other modifications of the trial based on the observed beneficial or adverse effects of the treatment under study.

● If appropriate, conduct interim analysis of efficacy in accordance with stopping criteria which are clearly defined in advance of data analysis and have the approval of the DSMB.

● Ensure the confidentiality of the data and the results of monitoring.

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● Recommend solutions to address problems with study conduct, enrollment, and sample size and/or data collection.

7.4 Adverse Event and Serious Adverse Event Reporting

All adverse events and adverse drug reactions will be reported in ASTROH Trial Subject Database under appropriate eCRF in REDCap. Adverse events that do not meet the criteria to be considered a serious adverse event should be entered into subject database within 5 working days/7 calendar days of becoming aware of the event.

ALthough this is not always possible, it is preferable the diseases or syndromes br listed as the primary AE within the subject Database, rather than associated signs and symptoms. Adverse events will be collected until study completion.

Adverse events that meet the criteria to be considered serious adverse events or unanticipated events should be reported to the Data Management Center within 24 hours of becoming aware of the event. Reporting on the SAE must be entered into REDCap even if limited information is available at that time, but must also be accompanied by a call to the ASTROH hotline. This call will trigger the Data Monitoring Center to anticipate information. Once a SAE is reported to the ASTROH Adverse Event Reporting System, the project manager monitoring the system will notify the Chair of the Clinical Events Committee. If the SAE is expected, then the SAE will be reviewed by the CEC at the next scheduled meeting. An unexpected SAE will be addressed directly by the CHair of the CEC within 10 business days of notification. If the CEC Chair deems it necessary, he/she may call an impromptu meeting for full CEC review, within an additional 10 days. The CEC may request further information if necessary. An audit trail will be maintained by the Adverse Event Reporting System, for any related communication regarding the event. If the CEC may determine that the SAE requires expedited reporting to the FDA, the Data Management Center will prepare the safety report for submission. The CEC will notify the DSMB if warranted, at which time the DSMB may recommend changes to the protocol or informed consent as a consequence of the serious or unanticipated event.

8. Non-Compliances

8.1 Protocol Deviation (PD) and Major Deviation

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A protocol deviation is any change or departure from the study design or procedure defined in the study protocol. A major deviation is a significant departure from the protocol that impacts the safety of the subject and/or the integrity of the study data. The deviation can stem from non-compliance with GCP guidelines as well as a divergence from the study protocol, and can occur on the part of the subject, Principal Investigator or staff member. The protocol deviation must be reported in the ASTROH Subject Database within 48 hours of becoming aware of the event, and the Data Monitoring Center must also be notified by email. The site is also responsible for reporting the deviation to the appropriate regulatory agency.

8.2 Management of Non-Compliances

The Data Monitoring Center will will manage all issues with non-compliance. If sites fail to complete data in REDCap, answer queries, or respond to issues with protocol adherence or regulatory compliance, a report will be generated and sent to the Lead Coordinator and site Principal Investigator.

If non-compliance issues remain, further action may be taken , which may include suspension from ASTROH study participation until issues are resolved, or termination of the site from participation in the ASTROH study.

Payment milestones are also tied to data completion and query resolution.

Enrollment through Hospital Discharge -50% of agree budget

90 Day follow-up - 33% of agreed budget

1 Year Follow-up - 17% of agreed budget

9. Amendments to the Monitoring Plan

Amendments to the Monitoring Plan will be approved by the Coordinating Center prior to being sent to the participating sites. A Monitoring Plan Signature page will be provide and will need to be signed by both the Primary Coordinator and the Principal Investigator as acknowledgment of the expectation included in the Monitoring Plan

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ASTROH MONITORING PLAN SIGNATURE PAGE

VERSION 1.0

23 November 2015

I acknowledged I have read and understand the information in the Monitoring Plan. I hereby accept the responsibilities for my role in the conduct and data collection for the ASTROH study. I will also inform the study team and anyone else assisting with the ASTROH study at this site, of their obligations and responsibilities contained is the document.

Site Name: ________________________________________________________ Site No.: _________

Name of Principal Investigator: ________________________________________

Signature of Principal Investigator: _____________________________________ Date: ___________

Signature of Primary Coordinator: _____________________________________ Date: ___________

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