clinical study report - eledon...

CLINICAL STUDY REPORT Study Title: Evaluation of safety of repeated doses of OP0201 metered dose

inhaler compared to placebo in healthy adult volunteers

Investigational Product: OP0201 Nasal Aerosol

Indication Studied: Otitis media

Description of Study: A randomized, double-blind, placebo-controlled, parallel-group, dose-escalation study in healthy adult volunteers to evaluate the safety and tolerability of OP0201 administered intranasally 3 times a day (TID) using a metered dose inhaler (MDI) for 14 consecutive days

Name of Sponsor: Novus Therapeutics, Inc.

Protocol Number: OP0201-C-002

Trial Registry Number(s): IND 106778 / NCT03748758

Development Phase: 1

First Subject Entered: 09 November 2018

Last Subject Completed: 19 March 2019

Principal Investigator: Martin Kankam, MD

Altasciences (Vince and Associates Clinical Research) 10103 Metcalf Ave Overland Park, Kansas, 66212 United States (US)

Sponsor Signatory: Janak A. Patel, MD

19900 MacArthur Blvd, Suite 550 Irvine, CA 92612 (949) 238-8090 [email protected]

GCP Compliance: This study was performed in compliance with International Council for Harmonisation (ICH) Good Clinical Practices (GCP), including the archiving of essential documents as well as the ethical principles of the Declaration of Helsinki.

Report Version and Date: Version No. 1.0, 14 November 2019

CONFIDENTIAL

3.0 TABLE OF CONTENTS

1.0 TITLE PAGE ...............................................................................................................1

2.0 SYNOPSIS ....................................................................................................................1

3.0 TABLE OF CONTENTS ............................................................................................2

4.0 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................8

5.0 ETHICS ......................................................................................................................10 5.1 Institutional Review Board ...........................................................................10 5.2 Ethical Conduct of the Study ........................................................................10 5.3 Subject Information and Consent ................................................................10

6.0 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .............................................................................................................11

7.0 INTRODUCTION......................................................................................................13

8.0 STUDY OBJECTIVES AND ENDPOINTS ............................................................15

9.0 INVESTIGATIONAL PLAN ...................................................................................16 9.1 Overall Study Design and Plan: Description ...............................................16 9.2 Discussion of Study Design, Including the Choice of Control

Groups .............................................................................................................17 9.3 Selection of Study Population .......................................................................17

9.3.1 Inclusion Criteria ...............................................................................17 9.3.2 Exclusion Criteria ..............................................................................18 9.3.3 Removal of Subjects from Therapy or Assessment ..........................20

9.4 Treatments ......................................................................................................20 9.4.1 Treatments Administered ..................................................................20 9.4.2 Identity of Investigational Products ...................................................21 9.4.3 Method of Assigning Subjects to Treatment Groups ........................22 9.4.4 Selection of Doses in the Study .........................................................22 9.4.5 Selection and Timing of Dose for Each Subject ...............................23 9.4.6 Blinding and Unblinding ...................................................................23 9.4.7 Prior and Concomitant Therapy ........................................................24 9.4.8 Treatment Compliance ......................................................................24

Sponsor Name: Novus Therapeutics, IncVersion No. 1.0

Protocol No. OP0201-C-00214 November 2019

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9.5 Efficacy, Pharmacokinetic, and Safety Variables .......................................25 9.5.1 Efficacy, Pharmacokinetic, and Safety Measurements,

and Schedule of Assessments ............................................................25 9.5.2 Appropriateness of Measurements ....................................................29 9.5.3 Primary Efficacy Variable(s) .............................................................29 9.5.4 Pharmacokinetic Measurements ........................................................29

9.5.4.1 Pharmacokinetic Measurements ......................................29 9.5.4.2 Pharmacokinetic Parameters ...........................................29

9.5.5 Safety Measurements .........................................................................30 9.5.5.1 Adverse Events ................................................................30 9.5.5.2 Medical Device Incidents (Including

Malfunctions) ..................................................................31 9.6 Data Quality Assurance .................................................................................31 9.7 Statistical Methods Planned in the Protocol and

Determination of Sample Size .......................................................................31 9.7.1 Statistical Analysis Plan ....................................................................31

9.7.1.1 General Approaches ........................................................32 9.7.1.2 Analysis Populations .......................................................32 9.7.1.3 Pharmacokinetic Analysis ...............................................32 9.7.1.4 Safety Analysis ................................................................34

9.7.2 Determination of Sample Size ...........................................................38 9.8 Changes in the Conduct of the Study or Planned Analyses .......................38

9.8.1 Changes in the Conduct of the Study ................................................38 9.8.2 Changes in the Planned Analyses ......................................................38

9.8.2.1 Changes Prior to Breaking the Blind ...............................38 9.8.2.2 Changes Following Study Unblinding ............................39

10.0 STUDY SUBJECTS ...................................................................................................40 10.1 Disposition of Subjects ...................................................................................40 10.2 Protocol Deviations ........................................................................................43 10.3 Data Sets Analyzed ........................................................................................44 10.4 Demographic and Other Baseline Characteristics ......................................44

10.4.1 Demographic Characteristics .............................................................44 10.4.2 Medical and Surgical History ............................................................48 10.4.3 Prior and Concomitant Medications ..................................................48

10.5 Measurements of Treatment Compliance ...................................................48 10.6 Conclusions on Study Subjects .....................................................................49

11.0 PHARMACOKINETIC EVALUATION ................................................................50 11.1 Pharmacokinetic Results ...............................................................................50

11.1.1 Serum Concentration-time Data ........................................................50 11.1.1.1 Serum DPPC Concentration-time Data ...........................50 11.1.1.2 Serum CP Concentration-time Data ................................52

11.1.2 Pharmacokinetic Parameters .............................................................54 11.1.2.1 DPPC Pharmacokinetic Parameters ................................54 11.1.2.2 CP Pharmacokinetic Parameters ......................................54



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11.2 Pharmacokinetic Conclusions .......................................................................55

12.0 SAFETY EVALUATION ..........................................................................................57 12.1 Extent of Exposure .........................................................................................57 12.2 Adverse Events ...............................................................................................58

12.2.1 Brief Summary of Adverse Events ....................................................58 12.2.2 Display of Adverse Events ................................................................59 12.2.3 Analysis of Adverse Events ...............................................................59

12.2.3.1 Overall Incidence of Treatment-Emergent Adverse Events ................................................................59

12.2.3.2 Incidence of Treatment-Emergent Adverse Events by Relationship and Severity to Study Treatment .........................................................................61

12.2.4 Listing of Adverse Events by Subject ...............................................63 12.3 Analysis of Deaths, Other Serious Adverse Events,

Discontinuations due to Adverse Events, and Other Clinically Relevant Adverse Events ...............................................................................63 12.3.1 Listing of Deaths, Other Serious Adverse Events,

Discontinuations due to Adverse Events, and Other Clinically Relevant Adverse Events ..................................................63

12.3.2 Narratives of Deaths, Other Serious Adverse Events, Discontinuations due to Adverse Events, and Adverse Events of Special Interest ..................................................................63

12.3.3 Analysis and Discussion of Deaths, Other Serious Adverse Events, and Other Clinically Relevant Adverse Events ................................................................................................63 12.3.3.1 Deaths ..............................................................................63 12.3.3.2 Other Serious Adverse Events .........................................63 12.3.3.3 Discontinuations Due to Adverse Events ........................63 12.3.3.4 Other Clinically Relevant Adverse Events ......................63

12.4 Clinical Laboratory Evaluation ....................................................................63 12.4.1 Listing of Individual Laboratory Measurements by

Subject and Each Abnormal Laboratory Value .................................63 12.4.2 Clinical Laboratory Values ................................................................64

12.4.2.1 Laboratory Values Over Time .........................................64 12.4.2.2 Individual Clinical Laboratory Abnormalities ................64

12.5 Vital Signs, 12-lead Electrocardiogram, Physical Examination Findings, and Other Observations Related to Safety .................................64 12.5.1 Vital Signs .........................................................................................64 12.5.2 12-lead Electrocardiogram ................................................................65 12.5.3 Physical Examinations .......................................................................65 12.5.4 Other Observations Related to Safety ...............................................66

12.5.4.1 Otoscopy ..........................................................................66 12.5.4.2 Tympanometry ................................................................66 12.5.4.3 Nasal Endoscopy .............................................................66 12.5.4.4 Epipharynx Endoscopy ....................................................67



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12.5.4.5 UPSIT Olfactory Test ......................................................67 12.5.4.6 Audiology Pure Tone Hearing Test .................................69

12.6 Safety Conclusions .........................................................................................69

13.0 DISCUSSION AND OVERALL CONCLUSIONS ................................................71 13.1 Discussion........................................................................................................71 13.2 Overall Conclusions .......................................................................................72

14.0 TABLES, FIGURES, AND GRAPHS ......................................................................73 14.1 Demographic Data .........................................................................................73 14.2 Efficacy Data ..................................................................................................82 14.3 Safety Data ......................................................................................................97

14.3.1 Display of Adverse Events ................................................................97 14.3.2 Listing of Deaths, Other Serious Adverse Events,

Discontinuations due to Adverse Events, and Clinically Relevant Adverse Events .................................................................106

14.3.3 Narratives of Deaths, Other Serious Adverse Events, and Certain Other Clinically Relevant Adverse Events .........................109

14.3.4 Clinical Laboratory Values and Other Safety Assessments .....................................................................................110

14.4 Other Data ....................................................................................................418

15.0 REFERENCE LIST .................................................................................................419

16.0 APPENDICES ..........................................................................................................421



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LIST OF IN-TEXT TABLES

Table 1 Study Objectives and Endpoints ......................................................................15 Table 2 Dose Cohorts and Dose Regimen ....................................................................21 Table 3 Schedule of Assessments .................................................................................26 Table 4 Serum Pharmacokinetic Parameters ................................................................30 Table 5 Disposition and Analysis Sets (Entered Analysis Set) ....................................41 Table 6 Major Protocol Deviations (Safety Analysis Set) ............................................43 Table 7 Demographics and Baseline Characteristics (Safety Analysis Set) .................45 Table 8 Summary of Study Treatment Exposure Compliance (Safety

Analysis Set) ....................................................................................................49 Table 9 Descriptive Statistics of DPPC PK Parameters (Pharmacokinetic

Analysis Set) ....................................................................................................54 Table 10 Descriptive Statistics of CP PK Parameters (Pharmacokinetic

Analysis Set) ....................................................................................................55 Table 11 Study Medication Exposure (Safety Analysis Set) ..........................................57 Table 12 Overview of Incidence of Treatment-Emergent Adverse Events

(Safety Analysis Set)........................................................................................58 Table 13 Incidence of Treatment-Emergent Adverse Events by System

Organ Class and Preferred Term (Safety Analysis Set) ...................................60 Table 14 Incidence of Study Treatment-Related Treatment-Emergent

Adverse Events by System Organ Class and Preferred Term (Safety Analysis Set)........................................................................................62



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LIST OF IN-TEXT FIGURES

Figure 1 Schematic of Study Design ..............................................................................16 Figure 2 Mean (+/- SD) Baseline-corrected DPPC Serum Concentration-

time Profiles (Day 14) on Linear and Semi-logarithmic Scales (Pharmacokinetic Analysis Set) .......................................................................51

Figure 3 Mean (+/- SD) Observed DPPC Serum Concentration-time Profiles (Day 14) on Linear and Semi-logarithmic Scales (Pharmacokinetic Analysis Set) .......................................................................51

Figure 4 Mean (+/- SD) Baseline-corrected CP Serum Concentration-time Profiles (Day 14) on Linear and Semi-logarithmic Scales (Pharmacokinetic Analysis Set) .......................................................................53

Figure 5 Mean (+/- SD) Observed CP Serum Concentration-time Profiles (Day 14) on Linear and Semi-logarithmic Scales (Pharmacokinetic Analysis Set) ....................................................................................................53



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4.0 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS

ABBREVIATIONS

Term/Abbreviation Definition AE Adverse event ALP Alkaline phosphatase ALT Alanine aminotransferase AOM Acute otitis media BLQ Below the limit of quantification BMI Body mass index CI Confidence interval Cmax Maximum baseline-corrected serum concentration CP Cholesteryl palmitate CSP Clinical Study Protocol CV% Coefficient of variation expressed as a percentage DPPC Dipalmitoylphosphatidylcholine ECG Electrocardiogram EaT Early termination ENT Ear, nose, and throat ET Eustachian tube eCRF Electronic Case Report Form FDA Food and Drug Administration GCP Good Clinical Practice GMP Good Manufacturing Practice IB Investigator’s Brochure ICF Informed Consent Form ICH International Council for Harmonisation IP Investigational product IRB Institutional Review Board LLOQ Lower limit of quantification mcg Microgram MDI Metered dose inhaler ME Middle ear OM Otitis media OME Otitis media with effusion PK Pharmacokinetics



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Term/Abbreviation Definition PT Preferred Term RDS Respiratory distress syndrome SAE Serious adverse event SAP Statistical Analysis Plan SD Standard deviation SoA Schedule of Assessments SOC System Organ Class SRC Safety Review Committee tmax Time of maximum baseline-corrected serum concentration (Cmax) TEAE Treatment-emergent adverse event TID Three times a day ULN Upper limit of normal US United States UPSIT University of Pennsylvania Smell Inventory Test

DEFINITION OF TERMS

QT interval The portion of an electrocardiogram between the onset of the Q wave and the end of the T wave



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5.0 ETHICS

5.1 Institutional Review Board The study protocol, all study protocol amendments, written study subject information, Informed Consent Form (ICF), Investigator’s Brochure and any other relevant documents were reviewed and approved by an Institutional Review Board (IRB) at the study center. Details of the IRB consulted during the conduct of this study are provided in Appendix 16.1.3.

5.2 Ethical Conduct of the Study The study was conducted in accordance with the protocol, the ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines, and applicable laws, and regulations.

5.3 Subject Information and Consent An ICF approved by the study center’s IRB was signed by the subject or their legally authorized representative and the authorized person obtaining the informed consent before the subject was entered in the study. A copy of the signed ICF was provided to the subject or their legally authorized representative, and the original was retained by the Investigator. Representative written information for the subject (subject information sheet) and a sample ICF, designated as the master version, is provided in the Trial Master File.



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6.0 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE

This study was conducted by 1 Investigator at 1 study center in the United States (US). A list of Investigators and other important participants in the study and their affiliations are provided in Appendix 16.1.4. Appendix 16.1.5 contains the signatures of the Principal Investigator as well as the signature of the Sponsor’s responsible medical officer, indicating that this Clinical Study Report accurately describes the conduct and results of this study.

Administrative Structure:

Principal Investigator:

Martin Kankam, MD

Altasciences (Vince and Associates Clinical Research) 10103 Metcalf Ave Overland Park, KS, 66212 United States (US)

For details of personnel involved in the study, see Appendix 16.1.4.

Monitoring and Evaluation Committee(s):

After all subjects in Cohort A had completed the Day 14 visit, a Safety Review Committee (SRC) reviewed all of the blinded safety data to determine whether the doses administered were safe and well tolerated. The SRC made a recommendation to escalate to the next cohort (Cohort B).

Details of the SRC decision on dose escalation and the SRC Charter and meeting minutes can be found in Appendix 16.1.13.

Clinical Laboratories:

Labone, LLC DBA Quest Diagnostics 10101 Renner Boulevard Lenexa, KS 66219-9752

Q2 Solutions – Central Laboratories 26081 Avenue Hall Valencia, CA 91355

Metabolon, Inc. 617 Davis Drive, Suite 400 Morrisville, NC 27560



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Contract Research Organization:

IQVIA 4820 Emperor Blvd Durham, NC 27703

Other Organizations:

Not applicable.



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7.0 INTRODUCTION OP0201 Nasal Aerosol (referred herein simply as OP0201) is a novel, intranasal drug device surfactant product being developed by Novus Therapeutics, Inc., for the treatment and prevention of otitis media (OM).

OP0201 is comprised of a 20:1 (weight/weight [w/w]) fixed combination of dipalmitoylphosphatidylcholine (DPPC; a phospholipid surfactant) and cholesteryl palmitate (CP; a neutral phospholipid spreading agent) suspended in propellant (hydrofluroalkane-134a [HFA-134a]). Both DPPC and CP are established endogenous components in human nasal passages, the Eustachian tube (ET), nasopharynx, and respiratory system. The study treatment is delivered as a local treatment through each nostril using a metered dose inhalation (MDI) device. It is sprayed directly backwards into each nostril by way of the anterior nostrils (not upwards towards the osteomeatal opening to the maxillary and ethmoid sinuses as other common intranasal products) towards the lateral wall of the nasal cavity so that the usual nasal mucociliary clearance pathway can facilitate delivery of the study treatment to the ET.

The ET is a compliant liquid-lined tube between the middle ear (ME) and the nasopharynx. The ET serves 3 major physiologic functions: 1) ventilation of the ME to maintain ambient air pressure, 2) clearance of fluid from the ME to nasopharynx, and 3) protection of the ME (Chandrasekhar and Mautone, 2004; Siebert and Danner, 2006). In children, ET dysfunction resulting in inflammation of the ME, referred to as OM, is often triggered by a viral infection of the upper respiratory system (Chonmaitree et al, 2008; Thomas et al, 2014; Schilder et al, 2016). Furthermore, the ET of infants and young children are short, floppy, horizontal, and function poorly, which makes ME fluid flow more challenging (Rosa Olivares et al, 2015; Rovers et al, 2004). A viral infection increases mucus production as well as alters the properties of mucus in the nasopharyngeal region, resulting in diminished normal mucociliary clearance by mucosal cells of the ET and nasopharynx and creating inflammation in the area. This causes dysfunction of the ET leading to negative ME pressure. The presence of viruses and/or bacteria in the ME results in inflammation and build-up of mucus or liquid behind the tympanic membrane (ie, OM). Common forms of OM are acute otitis media (AOM) and otitis media with effusion (OME). Otitis media with effusion is a build-up of mucus/liquid behind the tympanic membrane without symptoms of an ear infection. Often, there are no symptoms of OME; or there are subtle findings (eg, ear rubbing, clumsiness, conductive hearing loss, and disturbed sleep). In contrast, AOM often occurs when bacteria or viruses get trapped in the ME and cause fever, ear pain and active (acute) inflammation. Both AOM and OME are the result of a dysfunctional ET.

Among phospholipid compounds, DPPC is the most hydrophobic and surface active (Notter, 2000; Taeusch et al, 2002). The hydrophobic nature of DPPC causes it to spread very slowly over an aqueous surface. However, in the presence of a spreading agent (ie, CP),



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phospholipids easily “spread” along a surface pressure gradient of mucosal lined lumens (Colacicco and Basu, 1977; Notter, 2000). Together these 2 active ingredients effectively absorb to the mucosal air-liquid interface and reduce the interfacial surface tension of the ET, which reduces passive opening pressure required to open the ET. In other words, DPPC + CP promotes ‘de-sticking’ and restoration of physiologic activity of the ET. In turn, it is hypothesized that acute symptoms of OM will be relieved by providing a physiologic opening to the closed ME space, and, with repeat usage, future OM episodes will be prevented. The surfactant is delivered locally to the nasopharyngeal tissue via the nostrils to reduce the local surface tension and pressure that is preventing the ET from functioning normally. By restoring ET functionality, OP0201 facilitates normal ventilation of the ME, which in turn corrects the negative ME pressure that causes otalgia (ear pain) in patients with AOM. Restoring ET function facilitates ME drainage, which in turn may resolve hearing difficulties in patients with OME. In patients at risk of developing OM, delivering the surfactant to the nasopharyngeal tissue via the nostrils may prevent ET dysfunction and in turn prevent AOM and/or OME.

This Phase 1 safety study was designed to evaluate the safety and tolerability of daily intranasal OP0201 use for 14 consecutive days in 30 healthy adults. This was a randomized, double-blind, placebo-controlled, parallel-group study and included a dose escalation cohort design with evaluation of 30 mg per day (Cohort A) and 60 mg per day (Cohort B) of OP0201.

At the time this study was initiated, no safety and efficacy studies of OP0201 in human subjects had been performed and information regarding expected adverse events (AEs) in humans was not available. However, a limited amount of data from 9 human cases exposed to 1 or more intranasal doses of other formulations of the investigational drug product (DPPC:CP 16:1 w/w and DPPC:CP 200:1 w/w) was available (see Section 5.1.1 of the IB for further information). Following the initiation of this study, Novus completed 2 randomized, double-blind, placebo-controlled single-dose Phase 1 studies in healthy adults (Novus Study OP0201-C-001) and adults with AOM (Novus Study OP0201-C-004). In both studies, the primary objective was to evaluate safety and tolerability of a single 20 mg dose of OP0201. Results of these studies demonstrated a favorable safety and tolerability profile. The safety profile of OP0201 was similar to placebo when administered to healthy adults or adults with AOM.

This study was planned and conducted in accordance with regulatory guidelines and GCP. The Sponsor was to immediately notify the Principal Investigator if any additional safety or toxicology information became available during the study.



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8.0 STUDY OBJECTIVES AND ENDPOINTS

Table 1 Study Objectives and Endpoints

Objectives Endpoints

Primary

• To evaluate the safety and tolerability of OP0201 30 mg per day (given as 2 sprays per nostril TID for 14 consecutive days) and OP0201 60 mg per day (given as 4 sprays per nostril TID for 14 consecutive days) compared with 0 mg placebo (HFA-134a only) administered in a similar parallel-group fashion TID for 14 consecutive days in healthy adult volunteers.

• AEs, otoscopy, tympanometry, nasal and epipharynx endoscopy, UPSIT olfactory test, audiology pure tone hearing test, triplicate 12-lead ECG, physical examination, vital signs, and clinical laboratory tests.

Secondary/Exploratory

• To evaluate if any systemic exposure of DPPC can be detected in serum at levels higher than endogenous DPPC levels in serum in up to 15 healthy adult volunteers evaluated in the Cohort B dose (OP0201 60 mg per day) versus placebo.

• To evaluate if any systemic exposure of CP can be detected in serum at levels higher than endogenous CP levels in serum in up to 15 healthy adult volunteers evaluated in the Cohort B dose (OP0201 60 mg per day) versus placebo.

• Cmax of DPPC on Day 14.

• tmax of DPPC on Day 14.

• Cmax of CP on Day 14.

• tmax of CP on Day 14.

• Additional PK parameters may be calculated, if appropriate.

AE = Adverse event; Cmax = maximum baseline adjusted serum concentration; CP = cholesteryl palmitate; DPPC = dipalmitoylphosphatidylcholine; ECG = electrocardiogram; PK = pharmacokinetic; TID = 3 times a day; tmax = time to maximum concentration; UPSIT = University of Pennsylvania Smell Inventory Test.



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9.0 INVESTIGATIONAL PLAN

9.1 Overall Study Design and Plan: Description This was a Phase 1, randomized, double-blind, placebo-controlled, parallel-group, dose-escalation study in healthy adult volunteers to evaluate the safety and tolerability of OP0201 administered intranasally 3 times a day (TID) compared with a matching placebo (HFA-134a minus active ingredients) administered intranasally TID for 14 consecutive days (see Figure 1 for the study schematic). Study treatment was administered to the subjects by the study center staff. Two dose cohorts were planned (Cohort A and Cohort B; N=15 per cohort, see Cohort Dosing, Table 2) to be enrolled at 1 US study center. Within each cohort, subjects were randomized in a 4:1 ratio to receive either OP0201 or placebo. After all subjects in Cohort A had completed the Day 14 visit, a Safety Review Committee (SRC) reviewed all the blinded safety data to determine whether the doses administered were safe and well tolerated. The SRC made a recommendation to escalate to the next cohort (Cohort B).

A schematic of the study design is included in Figure 1.

Figure 1 Schematic of Study Design

Potential subjects were screened for eligibility during a screening period (Days -28 to -1). Eligible healthy adult volunteers were admitted to the study center on Day -1 and randomized on Day -1. Subjects remained resident at the study center until after all of the Day 15 assessments had been completed (see Table 3 for the Schedule of Assessments [SoA]), with a study exit visit at Day 21.

Copies of the Clinical Study Protocol (CSP) and protocol amendments are provided in Appendix 16.1.1. A sample electronic Case Report Form (eCRF) is provided in Appendix 16.1.2.



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9.2 Discussion of Study Design, Including the Choice of Control Groups This study was designed to evaluate the safety and tolerability of OP0201 versus placebo in healthy adult volunteers using a well-designed, scientific method for comparing treatments (FDA Drug Study Designs - Information Sheet).

The study design was that of a placebo-controlled clinical study that included elements necessary for a valid evaluation of safety and tolerability of repeat OP0201 doses for 14 consecutive days. The study was randomized, and treatment was masked for the Investigator, study center personnel, and the subjects to minimize bias arising from the assignment of subjects to treatment groups and the expectations of subjects, Investigators, and individuals collecting data. A parallel-group design eliminated possible confounding effects that are inherent in other study designs (eg, cross-over).

The placebo (HFA-134a minus active ingredients) was selected as a control arm to evaluate the comparative safety profile of OP0201. HFA-134a was chosen as the placebo control since it is the propellant used in the OP0201 formulation. HFA-134a is used as a propellant in other marketed nasal products and has a good safety and tolerability profile in patients suffering from perennial allergic rhinitis (Weber et al, 2006).

As this study was conducted in healthy adult human subjects, a health benefit to the subject was not expected.

For a discussion on the selection of doses for the study, see Section 9.4.4.

9.3 Selection of Study Population

9.3.1 Inclusion Criteria

Subjects were eligible for inclusion into the study if they met all of the following criteria:

1. Subject had signed an ICF before any study-specific procedures were performed. 2. Male or female healthy volunteers aged 18 to 50 years at the time of signed informed

consent. 3. Able and willing to follow study instructions (including compliance with daily study

treatment administration) and likely to complete all required study visits as assessed by the Investigator’s judgment.

4. Body mass index (BMI) of 18 to 30 kg/m2 (inclusive) and a minimum body weight of 50 kg at Screening.

5. Female subjects had to agree to use an acceptable method of contraception (see Appendix 6 of the CSP in Appendix 16.1.1 for pregnancy considerations and contraceptive requirements).



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6. Female subjects who were of childbearing potential had to have a negative urine pregnancy test result at Screening and Day -1 prior to randomization.

7. Male subjects had to agree to use contraception as detailed in Appendix 6 of the CSP in Appendix 16.1.1 during the treatment period.

8. Subjects had to agree to refrain from immersing their head fully under water (eg, swimming, diving) from the time of signed informed consent until after the study exit visit (Day 21).

9. Physiologic tympanogram classified as Type A (normal) by the Investigator or designee.

9.3.2 Exclusion Criteria

Subjects were excluded from the study if they met any of the following criteria:

1. History or presence of significant medical condition or a clinically significant abnormal finding, as determined by the Investigator. This included study screening results from: a) Medical history b) Physical examination c) Ear, nose, and throat (ENT) examination (ear history, otoscopy, tympanogram, nose

and epipharynx endoscopy) d) University of Pennsylvania Smell Inventory Test (UPSIT) olfactory test e) Audiology pure tone hearing test f) Electrocardiogram (ECG) g) Vital signs measurements h) Clinical laboratory tests

2. Presence of a clinically significant abnormal olfactory test finding at Screening defined as a total UPSIT score

13. Females of childbearing potential who were not willing to use an acceptable method of contraception during the study (see Appendix 6 of the CSP in Appendix 16.1.1).

14. Symptomatic herpes zoster within 12 weeks prior to Screening. 15. Lymphoma, leukemia or any malignancy within the past 5 years except for basal cell or

squamous epithelial carcinomas of the skin that had been resected with no evidence of metastatic disease for 3 years.

16. Breast cancer within the past 10 years. 17. Live vaccine within 30 days prior to Screening or plans to receive such vaccines during

the study. 18. Evidence of craniofacial anomalies (eg, cleft palate, Down’s Syndrome). 19. Disorders with decrease mucociliary clearance or higher viscosity of the mucous (eg,

cystic fibrosis, primary ciliary dyskinesia, Karfagener’s syndrome). 20. Use of any medication (either topically or systemically) for a condition related to the ear

or nose currently or within 12 weeks prior to Screening. 21. Use of medications with known vasoconstrictive properties (eg, local anesthetics,

decongestants) currently or within 2 weeks prior to Screening. 22. Use of medications with known anti-cholinergic side effects (eg, antihistamines,

antiemetics, muscle relaxants, antidepressants) currently or within 6 weeks prior to Screening.

23. Within 7 days prior to the first study treatment administration, use of any prescription drug (except oral contraceptive), nicotine-containing product (including nicotine patch), over-the-counter drug, herbal supplement, vitamin, or dietary supplement with the exception for occasional use of acetaminophen not exceeding 3 g/day.

24. Regular alcohol consumption within 24 weeks prior to Screening defined as an average weekly intake of >21 units for males and >14 units for females; 1 unit was equivalent to 8 g of alcohol (a half pint [approximately 240 mL] of beer, 1 glass [approximately 125 mL] of wine or 1 measure [approximately 25 mL] of spirit).

25. History of drug abuse or positive drug screening test at Screening or Day -1 prior to randomization (see Table 8, Appendix 3 of the CSP in Appendix 16.1.1).

26. Known allergy or sensitivity to the study treatment or any of its components. 27. Exposure to 3 or more new chemical entities within 12 months prior to Screening. 28. Investigator and study center personnel directly affiliated with this study and/or their

immediate families (defined as spouse, significant-other, parent, child, or sibling, whether adopted, or biologic).

29. Persons employed by the Sponsor or Investigator. 30. Persons held in an institution by legal or official order. 31. Concurrent enrollment in an investigational drug or device study other than the research

pertaining to OP0201, or participation in such a study within 30 days of Screening.



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32. Subject had a condition or was in a situation which, in the Investigator's opinion, may have put the subject at significant risk, may have confounded the study results, or may have interfered significantly with the subject's participation in the study.

9.3.3 Removal of Subjects from Therapy or Assessment

Study treatment for any individual subject was to be stopped if the subject experienced a serious adverse event (SAE) or a clinically significant possibly drug-related related AE, which, in the opinion of the study physician, Principal Investigator, or Sponsor’s medical representative, warranted discontinuation of the study for that subject’s wellbeing. See Section 7.1 of the CSP in Appendix 16.1.1 for general discontinuation procedures. Subjects who were discontinued from the study may have been replaced based on the Sponsor’s discretion.

Any female subject who became pregnant while participating in the study was to be withdrawn from the study.

Dose-escalation was to be stopped if any of the study stopping rules were met.

If any of the following scenarios occurred with a reasonable possibility of a causal relationship with the study treatment, the study was to be stopped:

• ≥1 subject experienced SAEs considered to have a reasonable possibility of relationship to the study treatment

• ≥2 subjects experienced non-tolerable AEs that were considered to have a reasonable possibility of relationship to the study treatment

• ≥1 subject receiving study treatment fulfilled Hy’s Law defined as alanine aminotransferase (ALT) >3 × the upper limit of normal (ULN) and bilirubin >2 × ULN in the absence of significant increase in alkaline phosphatase (ALP) and in the absence of an alternative diagnosis that explained the increase in total bilirubin, to be assessed from the first administration of study treatment up to and including follow-up

• ≥2 subjects who received study treatment had >2 ULN of either ALT, bilirubin, or ALP • ≥2 subjects who received study treatment had a QTc prolongation defined as QTcF

>500 ms, or an increase of QTcF >60 ms above baseline on the 12-lead ECG, confirmed (persistent for >5 minutes) on repeated 12-lead ECGs

9.4 Treatments

9.4.1 Treatments Administered

Dose cohorts and dose regimens for this study are presented in Table 2.



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Table 2 Dose Cohorts and Dose Regimen

Cohort Dose Regimen

Cohort Dose Allocation Total Subjects in Each Cohort

Total Subjects Per Dose Group

Per Day Total Dose (mg)

Cumulative Total Dose (mg)

A

2 sprays per nostril TID x 14

days

OP0201 (30 mg)a

placebo (0 mg)

OP0201 (420 mg) a

placebo (0 mg)

15

N=12 (OP0201)

N=3 (placebo)

B

4 sprays per nostril TID x 14

days

OP0201 (60 mg) a

placebo (0 mg)

OP0201 (840 mg) a

placebo (0 mg)

15

N=12 (OP0201)

N=3 (placebo)

N = number of subjects; TID = 3 times a day. a 2.5 mg per spray.

9.4.2 Identity of Investigational Products

The following study treatments were used in this study.

Study Treatment #1: OP0201

OP0201 is a Nasal Aerosol, a dosage form recognized by the US Pharmacopeia, comprised of 2 active ingredients, DPPC and CP, in approximately 20:1 w/w ratio, suspended in HFA-134a propellant. All OP0201 ingredients are synthetic; none of these ingredients contain any animal or human derivatives. OP0201 was supplied in mechanical packing parts that included a pressurized canister with a securely attached metering valve where the study treatment is contained, an actuator into which the canister is seated, the valve connects with device body, and a tip to deliver the study treatment to the nostrils.

OP0201 was manufactured using current Good Manufacturing Practices (GMP) with development phase appropriate compliance with global Health Authority guidelines (eg, US FDA Guidance for Industry: Nasal Spray and Inhalation Solution, Suspension and Spray Drug Products, July 2002) by Sciarra Laboratories, Inc., Hicksville, New Jersey, US. The OP0201 canisters are filled to deliver 100 actuations (sprays) per canister. Each MDI spray of OP0201 delivers 0.1 mL of HFA-134a containing a total of 2.5 mg of the active pharmaceutical ingredients as dry powder suspended in the HFA-134a.



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Batch number(s): OP0201 Cohort A Batch Number: 0002-058 OP0201 Cohort B Batch Number: 0002-062

See the IB for further details regarding OP0201.

Study Treatment #2: Placebo

The placebo was comprised of the same synthetic chlorofluorocarbon-free propellant, HFA-134a, an inactive ingredient as used in the study treatment #1 described above. The placebo is manufactured using GMP with development phase appropriate compliance with global Health Authority guidelines (eg, US FDA Guidance for Industry: Nasal Spray and Inhalation Solution, Suspension and Spray Drug Products, July 2002) by Sciarra Laboratories, Inc., Hicksville, New Jersey, USA. The placebo canisters are filled to deliver 100 actuations (sprays) per canister. Each 0.1 mL MDI spray of placebo delivers 0.1 mL of HFA-134a.

Batch number(s): Placebo Cohorts A and B Batch Number: 0002-060

9.4.3 Method of Assigning Subjects to Treatment Groups

On Day -1, each subject was assigned blinded study treatment, labeled with his/her unique randomization number, that was used throughout the study.

Within each dose cohort, subjects were randomly assigned in a 4:1 ratio to receive OP0201 or placebo. The randomization scheme was prepared by the Sponsor’s designee. A listing including each subject identifier, their randomization code, and treatment assigned is provided in Appendix 16.1.7.

9.4.4 Selection of Doses in the Study

The US FDA agreed that animal toxicology studies with OP0201 were not needed to proceed with evaluating this treatment in humans, since the active ingredients are present in other marketed products and are endogenous to the human respiratory tract. The composition of OP0201 was designed to maximize the lowering of the mucosal surface tension. The 2 active surfactant ingredients in OP0201 effectively absorb the mucosal air-liquid interface and reduce the interfacial surface tension of the ET, which reduces passive opening pressure required to open the ET, promoting ‘de-sticking’ and restoration of physiologic activity of the ET, the target end organ for OP0201 treatment.

Safety and proof of concept results from animal pharmacology studies were considered supportive of the formulation intended for human use. Across several nonclinical pharmacology studies, the beneficial effects of OP0201 were consistently better than those of no treatment and treatment with placebo alone (HFA-134a minus active ingredients) (see IB, Section 4, for more details). A multiple day dose of 20 mg twice daily was given to



22

chinchillas for 10 days. The total exposure was calculated at 400 mg over 10 days; approximately 800 to 1100 mg/kg for a chinchilla weighing 0.35 to 0.5 kg (Chandrasekhar and Mautone, 2004). No AE was observed in any of the animal studies.

The clinical safety and tolerability of OP0201 (DPPC:CP 20:1 w/w, manufactured by Novus Therapeutics, Inc.) for human use was further guided by a limited amount of data from 9 human cases exposed to 1 or more doses of other formulations of the investigational drug product. A total of 8 cases were exposed to DPPC:CP 16:1 w/w in HFA-134a with each 0.1 mL spray delivering 2.5 mg active ingredient. One case was exposed to DPPC:CP 200:1 w/w in HFA-134a, with each 0.1 mL spray delivering 5 mg of active ingredient (see IB, Section 5.1.1).

This Phase 1 safety study was designed to evaluate the safety and tolerability of OP0201 in 30 healthy volunteers. The dosing regimen for each of the 2 dose cohorts evaluated in this study are presented in Table 2. A TID dosing exceeded the anticipated once daily or maximum twice daily dosing interval that may be evaluated in patients in future studies. Because of the endogenous nature of the active ingredients, pharmacokinetic (PK) profiles could not be obtained to guide on dose or dosing interval. Furthermore, the treatment was anticipated to have a local effect on the ET, and thus systemic plasma levels would not necessarily have had relevance. The maximum number of sprays of 4 per nostril to be evaluated also exceeded the anticipated practical maximum number of sprays of 2 per nostril that will be evaluated in patients in future studies. The dose, number of sprays, and dosing interval for this Phase 1 study were chosen because they were anticipated to exceed the total daily dose and dosing schema that will be tested in patients in future studies, and thus establish a high safety threshold.

9.4.5 Selection and Timing of Dose for Each Subject

The study treatment was administered by the study center staff. Subjects received either 2 (Cohort A) or 4 (Cohort B) consecutive sprays first to the left nostril and then to the right nostril for a total of 4 (Cohort A) or 8 (Cohort B) sprays. The dose was repeated 3 times a day for a total of 14 consecutive days (42 doses).

The study treatment was administered approximately every 7 hours: a morning dose at 9:00 am, an afternoon dose at 16:00 pm and an evening dose at 23:00 pm.

9.4.6 Blinding and Unblinding

Study treatment was provided in identical canisters and kits to maintain masking of the study.

A sealed envelope that contained the study treatment assignment for each subject was to be provided to the Investigator. The sealed envelope was to be retained by the Investigator (or representative) in a secured area. In case of an emergency, the Investigator had the sole



23

responsibility for determining if unblinding of a subject’s treatment assignment was warranted. Subject safety had to always be the first consideration in making such a determination. If the Investigator decided that unblinding was warranted, the Investigator was to make every effort to contact the Sponsor and Medical Monitor prior to unblinding a subject’s treatment assignment unless this could delay emergency treatment of the subject. If a subject’s treatment assignment was unblinded, the Sponsor and Medical Monitor had to be notified within 24 hours after breaking the blind. Once the study was complete, all envelopes (sealed and opened) had to be inventoried and returned to the Sponsor or designee.

9.4.7 Prior and Concomitant Therapy

Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or herbal supplements) that the subject received within 7 days before enrollment or received during the study was to be recorded on the eCRF along with:

• Reason for use • Dates of administration including start and end dates • Dosage information including dose and frequency

The Medical Monitor was to be contacted if there were any questions regarding concomitant or prior therapy.

Subjects had to abstain from taking prescription or nonprescription drugs (including vitamins and dietary or herbal supplements) within 7 days or 5 half-lives (whichever was longer) before the start of study treatment until completion of the study exit visit (Day 21). In the case of medications (either topically or systemically) for a condition related to the ear or nose, subjects had to abstain from taking these within 12 weeks before the start of study treatment, or 2 weeks in the case of medications with known vasoconstrictive properties (eg, local anesthetics, decongestants), or 6 weeks in the case of medications with known anticholinergic side effects (eg, antihistamines, antiemetics, muscle relaxants, antidepressants). An exception was that women of childbearing potential may have taken protocol defined acceptable oral contraceptives.

Acetaminophen, at doses of ≤3 g/day, was permitted for use any time during the study. Other concomitant medication may have been considered on a case-by-case basis by the Investigator in consultation with the Medical Monitor (if required).

9.4.8 Treatment Compliance

The prescribed dosage, timing, and mode of administration may not have been changed.

Only subjects entered in the study may have received study treatment and only authorized study center staff may have administered the study treatment to the subject.



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The Investigator or qualified designee recorded each dose by noting the time and total number of sprays administered successfully in a dosing log.

9.5 Efficacy, Pharmacokinetic, and Safety Variables

9.5.1 Efficacy, Pharmacokinetic, and Safety Measurements, and Schedule of Assessments

The Schedule of Assessments (SoA) is presented in Table 3.



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Table 3 Schedule of Assessments

Study Period (with Visit Windows)

Screening Period

Confinement Perioda

(In-Clinic) Study Exit

Days -28 to -1

(Screening) In-Clinic

Day -1

(Admission) Day 1

(Enrollment) Day 4

Day 8

Day 14

Day 15

Day 21 (+5 Day) In-Clinic

EaTb

Informed Consent/Authorization X

Demographics X

Inclusion/Exclusion X X

Pregnancy Test (Urine)c X X X X

Follicle Stimulating Hormone Testd X

Urine Drug Screene X X

Viral Serologyf X

Medical, Surgical, Ear History X

Physical Examinationg X X X

Vital Signsh X X X X X X X X X

12-Lead ECGi X X X X X

Ear History X

Otoscopyj X X X X X

Tympanometry X X X X X Xo Xp

Nasal and Epipharynx Endoscopyk X X X X

Clinical Laboratory Testsl X X X

UPSIT Olfactory Testm X X X Xn X

Audiology Pure Tone Hearing Test X X Xo Xp



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Table 3 Schedule of Assessments

Study Period (with Visit Windows)

Screening Period

Confinement Perioda

(In-Clinic) Study Exit

Days -28 to -1

(Screening) In-Clinic

Day -1

(Admission) Day 1

(Enrollment) Day 4

Day 8

Day 14

Day 15

Day 21 (+5 Day) In-Clinic

EaTb

Admission X

Train Participant on Study Product Administrationq X X

Randomization X

Study Treatmentr X X X X

Concomitant Medications X X X X X X X X X

Adverse Events X X X X X X X X X

PK Sample Collection Xr Xs

Device Experience Questionnaire – Subjectt X X

u

Device Experience Questionnaire – Study Center Staff Administering the Treatmentt

X Xu

EaT = Early termination; ECG = electrocardiogram; CSP = Clinical Study Protocol; IP = investigational product; PK = pharmacokinetic; UPSIT = University of Pennsylvania Smell Inventory Test.

a Eligible healthy volunteers were admitted to the study center on Day -1 and randomized on Day -1. Subjects remained resident at the study center until after all of the Day 15 assessments had been completed.

b EaT: To be performed if the subject was treated but discontinued early from the study. c For all females, urine pregnancy test had to be negative to meet study enrollment criteria. d Performed on postmenopausal women at Screening to confirm menopausal status (see Appendix 6 of the CSP in Appendix 16.1.1). e Specific tests to be conducted were listed in Table 8, Appendix 3 of the CSP in Appendix 16.1.1. f Performed at Screening only (see Table 8, Appendix 3 of the CSP in Appendix 16.1.1).



27

g Included general appearance, overall status of the skin, head, neck, trunk, eyes, heart and lungs (eg, breathing sounds), abdomen, extremities, lymph nodes. Height and weight were recorded only at the Screening visit.

h Vital signs included blood pressure, respiratory rate, pulse rate, and body temperature. i A single 12-lead ECG was collected for screening purposes. For subjects in Cohort A, a single 12-lead ECG was collected on Day 1 prior to the first dose and

on the study exit visit (Day 21). For subjects in Cohort B, triplicate ECGs were collected on Day 1: 30 and 60 minutes prior to the first dose, Day 14: 30 minutes prior to the last dose and 5, 20, 35, 50 minutes following the last dose on Day 14. In cases where ECG and PK sampling overlapped, ECGs were to be collected first, to ensure that PK samples were collected at the scheduled time point.

j Otoscopy involved ear endoscopy, taking a picture of the tympanic membrane and assessing if there were any abnormal findings. k Nasal endoscopy included a measurement of nasal cavity length (in mm) at the Screening visit only. For all other scheduled assessments, the nasal and

epipharynx endoscopy assessment was to be done prior to the first dose of the day. l Included hematology, clinical chemistry, coagulation and urinalysis (see Table 8, Appendix 3 of the CSP in Appendix 16.1.1). m At Screening, a total UPSIT score of ≥35 (for females) and a total UPSIT score of ≥34 (for males) was required to meet study enrollment criteria. n Collected at the Day 21 study exit visit only if abnormal at the Day 14 visit. Abnormal was defined as UPSIT score

9.5.2 Appropriateness of Measurements

All safety assessments used in this study were standard, ie, widely used and generally recognized as reliable, accurate, and relevant.

9.5.3 Primary Efficacy Variable(s)

This was a Phase 1 safety study and there were no efficacy assessments.

9.5.4 Pharmacokinetic Measurements

9.5.4.1 Pharmacokinetic Measurements

Planned time points for blood sample collections to support PK analyses are provided in the SoA.

Collection of Samples

On Days 1 and 14, blood samples were collected for the determination of DPPC and CP concentrations only for subjects in Cohort B. The SoA presents the schedule for blood collection. Time 0 was defined as the time of the study treatment administration.

The timing of scheduled samples may have been adjusted according to clinical needs or needs for PK data. The actual collection times were recorded. The time and date of study treatment administration was also recorded. Instructions for the collection and handling of biological samples was provided by the Sponsor or designee. Blood samples were collected via a venous cannula or direct venipuncture. Samples were collected, labeled, stored, and shipped as detailed in the Laboratory Manual.

Determination of Study Treatment Concentration

Samples for the determination of DPPC in serum were analyzed on behalf of the Sponsor by Q2 Solutions (Ithaca, New York) using appropriate validated bioanalytical methods. Full details of the bioanalytical methods are described in a separate report (Appendix 16.1.14). Samples for the determination of CP in serum were analyzed on behalf of the Sponsor by Metabolon, Inc. (Morrisville, NC) using a proprietary complex lipid platform. Details of the bioanalytical methods are described in a separate report (Appendix 16.1.14).

Baseline samples collected from subjects who received placebo were analyzed to establish the endogenous DPPC and CP concentrations.

9.5.4.2 Pharmacokinetic Parameters

Pharmacokinetic parameters were derived using noncompartmental methods with Phoenix® WinNonlin® Version 8.0 (Certara, L.P. Princeton, New Jersey). Actual elapsed time from



29

dosing and baseline corrected DPPC and CP concentrations was used for the final serum PK parameter calculations.

The PK parameters in Table 4 were determined for serum DPPC and CP on Day 14, when possible.

Table 4 Serum Pharmacokinetic Parameters

Pharmacokinetic Parameter Definition

Cmax Maximum concentration obtained directly from the baseline adjusted concentration versus time data.

tmax Time to Cmax.

Study treatment concentration information that may have unblinded the study were not to be recorded to the study center or study personnel until the study had been unblinded.

9.5.5 Safety Measurements

Planned time points for all safety assessments are provided in the SoA.

The following safety assessments were performed throughout the study (for more details on these assessments, see Section 8.2 of the CSP in Appendix 16.1.1):

• Physical examination • Vital Signs • ECGs • Clinical laboratory assessments • Otoscopy • Tympanometry • Nasal and epipharynx endoscopy • Olfactory test • Audiology pure tone hearing test

9.5.5.1 Adverse Events

The definitions of an AE or SAE can be found in Appendix 4 of the CSP in Appendix 16.1.1.

The Investigator and any designees were responsible for detecting, documenting, and recording events that met the definition of an AE or SAE and remained responsible for following up AEs that were serious, considered related to the study treatment or study procedures, or that caused the subject to discontinue the study treatment or the study (see Section 4.6 and 7.0 of the CSP in Appendix 16.1.1). For the time period and frequency for collecting AE and SAE information, as well as the method of detection, follow-up, and



30

reporting requirements, see Sections 8.3.1 to 8.3.4 of the CSP in Appendix 16.1.1. Details on pregnancies are provided in Section 8.3.5 of the CSP in Appendix 16.1.1.

9.5.5.2 Medical Device Incidents (Including Malfunctions)

Instructions for documenting Medical Device Incidents are provided in Appendix 9 of the CSP in Appendix 16.1.1.

In this study, the study treatment was delivered via a medical device, ie, an MDI. In order to fulfill regulatory reporting obligations worldwide, the Investigator was responsible for the detection and documentation of events meeting the definitions of incident or malfunction that occurred during the study with such devices.

The definition of a Medical Device Incident can be found in Appendix 9 of the CSP in Appendix 16.1.1.

Incidents fulfilling the definition of an AE/SAE were to also follow the processes outlined in Section 8.3.3 and Appendix 4 of the CSP in Appendix 16.1.1.

9.6 Data Quality Assurance Monitoring visits to the study centers were made periodically during the study to ensure that all aspects of the protocol were followed; compared eCRFs against source data for completeness, accuracy, and legibility; monitored for unrecorded SAEs or discontinuations due to AEs; and retrieved completed eCRF segments. Source documents included study treatment dispensing records, subject records, laboratory records, informed consent documentation, eCRFs, and any other study-related document.

No audits were performed during the study. Documentation of inter-laboratory standardization methods and laboratory quality assurance procedures are located in Appendix 16.1.10.

Data from eCRFs were entered and verified with computerized cross-checking edits. Results were checked against predefined ranges to prevent entry of “medically impossible” values.

9.7 Statistical Methods Planned in the Protocol and Determination of Sample Size

9.7.1 Statistical Analysis Plan

This section presents statistical methods used in the analyses as described in the final Statistical Analysis Plan dated 03 April 2019. A detailed documentation of statistical methods is provided in Appendix 16.1.9.



31

9.7.1.1 General Approaches

Derivation of the PK parameters for DPPC and CP in serum was the responsibility of the clinical pharmacokineticist at IQVIA. The PK and safety summaries and data listings as well as the statistical analysis of the PK variables was the responsibility of the study biostatistician at IQVIA.

Some minor modifications may have been necessary to the planned design of tables, figures, and listings to accommodate data collected during the actual study conduct.

All derivations, statistical analyses, summaries, plots, and listings were generated using SAS Version 9.4 (SAS Institute, Inc., Cary, North Carolina). Noncompartmental analysis for PK parameter estimation was performed using Phoenix® WinNonlin® Version 8.0 (Certara, L.P., Princeton, New Jersey). Compliance of SDTM and ADaM datasets to CDISC standards were verified by using the Open CDISC Community tool Version 2.0.1 (Pinnacle 21, Plymouth Meeting, Pennsylvania).

9.7.1.2 Analysis Populations

Entered Analysis Set

The Entered Analysis Set contained all screened subjects who provided informed consent for this study, including screen failure subjects. Subjects in this population were used for the pre-treatment AE listing including SAEs and for the disposition listing and summary. Demographics and eligibility criteria were presented separately for screen failure subjects.

Safety Analysis Set

The Safety Analysis Set contained all subjects who were assigned to study treatment and received at least 1 dose of any study treatment (OP0201 or placebo). Subjects in this population were analyzed according to treatment received and were used for all safety, dosing, and demographic summaries.

Pharmacokinetic Analysis Set

The Pharmacokinetic Analysis Set included all subjects in Cohort B who received at least 1 dose of study treatment (OP0201 or placebo) and had at least 1 quantifiable serum DPPC or CP concentration collected postdose without any important protocol deviations/violations or events thought to significantly affect the PK of DPPC or CP. Subjects in this population were used for all PK analyses and summaries.

9.7.1.3 Pharmacokinetic Analysis

Serum Concentration Data

Subjects with partial data were to be evaluated on a case-by-case basis to determine if sufficient data were available for reliable estimation of PK parameters. If a subject was



32

missing both predose sample collections, their observed concentrations were to be listed and summarized but not included in baseline-corrected listings or summaries.

A listing of PK blood sample collection times as well as derived sampling time deviations was generated.

Baseline-corrected DPPC and CP serum levels were derived by subtracting the mean baseline on Day 1 predose from the observed levels at sample time on Day 14, if possible. If the resulting value was negative, the estimated baseline-corrected level was to be set to zero (0) for purposes of reporting and subsequent analysis.

Observed and baseline-corrected serum concentrations were summarized by treatment using descriptive statistics. Predose and postdose concentrations of DPPC and CP that were below the limit of quantification (BLQ) were to be treated as zero for the computation of descriptive statistics.

A subject listing of all observed and baseline-corrected concentration-time data is presented by treatment. Figures of arithmetic means of observed and baseline-corrected concentration-time data (±SD, as appropriate) are presented by treatment on linear and semi-logarithmic scales. Individual subject observed concentration-time data are graphically presented on linear and semi-logarithmic scales.

Pharmacokinetic Parameters

For PK parameter calculations, if both Day 1 predose samples were missing for a given subject, no PK parameters were to be estimated for this subject. If any predose sample was BLQ, it was to be assigned a numerical value of zero for PK parameter calculations and baseline calculations.

Other BLQ concentrations were to be assigned a value of zero if they preceded quantifiable samples in the initial portion of the profile on Day 14. A BLQ value that occurred between quantifiable data points, especially prior to Cmax, was to be evaluated to determine if an assigned concentration of zero made sense, or if exclusion of the data was warranted. Following Cmax, BLQ values embedded between 2 quantifiable data points were to be treated as zero when calculating PK parameters. If a BLQ value occurred at the end of the collection interval (after the last quantifiable concentration), it was to be set to zero.

The following PK parameters were estimated for serum DPPC and CP by noncompartmental methods using actual elapsed time from dosing:

• Cmax: Maximum baseline-corrected serum concentration (mcg/mL for DCCP, micromolar for CP) obtained directly from the baseline-concentration versus time data

• tmax: Time of maximum baseline-corrected serum concentration (h), obtained directly from the observed baseline-concentration versus time data



33

A subject listing of individual PK parameters was generated. Pharmacokinetic parameters were summarized by treatment using descriptive statistics.

9.7.1.4 Safety Analysis

All outputs for safety outcomes were based on the Safety Analysis Set.

There were no statistical comparisons between the treatment groups for safety data, unless otherwise specified in the relevant section.

Adverse Events

All AE tabulations were performed by treatment and with all active treated subjects combined overall as well as all placebo treated subjects combined from both cohorts displaying the number and percentage of subjects. Incidence of treatment-emergent AEs (TEAEs), defined as AEs that first occurred or worsened in severity after administration of the first dose of study treatment on Day 1, were tabulated as follows:

• Across System Organ Class (SOC) and Preferred Term (PT): all TEAEs, serious TEAEs, TEAEs leading to death or study discontinuation, related TEAEs, serious related TEAEs, and severe TEAEs

• By SOC and PT • By SOC and PT for serious TEAEs • By SOC, PT for TEAEs related to study treatment • By SOC, PT for serious TEAEs related to study treatment • By SOC, PT, and maximum severity • By SOC, PT, and maximum severity for TEAEs related to study treatment

Otoscopy

Individual results of all otoscopy assessments were listed including the result of the overall assessment (Normal or Abnormal) as recorded on the eCRF. The frequencies of overall assessment results as well as the categorical response to each otoscopy variable were tabulated along with the corresponding percentages by visit, ear (left and right) and treatment.

Each otoscopy variable was derived programmatically as Normal or Abnormal according to the following criteria descriptions:

• Contour had the following categories: normal, retracted, full, bulging, perforated, or not assessable. Normal response was interpreted as Normal whereas any other response was interpreted as Abnormal.

• Color had the following categories: normal, partly red, completely red, or not assessable. Normal response was interpreted as Normal whereas any other response was interpreted as Abnormal.



34

• Fluid had the following categories: No or Yes. The interpretation of normal/abnormal was as follows: a response of No was interpreted as Normal, whereas a response of Yes was interpreted as Abnormal. If the response was Yes indicating the presence of fluid behind the tympanic membrane, then the color of fluid was also recorded (yellow, dark red, bright red, green, or clear).

• Translucency had the following categories: translucent, semi-opaque, opaque, or not assessable. The response of translucent was interpreted as Normal whereas other responses were interpreted as Abnormal.

Shifts from baseline to each postbaseline visit were tabulated by ear and treatment for the results of assessments derived above as Normal or Abnormal. The shift tables presented the frequency and the corresponding incidences along with the 95% exact binomial confidence intervals (CIs) for the incidences.

Tympanometry

Tympanometry assessments were listed and tabulated for each ear by visit and treatment based on the Normal or Abnormal tympanogram assessments. Tympanogram overall result was derived programmatically as Normal for Type A assessments and as Abnormal for Type B and Type C assessments. Frequencies of Normal and Abnormal assessments were presented with the corresponding percentages.

A shift table presented the incidence of change from baseline to postbaseline Normal or Abnormal assessments for each ear by visit and treatment along with the corresponding 95% exact binomial CIs.

Nasal and Epipharynx Endoscopy

Results from Nasal and Epipharynx Endoscopy for Normal or Abnormal appearance were listed including the length of nasal cavity (defined as the distance from the tip of the nose to the entry point of the Eustachian tube) for both the left and right nares. Frequencies of results (Normal or Abnormal) for each assessment were tabulated by visit and treatment and were presented along with the corresponding percentages.

A shift table presented the incidence of change in overall result from baseline to postbaseline assessment for each ear by visit and treatment, including the corresponding 95% exact binomial CIs.

Results from Epipharynx Endoscopy (Normal and Abnormal) were listed and tabulated similarly as described above.

Olfactory Test (UPSIT)

The date and time of administration of the UPSIT test were listed along with the test scores. A total UPSIT score of

males. Based on this criterion the Olfactory diagnosis, recorded on the eCRF as Normal or Abnormal, was included in the listing. A shift table presented the incidence of change in diagnosis from baseline to all postbaseline assessments including the corresponding 95% exact binomial CIs. Changes from Normal to Abnormal were also recorded as AEs and were presented in the corresponding listings and summaries as described above.

Audiology Pure Tone Hearing Test

The date and time of audiology pure tone hearing test were listed including the results from each assessment at all tested frequencies. Results from speech audiometry and screening reflex threshold for both ears were listed. The interpretation of the results indicating the extent of hearing loss was also indicated. Frequencies and percentages for each category of hearing loss were tabulated by visit and treatment.

A shift table presented the incidence of change in overall hearing loss from baseline to postbaseline assessments including the corresponding 95% exact binomial CIs.

Laboratory Evaluations

Central laboratory results were included in the reporting of this study for hematology, clinical chemistry, coagulation, and urinalysis. Viral serology, urine drug and alcohol screening, pregnancy and follicle stimulating hormone (FSH) levels were assessed as part of subject screening to determine eligibility. A list of laboratory assessments was included in Table 6, Appendix 3 of the CSP in Appendix 16.1.1. Presentations are in Système international (SI) Units, as provided by the laboratories.

Protocol-specified clinical laboratory tests were summarized using descriptive statistics. Clinical laboratory data collected during study conduct, which were not required per protocol, such as for special testing to further evaluate an AE, were listed separately and not summarized.

Quantitative laboratory measurements recorded as “< X”, ie, BLQ, or “> X”, ie, above the upper limit of quantification (ULQ), were converted to X for the purpose of quantitative summaries, but were presented as recorded, ie, as “< X” or “> X” in the listings.

The following summaries were provided for laboratory data:

• Observed and change from baseline to Day 14 (for quantitative measurements) • Incidence of abnormal values according to normal range criteria • Shift from baseline to Day 14 according to normal range criteria (for quantitative

measurements and categorical measurements)



36

Quantitative laboratory measurements were compared with the relevant laboratory reference ranges and categorized as:

• Low: Below the lower limit of the laboratory reference range • Normal: Within the laboratory reference range (upper and lower limit included) • High: Above the upper limit of the laboratory reference range

Clinical laboratory reference/normal ranges were provided separately and results outside the normal range criteria were flagged as such in the listings.

ECG Evaluations

Results of 12-lead ECG assessments are included in the reporting of this study. For Cohort A the results of ECG results were listed. For triplicate ECG measurements taken for Cohort B the average over the triplicate readings were presented in addition to the individual triplicate assessment results.

The following ECG parameters were recorded for this study (ms): pulse rate (PR), QRS, QT, QTc, QTcF, QTcB, and heart rate (HR) (bpm). The average of triplicate readings in Cohort B were used for summary purposes.

Overall assessment of ECG results (Investigator’s judgment) were recorded as following:

• Normal • Abnormal, Not Clinically Significant (ANCS) • Abnormal, Clinically Significant (ACS)

The following summaries were provided for ECG data:

• Observed and change from baseline (for quantitative measurements and all postbaseline assessments) by visit

• Shift from baseline to postbaseline assessment according to overall assessment of ECG, as judged by the Investigator by visit

Clinically noteworthy quantitative ECG measurements were identified in accordance with the following criteria:

• Observed values for QTcF were classified as:

− >450 ms − >480 ms − >500 ms

• Change from QTcF were classified as:

− >30 ms increase from baseline − >60 ms increase from baseline



37

Vital Signs

The following vital signs measurements were recorded for this study:

• Sitting Systolic and Diastolic Blood Pressure (mm Hg) • Pulse Rate (bpm) • Respiratory Rate (breaths/min) • Temperature (⁰F)

The following summaries were provided by visit and treatment for vital signs data:

• Observed and change from baseline to postbaseline assessments

Physical Examination

Physical examination results were listed including the date and time of assessment, specification of abnormalities, and changes noted from baseline to postbaseline assessment.

9.7.2 Determination of Sample Size

The sample size was not based on statistical considerations, was typical for studies of this nature, and was considered adequate to characterize the distribution of the planned endpoints.

A total of 30 subjects was planned, 2 dose cohorts of 15 subjects each. Within each dose cohort, subjects were randomized in a 4:1 (OP0201:placebo) ratio to receive either OP0201 or placebo.

9.8 Changes in the Conduct of the Study or Planned Analyses

9.8.1 Changes in the Conduct of the Study

The original protocol dated 17 July 2018 was amended once. Amendment 1 was instituted before the first subject was entered. Changes to the protocol included the removal of stratification by gender and updating the Schedule of Assessments with regards to assessments and visits. Copies of the protocol and protocol amendment are provided in Appendix 16.1.1.

9.8.2 Changes in the Planned Analyses

9.8.2.1 Changes Prior to Breaking the Blind

There were no changes made to the planned analyses after the finalization of the Statistical Analysis Plan.



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9.8.2.2 Changes Following Study Unblinding

As per the protocol, blood samples for determining CP serum concentrations were obtained and stored for analysis. Prior to the unblinding of the data, a method for analyzing the CP samples had not yet been identified. After the blind was broken the Sponsor identified a method and analysis of CP levels in subject serum was performed. Subsequently, the database was unlocked to import the results from the CP level determinations so that analysis of the data as described in the SAP could be performed.



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10.0 STUDY SUBJECTS

10.1 Disposition of Subjects Subject disposition is presented in Table 14.1.1 and summarized in Table 5. Subjects who discontinued from the study and the reasons for discontinuation are presented in Listing 16.2.1.1.

A total of 101 subjects were entered into the study at 1 study center in the US; 71 (70.3%) subjects were screen failures. Thirty subjects were randomized and all except 1 subject (Cohort B, Subject 085, placebo) completed treatment. This subject discontinued early due to “other” reasons (family emergency).



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Table 5 Disposition and Analysis Sets (Entered Analysis Set)

Cohort Aa Cohort Ba

Subject Disposition/ Analysis Sets

Overall (N=15)

OP0201 30 mg (N=12)

Placebo (N=3)

Overall (N=15)

OP0201 60 mg (N=12)

Placebo (N=3)

All OP0201 Treated (N=24)

All Placebo Treated (N=6)

All Treated (N=30)

Screened Subjects (N=101)

Number of Subjects n (%):

Entered 101 (100.0%)

Screen failures 71 (70.3%)

Did not meet Incl 03 7 (6.9%)




Did not meet Excl 01 18 (17.8%)





Withdrawal by Subject 4 (4.0%)

Randomized 30 (29.7%)

Not Treated 0 0 0 0 0 0 0 0 0

Treated (Safety Analysis Set)

15 (100.0%) 12 (100.0%) 3 (100.0%) 15 (100.0%) 12 (100.0%) 3 (100.0%) 24 (100.0%) 6 (100.0%) 30 (100.0%)

Completed treatment 15 (100.0%) 12 (100.0%) 3 (100.0%) 14 (93.3%) 12 (100.0%) 2 (66.7%) 24 (100.0%) 5 (83.3%) 29 (96.7%)

Completed Study 15 (100.0%) 12 (100.0%) 3 (100.0%) 14 (93.3%) 12 (100.0%) 2 (66.7%) 24 (100.0%) 5 (83.3%) 29 (96.7%)



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Table 5 Disposition and Analysis Sets (Entered Analysis Set)

Cohort Aa Cohort Ba

Subject Disposition/ Analysis Sets

Overall (N=15)

OP0201 30 mg (N=12)

Placebo (N=3)

Overall (N=15)

OP0201 60 mg (N=12)

Placebo (N=3)

All OP0201 Treated (N=24)

All Placebo Treated (N=6)

All Treated (N=30)

Screened Subjects (N=101)

Prematurely Withdrawn

0 0 0 1 (6.7%) 0 1 (33.3%) 0 1 (16.7%) 1 (3.3%)

Adverse Event 0 0 0 0 0 0 0 0 0

Lost to Follow-up 0 0 0 0 0 0 0 0 0

Protocol Violation 0 0 0 0 0 0 0 0 0

Investigator Decision

0 0 0 0 0 0 0 0 0

Study Terminated by Sponsor

0 0 0 0 0 0 0 0 0

Withdrawal by Subject

0 0 0 0 0 0 0 0 0

Other 0 0 0 1 (100.0%) 0 1 (100.0%) 0 1 (100.0%) 1 (100.0%) Percentages for screen failures, reasons of screen failures, and randomized are based on the number of subjects who entered the study. Percentages for reasons of

premature withdrawal are based on the number of subjects who prematurely withdrew from the study. All other percentages are based on the number of subjects randomized.

MDI = metered dose inhaler. a Cohort A = OP0201 30 mg or placebo administered intranasally (2 sprays per nostril) 3 times a day using an MDI for 14 consecutive days.

Cohort B = OP0201 60 mg or placebo administered intranasally (4 sprays per nostril) 3 times a day using an MDI for 14 consecutive days. Source: Table 14.1.1.



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10.2 Protocol Deviations Listing 16.2.2.1 provides a by-subject list of all protocol deviations. Major protocol deviations are presented in Table 6.

Minor protocol deviations included: study procedures criteria, investigational product (IP) compliance, and laboratory assessment criteria. In most cases the protocol deviation involved the completion of assessments outside the scheduled window.

Two cases of major protocol deviations were recorded in Subjects 066 and 092 (both IP compliance). Neither major protocol deviation was deemed an SAE by the Principal Investigator or Sponsor, and neither was believed to have had an effect on the overall conclusions related to safety or PK.

Table 6 Major Protocol Deviations (Safety Analysis Set)

Cohorta/ Subject ID

Study Day

Deviation Date/Time

Type of Deviation Deviation Recorded Action Taken

Cohort B/066

3 2019-02-07 IP Compliance Day 3, Dose 3 was given incorrectly. Instead of 4 sprays being administered, 4.5 were administered to the subject.

Site was re-trained on the importance of correct dosing. This was a site staff error; a half spray was given in the right nostril during the 4th spray. A CAPA was completed and submitted to the IRB for the overdose. This was not deemed a SAE per the Principal Investigator and Sponsor.

Cohort B/092

13 2019-02-20 IP Compliance Day 13, Dose 2 was given incorrectly. Instead of 4 sprays being administered, 5 were administered to the subject.

Site was re-trained on the importance of correct dosing. This was a site staff error; a half spray was given in the right nostril during the 4th spray. A CAPA was completed and submitted to the IRB for the overdose. This was not deemed a SAE per the Principal Investigator and Sponsor.

Note(s): Protocol deviations listed are as recorded by the study site and clinical team. CAPA = Corrective Action / P

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