Clinical trial NCT02651584
Conditions: Opioid Use Disorders
Sponsor: Braeburn Pharmaceuticals
Start date: 2015-12-01; Completion date: 2016-11-01
Enrollment: 428 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase III, randomized, double-blind, double-dummy, active-controlled, parallel group multi-center trial, designed to evaluate the non-inferiority of CAM2038 compared to an existing standard of care (SL BPN/NX) in initiation and maintenance treatment with BPN.

Detailed description:
This is a Phase III, randomized, double-blind, double-dummy, active-controlled, parallel group multi-center trial, designed to evaluate the non-inferiority of CAM2038 compared to an existing standard of care (SL BPN/NX) in initiation and maintenance treatment with BPN. The trial will involve 4 phases: Screening, Phase 1 (weekly visits), Phase 2 (monthly visits), and Follow-up.

Approximately 380 subjects (190 subjects per arm) will be randomized.

Arms: arm 1: SL BPN/NX: 2 mg/0.5 mg or 8 mg/2 mg BPN/naloxone tablets administered daily, at doses of 8 mg/2 mg to 32 mg/8 mg per day.

CAM2038 placebo: 0.16, 0.32, 0.48 and 0.64 mL SC injection administered once weekly or once monthly (matching volumes for CAM2038 q1w and near-matching volumes for CAM2038 q4w). arm 2: CAM2038 q1w: BPN FluidCrystal® SC injection depot for once weekly administration (50 mg/mL) at doses of 8, 16, 24 or 32 mg (BPN base) (0.16, 0.32, 0.48 or 0.64 mL SC injection).

CAM2038 q4w: BPN FluidCrystal® SC injection depot for once monthly administration (356 mg/mL) at doses of 64, 96, 128 or 160 mg (BPN base) (0.18, 0.27, 0.36 or 0.45 mL SC injection).

SL placebo: tablets matching 2 mg/0.5 mg and 8 mg/2 mg SL BPN doses, administered daily
Interventions: intervention 1: CAM2038 SC injection intervention 2: SL BPN/NX tabs intervention 3: placebo SC injections intervention 4: SL placebo tablets
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_001.pdf: 
Clinical Trial Protocol 
Braeburn Pharmaceuticals
HS-11-421  
CONFIDENTIAL
 
Version: Original v 6.0 03-Nov-2016 
Page 1 of 77
 
 
 
Clinical Trial Protocol  
HS-11-421 
 
A Phase III, Randomized, Double-Blind, Active-Controlled, 
Parallel Group, Multi-center Trial Assessing the Efficacy 
and Safety of a Once-Weekly and Once-Monthly, Long-
Acting Subcutaneous Injectable Depot of Buprenorphine 
(CAM2038) in Treatment of Adult Outpatients with Opioid 
Use Disorder 
CAM2038 50 mg/mL q1w (buprenorphine FluidCrystal® once-weekly 
subcutaneous injection depot) 
CAM2038 356 mg/mL q4w (buprenorphine FluidCrystal® once-monthly 
subcutaneous injection depot) 
IND 114082 
Original Protocol: 19-Oct-2015 
Protocol Amendment 1: 24-Nov-2015 
Protocol Amendment 2: 10-Dec-2015 
Protocol Administrative Change 1: 15-Dec-2015 
Protocol Amendment 3: 18-Feb-2016 
Protocol Administrative Change 2-CORRECTED: 01-Mar-2016 
Protocol Amendment 4: 18-Oct-2016 
Protocol Amendment 5: 03-Nov-2016 
BRAEBURN PHARMACEUTICALS:  
47 Hulfish Street, Suite 441 
Princeton, NJ 08542 
CONFIDENTIAL 
This protocol is the property of Braeburn Pharmaceuticals and is intended solely for the 
guidance of the clinical investigation. This protocol may not—in full or part—be passed on, 
reproduced, published, or distributed to any person or entity who is not bound by written 
confidentiality agreement, for any purpose, without the prior consent of Braeburn 
Pharmaceuticals. 


Clinical Trial Protocol 
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Version: Original v 6.0 03-Nov-2016 
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1. 
SPONSOR AND KEY PERSONNEL CONTACT INFORMATION 
ROLE IN TRIAL  
NAME 
 CONTACT INFORMATION 
Trial Sponsor 
Braeburn 
Pharmaceuticals, Inc. 
47 Hulfish Street, Suite 441 
Princeton, NJ 08542 
 
Sponsor Project Manager 
Sonia Oosman, MS 
Braeburn Pharmaceuticals 
Director, Clinical Operations 
47 Hulfish Street, Suite 441 
Princeton, NJ 08542 
Office: 609-436-9636 
Mobile: 917-399-6987 
E-mail: 
sonia@braeburnpharma.com 
Medical Monitor 
Thomas Thompson, MD 
Senior Medical Director 
Medpace 
5375 Medpace Way 
Cincinnati, OH 45227 
Office: 513-579-9911 ext.1869 
Mobile: 919-602-5726 
E-mail: 
t.thompson1@medpace.com 
CRO Project Manager 
Theresa Veira 
Sr. Clinical Trial Manager 
Medpace 
5375 Medpace Way 
Cincinnati, OH 45227 
Office: 513-579-9911, ext. 2410 
E-mail: t.veira@medpace.com 
Principal Investigator 
Michelle Lofwall, MD 
University of Kentucky Medical 
Center 
845 Angliana Ave 
Lexington, KY 40508 
Office: 859-323-6774 
E-mail: 
michelle.lofwall@uky.edu 


Clinical Trial Protocol 
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Version: Original v 6.0 03-Nov-2016 
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2. 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company: Braeburn Pharmaceuticals 
Name of Investigational Products:  
CAM2038 50 mg/mL q1w (buprenorphine FluidCrystal® once-weekly subcutaneous injection depot) 
CAM2038 356 mg/mL q4w (buprenorphine FluidCrystal® once-monthly subcutaneous injection depot) 
Name of Active Ingredient: Buprenorphine  
Trial Title: 
A Phase III, Randomized, Double-Blind, Active-Controlled, Parallel Group, Multi-center Trial Assessing 
the Efficacy and Safety of a Once-Weekly and Once-Monthly, Long-Acting Subcutaneous Injection 
Depot of Buprenorphine (CAM2038) in Treatment of Adult Outpatients with Opioid Use Disorder 
Objectives: 
The primary objective is to demonstrate non-inferiority of the CAM2038 buprenorphine (BPN) treatment 
arm as compared to the sublingual (SL) BPN treatment arm in treating adult outpatients with opioid use 
disorder, as measured by the primary efficacy measure of response rate (RR). 
The secondary objectives are:  
 
To demonstrate non-inferiority of CAM2038 compared to SL BPN in adult outpatients with 
opioid use disorder, as measured by the secondary efficacy measure of percentage negative 
urines. 
 
To evaluate the efficacy of CAM2038 compared to SL BPN in adult outpatients with opioid use 
disorder, as measured by the secondary efficacy measure of time to sustained abstinence from 
illicit opioid use.  
 
To evaluate the efficacy of CAM2038 compared to SL BPN in adult outpatients with opioid use 
disorder, as measured by the secondary efficacy measure retention rate. 
 
To evaluate the efficacy of CAM2038 compared to SL BPN in adult outpatients with opioid use 
disorder, as measured by the exploratory efficacy measures. 
 
To evaluate the safety of CAM2038 in adult outpatients with opioid use disorder. 
Methodology: 
This is a randomized, double-blind, double-dummy, active-controlled, parallel group multi-center trial, 
designed to evaluate the non-inferiority of CAM2038 compared to an existing standard of care (SL BPN) 
in initiation and maintenance treatment with BPN. The trial will involve 4 phases: Screening, Phase 1 
(weekly visits), Phase 2 (monthly visits), and Follow-up. 
Following Screening and confirmation of eligibility, subjects will be randomized to one of two treatment 
groups in a 1:1 ratio:  
 
Group 1: SL BPN tablets + placebo subcutaneous (SC) injections 
 
Group 2: CAM2038 SC injections + SL placebo tablets 
Following randomization, subjects will undergo initiation of BPN treatment with either SL BPN or SC 
CAM2038 q1w, and participate in weekly visits for 12 weeks (Phase 1). After Week 12, subjects will be 
transitioned to Phase 2 with monthly visits. During Phase 2, subjects in Group 1 will continue treatment 


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Version: Original v 6.0 03-Nov-2016 
Page 4 of 77
 
Name of Sponsor/Company: Braeburn Pharmaceuticals 
Name of Investigational Products:  
CAM2038 50 mg/mL q1w (buprenorphine FluidCrystal® once-weekly subcutaneous injection depot) 
CAM2038 356 mg/mL q4w (buprenorphine FluidCrystal® once-monthly subcutaneous injection depot) 
Name of Active Ingredient: Buprenorphine  
with monthly dispensing of daily SL BPN treatment and monthly placebo SC injections, and subjects in 
Group 2 (receiving CAM2038 q1w) will be transferred to monthly injections of CAM2038 q4w and 
monthly dispensing of daily SL placebo. Subjects will participate in up to 6 visits during the 12 weeks of 
Phase 2; 3 scheduled monthly visits and 3 random urine toxicology visits. At each visit, efficacy and 
safety outcome measures will be assessed. After Phase 2, subjects will be followed-up for 4 weeks. 
A total of 18 opioid urine toxicology samples will be collected during Phase 1 and Phase 2 of the trial, 
whereof 12 samples will be collected at the scheduled weekly visits during Phase 1. A total of 6 opioid 
urine toxicology samples will be collected during the 12 weeks of Phase 2 (3 at the scheduled monthly 
visits and 3 at random urine toxicology visits). A self-report of drug use will accompany every urine 
toxicology test. 
Subjects who complete the 24 weeks of treatment (i.e., Phase 1 and Phase 2) will be transitioned to 
standard of care (e.g., SL BPN) and be followed up for 4 weeks. 
All subjects will be blinded to their treatment group assignment, as will all trial staff with the exception of 
the clinician(s)/staff performing the SC injections and designated personnel who will be responsible for 
drug accountability (i.e., counting the active and placebo SL BPN returned tablets). 
To ensure adequate enrollment and address potential inconvenience to subjects, all subjects (regardless of 
randomized group) will receive appropriate compensation for time and travel expenses related to 
attendance at trial visits. All costs of medications and counseling will also be covered. 
Investigators will be instructed to use manual-guided psychosocial counseling for trial subjects 
throughout the trial period. 
Number of Subjects (Planned):  
Approximately 380 subjects (190 subjects per arm) will be randomized. 
Diagnosis and Main Criteria for Inclusion: 
This trial will enroll adult outpatients with opioid use disorder, as defined by the Diagnostic and 
Statistical Manual of Mental Disorders – Fifth Edition (DSM-V) who are not currently being treated and 
have not been treated with opioid maintenance therapy for the past 60 days before randomization.  
Investigational Product, Dosage and Mode of Administration: 
CAM2038 q1w: BPN FluidCrystal® SC injection depot for once weekly administration (50 mg/mL) at 
doses of 8, 16, 24 and 32 mg (BPN base) (0.16, 0.32, 0.48 or 0.64 mL SC injection). 
CAM2038 q4w: BPN FluidCrystal® SC injection depot for once monthly administration (356 mg/mL) at 
doses of 64, 96, 128 or 160 mg (BPN base) (0.18, 0.27, 0.36 or 0.45 mL SC injection).  
Reference Therapy, Dosage and Mode of Administration: 
Active Comparator 
SL BPN: 2 mg/0.5 mg or 8 mg/2 mg BPN/naloxone tablets administered daily, at doses of 8 mg/2 mg to 
32 mg/8 mg per day.  


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Braeburn Pharmaceuticals
HS-11-421  
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Version: Original v 6.0 03-Nov-2016 
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Name of Sponsor/Company: Braeburn Pharmaceuticals 
Name of Investigational Products:  
CAM2038 50 mg/mL q1w (buprenorphine FluidCrystal® once-weekly subcutaneous injection depot) 
CAM2038 356 mg/mL q4w (buprenorphine FluidCrystal® once-monthly subcutaneous injection depot) 
Name of Active Ingredient: Buprenorphine  
Placebos 
CAM2038 placebo: 0.16, 0.32, 0.48 and 0.64 mL SC injection administered once weekly or once monthly 
(matching volumes for CAM2038 q1w and near-matching volumes for CAM2038 q4w). 
SL placebo: tablets matching 2 mg/0.5 mg and 8 mg/2 mg SL BPN doses, administered daily. 
Duration of Trial: 
Each subject will participate in the trial for up to 31 weeks, including up to 24 weeks of treatment with SL 
BPN or SC CAM2038.  
Criteria for Evaluation: 
Primary Efficacy Variable 
The primary efficacy variable will be the responder rate. The responder rate will be derived based on 
urine samples obtained from Weeks 10, 11, 12 and 13 in Phase 1 and samples obtained at Weeks 17 
(Month 1), 21 (Month 2) and 25 (Month 3) and at the 3 random samples in Phase 2.  
To be a responder for Phase 1, the subject must have no evidence of illicit opioids use at Week 13 and 
have no evidence of illicit opioids use for at least 2 out of the three weeks from Week 10 to Week 12. To 
be a responder for Phase 2, the subject must have no evidence of illicit opioids use at Month 6 (last illicit 
opioids use assessment in Month 6 or Week 25) and have no evidence of illicit opioids use in 5 out of the 
6 illicit opioids use assessments in Phase 2. To be a responder for the study, the subject must be a 
responder for both Phases 1 and 2. 
 
Secondary Efficacy Variables: 
 
Percentage of urine samples negative for illicit opioids (This variable will be defined in the manner 
per EMA’s request.  This variable will serve as the primary efficacy variable for EMA NDA and will 
not be applicable for US NDA submission) 
 
Cumulative Distribution Function (CDF) of percent samples that are negative for illicit opioids 
(Weeks 5-25) 
 
Time to sustained abstinence of opioid use 
 
Percent of subjects remainin in the trial (retention rate) 
 
Exploratory Efficacy Variables: 
 
RR for Phase 1 
 
RR for Phase 2  
 
Percent negative urine samples in Phase 1 
 
Percent negative urine samples in Phase 2 


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Name of Sponsor/Company: Braeburn Pharmaceuticals 
Name of Investigational Products:  
CAM2038 50 mg/mL q1w (buprenorphine FluidCrystal® once-weekly subcutaneous injection depot) 
CAM2038 356 mg/mL q4w (buprenorphine FluidCrystal® once-monthly subcutaneous injection depot) 
Name of Active Ingredient: Buprenorphine  
 
Percent of subjects with evidence of no illicit opioid use by time point 
 
Cumulative percentage of subjects with evidence of no illicit opioid use by time point 
 
Percent of subjects with no self-reported illicit opioid use by time point 
 
Percentage of subjects meeting criteria of stability at Week 13 
 
Measures of opioid craving: 
o 
Desire to Use visual analogue scale (VAS)  
o 
Need to Use VAS 
 
Measures of opioid withdrawal:  
o 
Clinical Opioid Withdrawal Scale (COWS) 
o 
Subjective Opioid Withdrawal Scale (SOWS) 
 
Percentage of subjects without evidence of using other drugs of abuse by time point 
 
Supplemental BPN use  
 
Additional supplemental counseling 
 
Measures of morning need to use/desire to use 
 
Quantity of illicit opioid use 
 
Safety Variables 
Safety data including adverse events, clinical laboratory parameters, electrocardiogram, physical and 
injection site examinations, concomitant medications, vital signs and C-SSRS.  
 
 


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Name of Sponsor/Company: Braeburn Pharmaceuticals 
Name of Investigational Products:  
CAM2038 50 mg/mL q1w (buprenorphine FluidCrystal® once-weekly subcutaneous injection depot) 
CAM2038 356 mg/mL q4w (buprenorphine FluidCrystal® once-monthly subcutaneous injection depot) 
Name of Active Ingredient: Buprenorphine  
Statistical Methods (Data Analysis): 
Primary Efficacy Analysis 
The primary efficacy variable will be the responder rate. The responder rate will be derived based on 
urine samples obtained from Weeks 10, 11, 12 and 13 in Phase 1 and samples obtained at Weeks 17 
(Month 1), 21 (Month 2) and 25 (Month 3) and at the 3 random samples in Phase 2.  
To be a responder for Phase 1, the subject must have no evidence of illicit opioids use at Week 13 and 
have no evidence of illicit opioids use for at least 2 out of the three weeks from Week 10 to Week 12. To 
be a responder for Phase 2, the subject must have no evidence of illicit opioids use at Month 6 (last illicit 
opioids use assessment in Month 6 or Week 25) and have no evidence of illicit opioids use in 5 out of the 
6 illicit opioids use assessments in Phase 2. To be a responder for the study, the subject must be a 
responder for both Phases 1 and 2. 
 
An analysis of non-inferiority in the primary efficacy variable between the two treatment arms will be 
performed using a margin of 13.5% point.  
Non-inferiority will be concluded if the two-sided 95% confidence interval for the difference between the 
probabilities of response (Active- Control) is above –0.135.  The 95% confidence interval, (LB, UB), will 
be derived using normal approximation: 
LB = (PT-PC) – 1.96*(1/NT*PT*(1-PT)+ 1/NC*PC*(1-PC))0.5 , and 
UB = (PT-PC) + 1.96*(1/NT*PT*(1-PT)+ 1/NC*PC*(1-PC))0.5, where 
PT and PC are observed proportions of the responders for the treatment and the control, respectively, and 
NT and NC are the sample sizes for the treatment and the control, respectively. 
Sample Size Calculation 
The primary efficacy variable is based on data from Week 2 to Week 25. Approximately 380 subjects (190 
subjects per arm) will be randomized. 
The sample size of 190 subjects per treatment arm (380 total) was selected to achieve approximately 82% 
power to establish non-inferiority based on the primary efficacy variable, RR (Week 2-25). In the sample 
size calculation, it is assumed that both arms have a 70% RR, and that the non-inferiority margin is 
13.5%. 
 
 


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3. 
TABLE OF CONTENTS 
1. SPONSOR AND KEY PERSONNEL CONTACT INFORMATION 
2 
2. PROTOCOL SYNOPSIS 
3 
3. TABLE OF CONTENTS 
8 
4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
12 
5. INTRODUCTION 
14 
5.1. 
BACKGROUND 
14 
5.1.1. CAM2038 Q1W (ONCE WEEKLY) 
14 
5.1.2. CAM2038 Q4W (ONCE MONTHLY) 
16 
5.1.3. DOSING RATIONALE 
16 
5.2. 
TRIAL RATIONALE 
20 
5.3. 
BENEFIT – RISK ASSESSMENT 
23 
6. TRIAL OBJECTIVES 
25 
6.1. 
PRIMARY OBJECTIVE 
25 
6.2. 
SECONDARY OBJECTIVES 
25 
7. INVESTIGATIONAL PLAN 
26 
7.1. 
OVERALL TRIAL DESIGN AND PLAN 
26 
7.1.1. SCREENING VISIT (WEEK -3 TO WEEK -1) 
28 
7.1.2. PHASE 1 (WEEKLY VISITS) 
28 
7.1.3. PHASE 2 (MONTHLY VISITS) 
32 
7.1.4. FOLLOW-UP PHASE (WEEK 25 TO WEEK 29) 
33 
7.2. 
DISCUSSION OF TRIAL DESIGN 
33 
8. SELECTION OF TRIAL POPULATION 
34 
8.1. 
INCLUSION CRITERIA 
34 
8.2. 
EXCLUSION CRITERIA 
34 
8.3. 
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT 
35 
9. TREATMENTS 
37 
9.1. 
TREATMENT ADMINISTRATION 
37 
9.1.1. PHASE 1 (WEEKLY VISITS) 
37 
9.1.2. PHASE 2 (MONTHLY VISITS) 
38 
9.2. 
IDENTITY OF INVESTIGATIONAL PRODUCTS 
38 
9.2.1. HANDLING, STORAGE, AND ACCOUNTABILITY 
39 
9.2.2. DISPENSING AND ADMINISTRATION 
40 
9.3. 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS 
40 
9.4. 
SELECTION OF DOSES 
41 


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9.5. 
SELECTION AND TIMING OF DOSE 
41 
9.6. 
BLINDING 
41 
9.7. 
PRIOR AND CONCOMITANT THERAPY 
42 
10. TRIAL PROCEDURES AND ASSESSMENTS 
44 
10.1. 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
49 
10.1.1. INFORMED CONSENT 
49 
10.1.2. DEMOGRAPHICS 
49 
10.1.3. MEDICAL HISTORY 
49 
10.1.4. MEDICATION HISTORY 
49 
10.1.5. SUBSTANCE USE AND TREATMENT HISTORY 
49 
10.1.6. CONTRACEPTIVE REQUIREMENTS 
50 
10.2. 
ELIGIBILITY REVIEW AND RANDOMIZATION 
50 
10.3. 
EFFICACY ASSESSMENTS 
50 
10.3.1. URINE TOXICOLOGY SAMPLES FOR OPIOIDS 
50 
10.3.2. SELF-REPORTED ILLICIT DRUG USE 
51 
10.3.3. MEASURES OF DESIRE AND NEED TO USE 
51 
10.3.4. MEASURES OF WITHDRAWAL 
51 
10.3.5. URINE SAMPLES FOR OTHER DRUGS OF ABUSE 
52 
10.3.6. UNSCHEDULED VISITS, MEDICATION AND COUNSELING 
52 
10.3.7. MEASURES OF MORNING DESIRE TO USE/NEED TO USE 
52 
10.4. 
SAFETY ASSESSMENTS 
52 
10.4.1. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
52 
10.4.2. PREGNANCY 
55 
10.4.3. CLINICAL LABORATORY ASSESSMENTS 
55 
10.4.4. VITAL SIGNS 
57 
10.4.5. 12-LEAD ELECTROCARDIOGRAM (ECG) 
57 
10.4.6. C-SSRS 
57 
10.4.7. PHYSICAL EXAMINATION 
58 
10.4.8. INJECTION SITE EXAMINATION 
58 
10.4.9. PSYCHOSOCIAL COUNSELING 
58 
10.4.10. TREATMENT IDENTIFICATION CARD 
58 
10.4.11. OTHER SAFETY CONSIDERATIONS 
58 
10.5. 
APPROPRIATENESS OF MEASURES 
59 
10.6. 
EFFICACY AND SAFETY VARIABLES 
59 
10.6.1. PRIMARY EFFICACY VARIABLE 
59 
10.6.2. SECONDARY EFFICACY VARIABLES 
59 
10.6.3. EXPLORATORY EFFICACY VARIABLES 
60 
10.6.4. SAFETY VARIABLES 
60 
11. DATA QUALITY ASSURANCE 
61 
11.1. 
DATA COLLECTION 
61 
11.2. 
TRIAL AUDITING AND MONITORING 
61 
12. STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
63 
12.1. 
STATISTICAL AND ANALYTICAL PLANS 
63 


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12.2. 
ANALYSIS POPULATIONS 
63 
12.3. 
PLANNED ANALYSES 
63 
12.3.1. DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
63 
12.3.2. ANALYSIS OF EFFICACY MEASURES 
64 
12.4. 
ANALYSIS OF SAFETY 
67 
12.5. 
DETERMINATION OF SAMPLE SIZE 
67 
13. TRIAL ADMINISTRATION AND INVESTIGATOR RESPONSIBILITIES 
70 
13.1. 
REGULATORY AND ETHICAL CONSIDERATIONS 
70 
13.1.1. ETHICAL CONDUCT OF THE TRIAL 
70 
13.1.2. ETHICS APPROVAL 
70 
13.1.3. SUBJECT INFORMED CONSENT 
70 
13.2. 
PRIVACY AND CONFIDENTIALITY 
71 
13.3. 
TRIAL AND SITE CLOSURE 
71 
13.4. 
REGULATORY DOCUMENTS AND RECORDS RETENTION 
72 
13.5. 
DELEGATION OF RESPONSIBILITIES AND ADEQUATE RESOURCES 
72 
13.6. 
PROTOCOL AMENDMENTS 
73 
13.7. 
FINANCIAL DISCLOSURE 
73 
14. SPONSOR APPROVAL PAGE 
74 
15. INVESTIGATOR PROTOCOL AGREEMENT PAGE 
75 
16. REFERENCES 
76 
 
Table of Tables 
TABLE 1 
OBSERVED AND PREDICTED BUPRENORPHINE EXPOSURE AFTER SINGLE 
ADMINISTRATION OF SUBCUTANEOUS CAM2038 Q1W, SUBCUTANEOUS CAM2038 Q4W, 
AND SUBLINGUAL SUBUTEX® IN HEALTHY SUBJECTS 
19 
TABLE 2 
OBSERVED AND PREDICTED BUPRENORPHINE EXPOSURE AFTER STEADY STATE 
ADMINISTRATION OF SUBCUTANEOUS CAM2038 Q1W, SUBCUTANEOUS CAM2038 Q4W, 
AND SUBLINGUAL SUBUTEX® IN HEALTHY SUBJECTS 
19 
TABLE 3 
SCHEDULE OF ASSESSMENTS: SCREENING AND PHASE 1 (WEEKLY VISITS) 
45 
TABLE 4 
SCHEDULE OF ASSESSMENTS: PHASE 2 (MONTHLY VISITS) AND FOLLOW-UP 
47 
TABLE 5 
CLINICAL LABORATORY ASSESSMENTS 
56 
 
Table of Figures 
FIGURE 1 
OBSERVED STEADY STATE ARITHMETIC MEAN CMAX AND CTROUGH OF BUPRENORPHINE 
AFTER SUBLINGUAL ADMINISTRATION OF SUBUTEX®, AND OBSERVED (OBS) AND 
PREDICTED (PRED) STEADY STATE PLASMA CONCENTRATION PROFILES AFTER 
SUBCUTANEOUS ADMINISTRATION OF CAM2038 Q1W AND CAM2038 Q4W BASED ON 
DATA FROM TRIALS HS-11-426 AND HS-13-487 (SEMI-LOGARITHMIC SCALES) 
18 


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FIGURE 2 
PLASMA CONCENTRATION-TIME CURVES OF BUPRENORPHINE AFTER A SINGLE DOSE OF 
8 MG SUBLINGUAL BUPRENORPHINE AND A SINGLE DOSE OF 16 MG SUBCUTANEOUS 
CAM2038 Q1W (ARITHMETIC MEAN ± SD), TRIAL HS-11-426 
20 
FIGURE 3 
OVERVIEW OF TRIAL DESIGN 
27 
FIGURE 4 
OVERVIEW OF INDUCTION PROCEDURES 30 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse event 
AIDS 
Acquired immune deficiency syndrome  
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
AUCinf 
Area under the plasma concentration-time curve from time zero to infinity 
BMI 
Body mass index 
BPN 
Buprenorphine 
CDF 
Cumulative Distribution Function 
CFR 
Code of Federal Regulations 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
COWS 
Clinical Opiate Withdrawal Scale 
CRF 
Case report form (may include electronic data capture systems or paper forms) 
CS 
Clinically significant 
CSA 
Clinical Study Agreement 
Css,av 
Average plasma concentration during a dosing interval at steady state 
Css,max 
Maximum plasma concentration during a dosing interval at steady state 
C-SSRS 
Columbia Suicide Severity Rating Scale 
Css,trough 
Trough plasma concentration during a dosing interval at steady state 
Ct 
Plasma concentration at time t post administration 
Ctrough 
Trough plasma concentration 
CV 
Coefficient of variation 
CYP3A4 
Cytochrome P450 3A4 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
EOT 
End Of Treatment 
FC 
FluidCrystal® 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus 


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ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
Intravenous  
MedDRA 
Medical Dictionary of Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MOP 
Manual of procedures 
NCS 
Not clinically significant 
PT 
Prothrombin time 
QTc 
Fridericia's corrected QT interval 
RBC 
Red blood cell 
RR 
Response rate 
SAE 
Serious adverse event  
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SL 
Sublingual 
SOC 
System Organ Class 
SOWS 
Subjective Opiate Withdrawal Scale 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
VAS 
Visual analogue scale 


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5. 
INTRODUCTION 
5.1. 
Background 
Buprenorphine (BPN) is an opioid with mixed agonist-antagonist properties that, together with 
appropriate counselling and psychotherapy, has been shown to be effective in the treatment of 
opioid dependence. Treatment with BPN has been demonstrated to significantly reduce opioid-
positive urines, i.e., to reduce illicit drug use, and increase retention of patients in outpatient 
treatment programs (1-4). 
CAM2038 (BPN FluidCrystal® [FC] subcutaneous [SC] injection depot) once-weekly (hereafter 
referred to as CAM2038 q1w) and once-monthly (hereafter referred to as CAM2038 q4w) are 
ready-to-use, extended release BPN products developed for opioid dependence treatment with a 
target of once-weekly or once-monthly SC dosing posology, respectively.  
CAM2038 q1w and q4w were developed using the proprietary lipid-based and ambient 
responsive FC Injection depot technology. The principle behind the FC Injection depot is a 
liquid-to-gel phase transition, occurring immediately as the lipid based FC system is exposed to 
in vivo conditions in the SC tissue. The phase transition proceeds from the outside towards the 
center of the injected FC by absorption of minute quantities of water. Thus, injection of 
CAM2038 q1w or q4w into SC tissue results in an immediate and spontaneous formation of 
controlled BPN release matrix providing long-acting release in vivo with a minimum initial burst 
release. The dual nature of the FC system, i.e., a true liquid drug product in vitro before injection 
and stable gel in vivo after injection, enables a ready-to-use drug product in a prefilled syringe. 
CAM2038 q1w and q4w are designed for convenient and safe SC injection using a prefilled 
syringe including a needle safety device and with no need for mixing or temperature adjustment 
prior to administration. In addition, the injection volumes for CAM2038 q1w and q4w are 
relatively low (from 0.15 to 0.6 mL volume, depending on dose and product) and can be 
administered using a fine gauge needle (23 G). CAM2038 depots have been designed with a 
focus on enabling easy administration, dosing flexibility, and importantly, minimizing risks of 
misuse, diversion and poor patient adherence.  
5.1.1. 
CAM2038 q1w (Once Weekly) 
SC CAM2038 q1w has so far been investigated after single and repeated doses in three clinical 
trials, where a total of 176 human subjects (patients and healthy volunteers) have been exposed 
to the CAM2038 drug products. An initial trial assessed pharmacokinetics, pharmacodynamics 
and safety in opioid dependent patients (Trial HS-07-307). The results showed that CAM2038 
q1w was well tolerated, both locally and systemically. Importantly, no treatment emergent 
serious adverse events (SAEs) were observed and drug-related local tolerability findings were 
limited to 4 of 42 patients (9.5%). Three patients experienced mild injection site pain and 
1 patient exhibited transient injection site inflammation (mild) and injection site pruritus 
(moderate).  


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Two additional clinical trials were subsequently performed in healthy volunteers (under 
naltrexone blockade) to assess the pharmacokinetics and bioavailability of single and repeated 
doses of CAM2038 q1w versus repeated doses of sublingual (SL) BPN (i.e., at steady state) and 
single dose of intravenous (IV) BPN (Trials HS-11-426 and HS-13-487). These two trials 
demonstrated that after administration of the studied doses of CAM2038 q1w, the plasma 
concentrations corresponded to those obtained after administration of SL BPN at approved doses 
(i.e., 8 mg, 16 mg, or 24 mg doses). The BPN levels after administration of CAM2038 q1w were 
furthermore similar in healthy volunteers and patients with opioid dependence. The systemic 
tolerability of CAM2038 q1w was good in both trials and similar to the reference products, IV 
and SL BPN. Local tolerability was very good with no local adverse events (AEs) reported in 
Trial HS-11-426 (Nsafety=60) related to injection site tolerability. Similarly, local tolerability of 
CAM2038 q1w was also very good in Trial HS-13-487, featuring 4 repeat SC injections of 
CAM2038 q1w into the buttock site (1 subject reported 1 AE of injection site pain).  
Based on these trials, the following main conclusions were drawn regarding clinical properties of 
CAM2038 q1w:  
 Extended BPN release over one week in target plasma concentrations ranges   
 Dose proportionality and flexible/multiple dosing options 
 6- to 8-fold higher bioavailability versus SL BPN 
 BPN plasma concentrations over 7 days within ranges of those produced by corresponding 
SL BPN doses at steady state (i.e., approved 8 mg, 16 mg, or 24 mg doses), supporting dose 
selection for this Phase III trial 
 Observed and predicted average plasma concentration during a dosing interval at steady state 
(Css,av) and trough plasma concentration during a dosing interval at steady state (Css,trough) 
values for CAM2038 q1w within known therapeutic plasma levels 
 Good safety and systemic tolerability in patients  
 Safety in healthy volunteers comparable to reference IV and SL BPN treatments  
 Good local tolerability in patients and healthy volunteers 
The clinical pharmacokinetic profile and good systemic and local tolerability of CAM2038 q1w 
evidenced in subjects in these 3 trials is also supported by a large body of data generated in non-
clinical pharmacokinetic and toxicology studies in the dog, mini-pig and rat of single and repeat 
SC doses of CAM2038 q1w, including repeat weekly doses of the FC vehicle formulation for 
6 months. SC administration of CAM2038 q1w has been shown to be well tolerated both 
systemically and locally in the non-clinical studies. The treatment-related findings have been 
limited to clinical observations in agreement with and considered related to known 
pharmacological effects of the drug substance BPN, and to reversible, local inflammatory 
reactions at the SC site of injection. The latter findings were similar to the physiological response 
to a foreign body. The FC related injection site findings appeared to be reversible and self-
limiting, and only apparent at the immediate vicinity of test article deposition. In summary, non-
clinical data have indicated no systemic toxicity associated with CAM2038 q1w or the FC 
injection depot vehicle. 


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5.1.2. 
CAM2038 q4w (Once Monthly) 
SC CAM2038 q4w has been investigated in one bridging clinical pharmacokinetic trial in 
healthy volunteers versus repeat dose CAM2038 q1w (i.e., at steady state), repeat dose SL BPN 
(i.e., at steady state), and single dose of IV BPN (Trial HS-13-487). The following conclusions 
can be drawn regarding the clinical properties of CAM2038 q4w:  
 Extended BPN release over 4 weeks at target plasma concentrations   
 6- to 8-fold higher bioavailability versus SL BPN, comparable to CAM2038 q1w 
 BPN plasma concentrations over 4 weeks comparable to CAM2038 q1w over one week, and 
to SL BPN over 24 hours at steady state (i.e., for approved 8 mg, 16 mg, or 24 mg doses), 
supporting dose selection for this Phase III trial 
 Predicted  Css,av and Css,trough values for CAM2038 q4w similar to CAM2038 q1w and SL 
BPN (i.e., for approved 8 mg, 16 mg, or 24 mg doses) 
 Safety profile comparable to reference IV and SL BPN treatments  
 Good local tolerability 
The most commonly reported drug-related AEs after CAM2038 q1w and CAM2038 q4w 
administration were nausea (63% of subjects), dizziness (54% of subjects) and vomiting (39% of 
subjects). The local tolerability was good with 6 subjects experiencing 7 AEs that were assessed 
as related to CAM2038 q4w (injection site reactions, injection site pain, injection site induration 
and application site bruise). Two SAEs were reported by 2 subjects after treatment with 192 mg 
CAM2038 q4w. The first SAE was an event of withdrawal reaction and the second SAE was an 
event of dehydration due to nausea and vomiting. Both SAEs were assessed as related to 
CAM2038 q4w (withdrawal reaction was also assessed as related to the concomitant treatment 
with naltrexone) and the event of withdrawal reaction qualified for reporting as a suspected 
unexpected serious adverse reaction (SUSAR). There were no deaths or any other significant 
AEs and most of the AEs were mild and transient. Analysis of clinical chemistry, hematology 
and urinalysis parameters did not suggest any significant safety issues for CAM2038 q4w. 
The non-clinical assessment of CAM2038 q4w and the FC vehicle, supported by publically 
available data for the drug substance BPN, and for the components of the vehicle, suggests safe 
use of CAM2038 q4w for the proposed clinical development. This conclusion is further 
supported by results from non-clinical studies and clinical trials of the once weekly product, 
CAM2038 q1w, comprising the same active substance and functional lipid components.   
Additional information about CAM2038 can be found in the current version of the Investigator’s 
Brochure. 
5.1.3. 
Dosing Rationale 
In this Phase III trial, several dose levels of the weekly product CAM2038 q1w, the monthly 
product CAM2038 q4w and the daily product SL BPN (administered as Subutex®) will be 
investigated. Figure 1 A-C presents observed and/or predicted BPN exposure after steady state 
administration of CAM2038 q1w and CAM2038 q4w SC injections and SL BPN at comparable 
dose levels in healthy volunteers under naltrexone blockade. Table 1 and Table 2 summarize 
observed and predicted BPN exposure after single (Table 1) and repeat administration (Table 2) 


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of the products. Although there are inherent differences in the pharmacokinetic profiles for daily, 
weekly and monthly administered products, the results presented in Figure 1 A-C demonstrate 
that the pharmacokinetic profiles of the CAM2038 q1w and q4w formulations are similar with 
respect to steady state maximum plasma concentration (Cmax) and trough plasma concentration 
(Ctrough) of BPN and that CAM2038 q1w and q4w products can be dose adjusted to the 
pharmacokinetic profiles after SL BPN administration. Based on these similarities, the two 
CAM2038 products are expected to be interchangeable when subjects go from weekly to 
monthly dosing regimen, and the treatments can be adjusted in accordance with subject needs 
and maintenance doses of SL BPN. 
 
Figure 1A 
 
Figure 1B 
 
0.1
1
10
100
0
7
14
21
28
SC CAM2038 q1w 16 mg pred 
SC CAM2038 q1w 16 mg obs
SC CAM2038 q4w 64 mg pred 
Ctrough for SL buprenorphine 8 mg at steady state
Cmax for SL buprenorphine 8 mg at steady state
Plasma BPN conc (ng/mL)
Time (days)
0.1
1
10
100
0
7
14
21
28
SC CAM2038 q1w 24 mg pred 
SC CAM2038 q4w 96 mg pred 
Ctrough for SL buprenorphine 16 mg at steady state
Cmax for SL buprenorphine 16 mg at steady state
Plasma BPN conc (ng/mL)
Time (days)


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Figure 1C 
 
Figure 1 Observed steady state arithmetic mean Cmax and Ctrough of buprenorphine after 
sublingual administration of Subutex®, and observed (obs) and predicted (pred) 
steady state plasma concentration profiles after subcutaneous administration of 
CAM2038 q1w and CAM2038 q4w based on data from Trials HS-11-426 and HS-
13-487 (semi-logarithmic scales) 
Cmax= maximum plasma concentration; Ctrough= trough plasma concentrations; q1w= once-weekly dosing; q4w= once-monthly 
dosing 
Geometric mean observed steady state Cmax and Ctrough for Subutex® from Trials HS-11-426 and HS-13-487 
Predicted plasma concentration versus time profiles for CAM2038 q1w from single and repeat dose data in Trial HS-13-487 
Observed steady state plasma concentration versus time profiles for CAM2038 q1w 16 mg from Trial HS-13-487 
Predicted steady state plasma concentration versus time profiles for CAM2038 q4w from single-dose data in Trial HS-13-487 
0.1
1
10
100
0
7
14
21
28
SC CAM2038 q1w 32 mg pred 
SC CAM2038 q4w 128 mg pred 
Ctrough for SL buprenorphine 24 mg at steady state
Cmax for SL buprenorphine 24 mg at steady state
Plasma BPN conc (ng/mL)
Time (days)


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Table 1 
Observed and predicted buprenorphine exposure after single administration of 
subcutaneous CAM2038 q1w, subcutaneous CAM2038 q4w, and sublingual 
Subutex® in healthy subjects  
 
 
Geometric Mean (geometric CV%) 
 
 
Cmax  
Ct  
AUCinf  
Treatment 
Trial 
(ng/mL)
(ng/mL)a
(ng*h/mL) 
SC CAM2038 q1w 
 
 
 
 
8 mg  
HS-11-426 
1.7 (36) 
0.30 (26) 
166 (20) 
16 mg  
HS-11-426 
3.1 (49) 
0.61 (25) 
335 (13) 
24 mg 
 
4.2b 
0.86b 
487b 
32 mg  
HS-11-426 
5.3 (45) 
1.1 (24) 
638 (12) 
SC CAM2038 q4w 
 
 
 
 
64 mg  
HS-13-487 
3.8 (60) 
0.45 (57) 
1360 (33) 
96 mg 
 
5.2b 
0.69b 
1960b 
128 mg  
HS-13-487 
6.6 (68) 
0.93 (33) 
2550 (26) 
160 mg 
 
7.9b 
1.2b 
3120b 
SL Subutex 
 
 
 
 
8 mg  
HS-11-426 
4.3 (32) 
0.25 (38) 
NC 
16 mg  
HS-11-426 
6.7 (62) 
0.38 (36) 
NC 
24 mg  
HS-11-426 
7.1 (19) 
0.49 (39) 
NC 
AUCinf = area under the plasma concentration-time curve from time zero to infinity; Cmax = maximum plasma concentration; Ct = 
plasma concentration at time t post administration; CV = coefficient of variation; NC = Not calculated; SL = sublingual 
a. 
Ct at 7 days for SC CAM2038 q1w, Ct at 28 days for SC CAM2038 q4w and Ct at 1 day (24 hours) for SL Subutex® 
b. 
Predicted from linear regression analysis of logarithmic pharmacokinetic variable vs. logarithmic dose 
 
Table 2 
Observed and predicted buprenorphine exposure after steady state administration 
of subcutaneous CAM2038 q1w, subcutaneous CAM2038 q4w, and sublingual 
Subutex® in healthy subjects 
 
 
Geometric Mean (geometric CV%) 
 
 
Css,max 
Css,av 
Css,trough 
Treatment 
Trial 
(ng/mL) 
(ng/mL) 
(ng/mL) 
SC CAM2038 q1w 
 
 
 
 
8 mg 
 
1.7a 
1.0b 
0.45 a 
16 mg 
HS-13-487 
4.3 (44) 
2.1 (24) 
0.84 (22) 
24 mg 
 
5.2a 
2.9 b,c 
1.4 a 
32 mg 
 
6.9 a 
3.8 b 
1.8 a 
SC CAM2038 q4w  
 
 
 
 
64 mg 
 
3.9 a 
2.0 b 
1.1 a 
96 mg 
 
5.8 a 
2.9 b,c 
1.6 a 
128 mg 
 
7.8 a 
3.8 b 
2.1 a 
160 mg 
 
9.8 a 
4.6 b,c 
2.7 a 
SL Subutex 
 
 
 
 
8 mg 
HS-11-426 
4.7 (29) 
1.1 (34) 
0.61 (46) 
16 mg 
HS-11-426 
6.3 (49) 
1.6 (37) 
0.79 (58) 
24 mg 
HS-11-426 
7.8 (37) 
2.3 (29) 
1.2 (44) 
Css,max = maximum plasma concentration at steady state; Css,av = average plasma concentration during a dosing interval at steady 
state; Css,trough = trough plasma concentration during a dosing interval at steady state; CV = coefficient of variation 
a. 
Predicted by simulation from a nonlinear mixed effects pharmacokinetic model describing observed pharmacokinetic data 
b. 
Predicted and calculated from AUCinf after single dosing and assuming time-independent pharmacokinetics 
c. 
Predicted from linear regression analysis of logarithmic pharmacokinetic variable vs. logarithmic dose 
 
 


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On the first trial day, all subjects will receive a test dose of 4 mg SL BPN prior to randomization 
to confirm tolerability by assessing signs and symptoms of withdrawal as measured by the 
Clinical Opiate Withdrawal Scale (COWS). Additionally, the 4 mg SL BPN test dose will 
provide adequate BPN exposure until clinically relevant levels of BPN are achieved with 
CAM2038 q1w, which is expected within approximately 2-4 hours post injection. Figure 2 
shows plasma concentration-time curves of BPN after a single dose of 8 mg SL BPN (i.e., double 
test dose) and a single dose of 16 mg SC CAM2038 q1w. Dose proportional pharmacokinetic 
parameters were assumed between 4 and 8 mg of SL BPN, as indicated by Ciraulo D et al. (5). 
 
Figure 2 Plasma concentration-time curves of buprenorphine after a single dose of 8 mg 
sublingual buprenorphine and a single dose of 16 mg subcutaneous CAM2038 
q1w (arithmetic mean ± SD), Trial HS-11-426 
5.2. 
Trial Rationale 
Opioid drug use disorder is a major health and social issue and is a chronic medical condition 
that often requires long-term maintenance treatment. An important aim of the treatment 
programs for opioid drug dependence is to assist in helping the patients stop abusing illicit drugs. 
Further important aims are to improve their mental and physical health, as well as their social 
conditions. This can be achieved by increasing patients’ quality of life and will also reduce the 
burden on the society and relatives. Moreover, opioid addicts often inject with used syringes and 
0
2
4
6
8
0
4
8
12
16
20
24
SC CAM2038 q1w 16 mg
SL buprenorphine 8 mg
Plasma BPN conc (ng/mL)
Time (hours)


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needles, and thus expose themselves to high risk of transmission of infectious diseases, including 
human immune deficiency virus (HIV) and hepatitis C.  
Opioid maintenance treatment, such as SL BPN, is one of the most effective treatment options 
available for opioid dependent drug users and is associated with substantial reductions in illicit 
opioid use, criminal activity, deaths, and HIV transmission (6). Patients often discontinue 
treatment prematurely, an outcome associated with higher rates of relapse to drug use, which 
means that treatment strategies that aim to keep patients in treatment longer and/or improve 
patient adherence may have additional advantages (7). While daily dosing with SL BPN has 
proven effective, the need for daily administration of treatment may negatively influence 
patients’ adherence and duration of therapy. Moreover, SL tablets or film can be easily abused 
and diverted for illicit use, injected for greater effect, or accidentally ingested, especially by 
children (7, 8). The limitations associated with SL BPN are of particular relevance to patients 
who have children at home, to those who have difficulty making frequent visits to the 
physician’s office (e.g., patients in remote locations, those with limited mobility, or those who 
travel frequently) or to those who have difficulty managing the responsibility of daily dosing.  
During initiation of treatment with BPN, some patients do not actually take the SL tablets 
dispensed to them, and they may also request doses that are higher than necessary in order to 
potentially abuse or divert the extra doses (9). In this regard, CAM2038 q1w is ideal for 
initiation as it can’t be abused or diverted by patients and may help prevent patients from 
requesting medically unnecessary doses, giving clinicians greater control over what the patient 
actually needs and receives. CAM2038 q1w is available in multiple doses, thereby permitting 
flexibility in dosing options and allowing for weekly visits during the initial stages of treatment 
to provide clinicians with the opportunity to optimize and individualize treatment for each 
patient. 
In addition to the above mentioned potential advantages, CAM2038 q1w demonstrated more 
stable concentrations with less peak-trough fluctuation over 7 days as compared with daily doses 
of SL BPN. Moreover, the bioavailability of BPN administered as CAM2038 q1w is 
approximately 7-fold that of SL BPN products. The pharmacokinetic profile of CAM2038 q1w 
indicates that a rapid and long-acting release of BPN should lead to rapid and smooth onset of 
action, in combination with a prolonged and stable treatment effect in opioid dependent patients 
with control of withdrawal symptoms for at least 7 days following a single dose. Notably, the 
pharmacokinetic profile of CAM2038, with a smooth and stable release of BPN and time to peak 
plasma concentrations within the first 24 hours after dosing, mimics a typical SL BPN titration 
schedule with low but increasing starting doses of SL BPN or BPN/naloxone tablets during the 
first 24 to 48 hours, followed by more constant dosing. Patients who have recently used opioids 
and are not in withdrawal at the time of BPN ingestion or who have taken a long-acting opioid 
too recently, may experience precipitated withdrawal with onset of BPN treatment. The primary 
motivation behind the initial 4 mg incremental titration schedule in the present trial is to follow 
current guidelines that recommend gradually introducing patients to an appropriate maintenance 
dose of BPN while minimizing the risk of precipitated withdrawal. CAM2038 q1w provides this 
slow increase in plasma levels without the potential compliance and diversion issues associated 
with taking multiple SL tablets during the day. Thus, the pharmacokinetic profile of CAM2038 
q1w may help to improve tolerability during treatment induction (including potentially reducing 
the probability of withdrawal symptoms in individuals with residual full opioid agonist). This 


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possibility has been supported in a previous clinical trial (Trial HS-07-307) in opioid dependent 
patients where the pharmacokinetic profile of CAM2038 q1w was associated with decreased 
subjective and clinical opiate withdrawal scores (Subjective Opiate Withdrawal Scale [SOWS] 
and COWS), over at least 1 week. Both SOWS and COWS scores were sustained below the limit 
of “mild” symptoms for the majority of patients up to and beyond 7 days after a single SC dose. 
Similarly, the mean time to first intake of rescue BPN medication was 10 days after a single dose 
of CAM2038 q1w.  
Patients in greater stages of withdrawal or those who have a lesser degree of physical 
dependence at onset of initiation may experience agonist effects of BPN during initiation. 
Although less than full agonist opioids, BPN may nonetheless be associated with euphoria and 
other opioid-like effects, even in opioid-dependent individuals (10-12). Thus, for some patients, 
use of CAM2038 q1w, with its more gradual onset, may result in lower peak euphoria and other 
desirable effects that can be associated with the relatively rapid and defined peak in plasma 
concentrations associated with SL BPN. The potential for reducing these lingering desirable 
effects of BPN may help patients start the recovery process in a more optimal way than with 
current SL BPN treatments. 
Generally, stabilization of opioid maintenance treatment with BPN begins after initiation with 
BPN and is usually completed within 1 to 2 months, when the patient is not experiencing 
withdrawal symptoms, is experiencing minimal or no side effects, and no longer has 
uncontrollable cravings for opioid agonist. During the stabilization phase, dose adjustments and 
frequent contact with patients increase the likelihood of compliance and successful treatment 
outcomes. Therefore, weekly assessment is usually indicated to make necessary dose 
adjustments. The profile of CAM2038 q1w provides an alternative to SL BPN products during 
this phase with potential added benefits of obtaining consistent and stable plasma levels of BPN, 
taking away the need to take daily medications, and helping to prevent diversion and accidental 
pediatric exposures during initial phases of opioid maintenance treatment. 
Similarly, pharmacokinetic results indicate that CAM2038 q4w produces consistent and stable 
plasma levels over 4 weeks with flexible and multiple dosing options. These results suggest that 
CAM2038 q4w may be an effective and safe BPN formulation for delivery of relatively constant 
levels of BPN over one month. Monthly visits and injection are regarded as a suitable frequency 
for stabilized patients on BPN maintenance treatment. Therefore, CAM2038 q4w is considered 
as a promising alternative to current daily medications for BPN maintenance treatment of 
patients with opioid use disorder who have been stabilized and qualify for monthly visits for 
BPN therapy.  
Overall, features of CAM2038 q1w and q4w may increase patient compliance relative to daily 
SL BPN dosage forms, and may help prevent treatment noncompliance in higher-risk patients 
(i.e., those patients who take “drug holidays” from their BPN when they wish to abuse illicit 
opioids). In addition, CAM2038 q1w and q4w may provide significant potential for reducing 
risks of diversion, abuse, and accidental pediatric exposure, which continue to be important 
public health consequences of SL BPN therapy.  


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Therefore, the purpose of this trial is to demonstrate the efficacy and safety of CAM2038 (q1w 
and q4w) as an office-based therapy for initiation and continuation of opioid maintenance 
treatment with BPN in patients with opioid use disorder. 
5.3. 
Benefit – Risk Assessment 
BPN is a substance with well-established use for treatment of opioid drug dependence. The 
CAM2038 products contain BPN in a new FC formulation for SC injection. Clinical trials have 
demonstrated effectiveness of BPN in reducing illicit opioid use and improving retention rates of 
patients in outpatient maintenance treatment of opioid dependence, as well as substantial 
reduction in criminal activity, deaths, and HIV transmission. The need for daily administration of 
SL BPN may negatively influence patients’ compliance and BPN tablets or film can be easily 
diverted for illicit use, injected for greater effect, or accidentally ingested, especially by children. 
CAM2038 q1w and CAM2038 q4w are ready-to-use, SC BPN FC Injection depots that are being 
developed as substitution treatment of opioid drug dependence, and provide extended BPN 
release at target plasma concentrations over the weekly and monthly dosing intervals, 
respectively. Due to the fact that CAM2038 products need to be administered by a clinician, 
CAM2038 products cannot be abused or diverted by patients. In addition, it may help preventing 
patients from requesting unnecessarily high BPN doses, and it will provide clinicians greater 
control over what the patient actually needs and receives. Compared with the SL BPN products 
on the market, CAM2038 q1w and CAM2038 q4w have several potential advantages: 1) Rapid 
therapeutic onset (with maximum plasma concentrations established within 24 hours after 
injection) followed by steady long-acting release, 2) Reduced variation in BPN plasma levels 
over time (stable plasma levels attained for at least 28 days [CAM2038 q4w] and 7 days 
[CAM2038 q1w]) resulting in more consistent therapeutic plasma levels and a possible reduction 
in morning “cravings”, 3) Less frequent dosing resulting in reduced frequency of clinic visits and 
need for medical support, 4) Significantly higher bioavailability, meaning less drug substance in 
circulation and on the street, 5) Decreased risk of drug diversion, and 6) Easier dose adjustment. 
To date, three Phase I/II clinical trials (HS-07-307, HS-11-426 and HS-13-487) have been 
conducted in both opioid dependent and healthy volunteers under naltrexone block. The safety 
profile of CAM2038 q1w and CAM2038 q4w is comparable to reference SL BPN approved 
treatment and good local tolerability was demonstrated with findings limited to only a few cases 
of transient, mild, local inflammation, pruritus and/or injection site pain. 
A number of potential AEs can be associated with the administration of long-acting depots. The 
most severe side-effects specific for the investigational product that may occur are related to 
local reactions at the site of injection after SC administration and include dermal ulcers or 
necrotic wounds at the injection site. Additional potential AEs include over-dose of BPN and 
allergy to BPN. There is also a potential risk of local obstruction and blockage at the injection 
site with accidental intravascular injection 
Systemic repeated toxicity for up to 4 months of once-weekly SC administration of CAM2038 
q1w and once-every-4-week administration of CAM2038 q4w in dogs showed absence of 
systemic toxicity by assessment of complete clinical pathology, histopathology and 
toxicokinetics. The treatment related findings were limited to reversible clinical effects 


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compatible with known pharmacological effects of BPN (reduced activity, ataxia, sporadic 
salivation, and intermittent soft feces, as well as reduction in body weight and food consumption) 
and to local, transient injection site findings, characterized as foreign body response. No novel 
toxicological aspects arose for BPN in the CAM2038 drug product formulations in comparison 
with available information on the drug substance alone. Absence of systemic toxicity has also 
been shown for up to chronic SC exposure of the FC system in rodents and non-rodents. The 
local toxicity findings at the injection site following SC administration of the CAM2038 drug 
products in a large number of non-clinical studies were described by necropsies and 
histopathology as a reversible local continuum of an inflammatory response consistent with the 
physiological inflammatory reactions occurring in response to the injection of an insoluble 
material. 
The current protocol is intended to evaluate the efficacy of CAM2038 q1w and q4w by 
demonstrating non-inferiority of CAM2038 in BPN treatment compared to SL BPN in adult 
outpatients with opioid use disorder. The safety monitoring practices employed by this protocol 
are adequate to protect the patients’ safety and should detect all treatment-emergent AEs. 
The approximate volume of blood is 94 mL for each subject over the course of the entire trial 
(Screening to End of Treatment (EOT) visit), but not including repeat or additional tests ordered 
by the Investigator) and presents no undue risk to the subjects. 
Therefore, CAM2038 q1w and q4w may provide alternative treatment options that potentially 
can increase patient compliance relative to daily SL BPN dosage forms, and may help prevent 
treatment noncompliance in higher-risk patients (i.e., those patients who take “drug holidays” 
from their BPN when they wish to abuse illicit opioids). In addition, CAM2038 q1w and q4w 
may provide significant potential for reducing risks of diversion, abuse, and accidental pediatric 
exposure, which continue to be important public health consequences of SL BPN therapy. 
The available information suggests that the present clinical trial has a favorable benefit-risk ratio. 


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6. 
TRIAL OBJECTIVES 
6.1. 
Primary Objective 
The primary objective of the trial is:  
 To demonstrate non-inferiority of the CAM2038 BPN treatment arm as compared to the SL 
BPN treatment arm in treating adult outpatients with opioid use disorder, as measured by the 
primary efficacy measure of response rate (RR). 
6.2. 
Secondary Objectives 
The secondary objectives of the trial are:  
 To demonstrate non-inferiority of CAM2038 compared to SL BPN in adult outpatients with 
opioid use disorder, as measured by the secondary efficacy measure of percentage negative 
urines. 
 To evaluate the efficacy of CAM2038 compared to SL BPN in adult outpatients with opioid 
use disorder, as measured by the secondary efficacy measure of time to sustained abstinence 
from illicit opioid use.  
 To evaluate the efficacy of CAM2038 compared to SL BPN in adult outpatients with opioid 
use disorder, as measured by the secondary efficacy measure retention rate. 
 To evaluate the efficacy of CAM2038 compared to SL BPN in adult outpatients with opioid 
use disorder, as measured by the exploratory efficacy measures. 
 To evaluate the safety of CAM2038 in adult outpatients with opioid use disorder. 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Trial Design and Plan 
This is a randomized, double-blind, double-dummy, active-controlled, parallel group multi-
center trial, designed to evaluate the non-inferiority of CAM2038 compared to an existing 
standard of care (SL BPN) in initiation and maintenance treatment with BPN. The trial will 
involve 4 phases: Screening, Phase 1 (weekly visits), Phase 2 (monthly visits), and Follow-up. 
Following Screening and confirmation of eligibility, subjects will be randomized to one of two 
treatment groups in a 1:1 ratio:  
 Group 1: SL BPN tablets + placebo SC injections 
 Group 2: CAM2038 SC injections + SL placebo tablets 
Following randomization, subjects will undergo initiation of BPN with either SL BPN or SC 
CAM2038 q1w and participate in weekly visits for 12 weeks (Phase 1). After Week 12, subjects 
will be transitioned to Phase 2 with monthly visits. During Phase 2, subjects in Group 1 will 
continue treatment with monthly dispensing of daily SL BPN treatment and monthly placebo SC 
injections, and subjects in Group 2 (receiving CAM2038 q1w) will be transferred to monthly 
injections of CAM2038 q4w and monthly dispensing of daily SL placebo. Subjects will 
participate in up to 6 visits during the 12 weeks of Phase 2; 3 scheduled monthly visits and 
3 random urine toxicology visits. At each visit, efficacy and safety outcome measures will be 
assessed. After Phase 2, the subjects will be followed-up for 1 month. 
A total of 20 opioid urine toxicology samples will be collected during the study:  
• 1 sample at Screening 
• 1 sample at baseline (Day 1/Week 1) before first dose of CAM2038 q1w 
• 12 samples will be collected at the scheduled 12 weekly visits of Phase 1 (Week 2 to 
Week 13 [i.e. 1 week after the last CAM2038 q1w treatment]) 
• 6 samples will be collected during the 12 weeks of Phase 2  
o 3 at the scheduled monthly visits (Weeks 17, 21 and 25) 
o 3 at random urine toxicology visits (taken during the period from Week 13 to 
Week 25). 
 
A self-report of drug use will accompany every urine toxicology test as outlined in Table 3 and 
Table 4.  Each subject will participate in the trial for up to 31 weeks, including up to 24 weeks of 
treatment with SL BPN or CAM2038. Subjects who complete the 24 weeks of treatment will be 
transitioned to standard of care (e.g., SL BPN) and be followed up for 4 weeks. 
All subjects will be blinded to their treatment group assignment, as will all trial staff with the 
exception of the clinician(s)/staff performing the SC injections and designated personnel who 
will be responsible for drug accountability (i.e., counting the active and placebo SL BPN 
returned tablets). 


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To ensure adequate enrollment and address potential inconvenience to subjects, all subjects 
(regardless of randomized group) will receive appropriate compensation for time and travel 
expenses related to attendance at trial visits. All costs of medications and counseling will also be 
covered. 
Investigators will be instructed to use manual-guided psychosocial counseling for trial subjects 
throughout the trial period. 
An overview of the trial design is provided in Figure 3. 
Section 10 provides additional information on the baseline, efficacy and safety assessments 
included in the trial. Efficacy and safety variables are described in Section 10.6 and the statistical 
analyses are described in Section 12. 
 
Figure 3 Overview of Trial Design 
BPN = buprenorphine; R= randomization; SL = sublingual 


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7.1.1. 
Screening Visit (Week -3 to Week -1) 
Medical and eligibility screening will occur within 3 weeks of the first day of Phase 1 (Day 1). 
At Screening, subjects will provide written informed consent to participate in the trial before any 
protocol-specified procedures or assessments are completed.  
The Screening visit will include standard medical screening procedures, complete 
medical/psychosocial history, urine toxicology and detailed substance use and treatment history, 
as outlined in Table 3.  
Following Screening, subjects will be eligible for further participation if they meet all of the 
inclusion criteria and do not meet any of the exclusion criteria. 
7.1.2. 
Phase 1 (Weekly Visits) 
Week 1 (Initiation of Treatment): 
Eligible subjects will be initiated on BPN treatment, during which time they will attend trial 
visits at the site as needed based on their withdrawal symptoms. Prior to Day 1, subjects will be 
instructed to arrive at their Day 1 visit in a state of mild withdrawal, to avoid precipitated 
withdrawal with BPN.  
A flow chart summarizing induction procedures is provided in Figure 4.  
Day 1:  On Day 1, after confirmation that subjects are in at least mild state of withdrawal, 
subjects will have an ECG performed as well as have their vitals taken. Subjects will then 
receive a test dose of unblinded 4 mg SL BPN film under observation prior to randomization to 
confirm tolerability by assessing signs and symptoms of precipitated withdrawal as measured by 
COWS.  
One (1) hour, after tolerability has been confirmed and eligibility criteria have been re-checked, 
subjects will be randomized to one of two groups in a 1:1 ratio: 
 Group 1 (SL BPN): Daily SL BPN + placebo SC injections  
 Group 2 (CAM2038): CAM2038 SC BPN injections + daily SL placebo 
After randomization, subjects will receive the following, while on site:  
 A blinded dose of 4 mg SL tablets (active or placebo) will be administered under observation. 
Thus, the total Day 1 SL BPN dose is 8 mg (4 mg unblinded BPN film + 4 mg blinded BPN 
tablets) for Group 1 and 4 mg (4 mg unblinded BPN film) for Group 2.  
 A single CAM2038 q1w (once-weekly) 16 mg SC injection (0.32 mL of active or placebo) 
will be administered. 
 After receiving the first dose of study medications, the ECG and vitals will be repeated. 
 If withdrawal symptoms are still not relieved after the second SL dose on Day 1, 
symptomatic relief with non-opioid medications should be provided. 
 Subjects will be instructed to return to the clinic on Day 2 for observation and Day 2 dosing. 


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Day 2 and Day 3: All subjects will return to the clinic only on Day 2 for an additional observed 
dosing of SL BPN/Placebo to ensure continued tolerability. All subjects will receive 16 mg SL 
BPN/Placebo (two 8mg SL BPN or placebo tablets).  
Administration of Day 2 SL BPN/Placebo dose will be observed in the clinic. 
Subjects will also be provided with Day 3 take-home dose (two 8 mg SL BPN/Placebo tablets 
per day). 
Day 4: All subjects will return to the clinic on Day 4 and will receive a single CAM2038 q1w 
8 mg or Placebo SC injection (0.16 mL of active or placebo). In situations where the visit cannot 
occur on Day 4 due to logistical constraints, the visit may occur one day early or one day late 
(+/- 1 day).  However, it is strongly encouraged to have the subject return on Day 4. 
All subjects will continue with the 16 mg SL BPN/Placebo (two 8mg SL BPN or placebo tablets 
per day). This may be observed in the clinic or be taken at home.  
Subjects will be provided with adequate amount of SL BPN/Placebo tablets for take-home to last 
through Day 7.  
Days 5 to 7: All subjects will be allowed to return to the clinic through an Unscheduled Visit, if 
continued withdrawal symptoms are present. During Days 5 to 7, one additional SC injection 
(CAM2038 q1w 8 mg or Placebo – not to exceed total weekly dose of CAM2038 q1w 32mg or 
placebo) and increase in SL BPN/Placebo dose may be provided (not to exceed 24 mg SL 
BPN/Placebo per day).  
Additional outcomes measures and procedures to be performed at each visit are outlined in 
Table 3.  


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Figure 4 Overview of Induction Procedures 
BPN=buprenorphine; SC=subcutaneous; SL=sublingual 
On Day 2, subjects will be provided with SL tablets and instructions for dosing. The daily SL BPN/Placebo dose for 
Days 2-4 will be 16 mg and the maximum daily SL BPN/Placebo dose for Days 5-7 will be 24 mg. 


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Weeks 2 to 12: 
Day 8 (Week 2): All subjects will return to the clinic on Day 8.  
Subjects will receive a CAM2038 q1w SC injection (24 mg or 32 mg or Placebo, based on total 
dose given by end of Week 1/Day 7). Subjects will also be provided with one-week take-home 
SL BPN/Placebo (16 mg, or 24 mg SL BPN/Placebo, based on total daily dose established at end 
of Week 1/Day 7 (the take home medication will be provided in 7 count bottles of 8 mg tablets)).  
If subject is still experiencing withdrawal symptoms on Day 8, the Investigator can increase the 
dose to a maximum of 24 mg per day SL BPN/Placebo and a 32 mg injection of 
CAM2038/Placebo. 
Week 3 to Week 12: From Week 3 to Week 12, at minimum subjects will attend weekly 
scheduled visits. At each scheduled visit, a SC injection of CAM2038 q1w (or placebo) will be 
administered. The scheduled visit should be at the beginning of each week (±2 days), preferably 
Mondays (see Section 10.3.1). During these visits, additional dose adjustments will be allowed 
(increases and decreases). At each weekly visit, sufficient SL tablets (BPN or placebo) will be 
dispensed to last until the next visit. Dosage adjustments are given in 8 mg increments for both 
SL BPN and SC CAM2038 and can only be done at scheduled clinic visits.  Total daily dose of 
SL BPN/Placebo cannot exceed 24 mg/day.  Total weekly dose of CAM2038/placebo q1w 
cannot exceed 32 mg injection per week. 
Weekly visit assessments will include: 
 Urine samples for opioid toxicology, evaluated using both qualitative and quantitative 
methods. Urine will also be tested for other drugs of abuse using qualitative methods. 
 Self-reported use of all drugs, including illicit or prescription opioids and other prescribed or 
illicit drugs. 
 Measures of withdrawal using COWS and SOWS 
 Measures of craving using Desire to Use and Need to Use visual analogue scales (VAS) 
 Psychosocial counseling 
 Additional outcomes measures and safety assessments for each visit, as outlined in Table 3. 
At each weekly visit, starting at Week 5, the subjects will be evaluated with regard to the 
following stability criteria: 
o Has the subject been on a stable dose of CAM2038 q1w/Placebo SC injections 
without any fluctuations in doses for the last 4 weeks? 
o Does the subject exhibit minimal subjective and no objective withdrawal symptoms, 
based on SOWS ≤7 and COWS <5? 
o Does the subject exhibit diminished desire/need to use, based on VAS scores? 
o Does the subject exhibit diminished use of illicit opioids, according to the 
Investigator’s discretion? 
The results of the evaluations will be recorded for data collection purposes, but no subject will be 
transitioned to monthly dosing before Week 13.  


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7.1.3. 
Phase 2 (Monthly Visits)  
Weeks 13 to 24: 
At Week 13 visit, all subjects will be transitioned to monthly treatment (dispensing for SL 
BPN/Placebo or SC injections). Before transitioning to CAM2038 q4w, subjects will be 
evaluated for the stability criteria described above.  
Treatment:  Subjects will receive the following treatments for a duration of 12 weeks: 
 Group 1 (SL BPN): daily SL BPN + injections of once monthly SC placebo  
 Group 2 (CAM2038): injections of once monthly CAM2038 q4w SC + daily SL placebo 
Subjects will therefore receive their first dose of CAM2038 q4w (or placebo) at the beginning of 
Week 13 (±2 days), preferably Monday. Subjects will receive their monthly SL tablets (SL BPN 
or placebo) and an SC injection (CAM2038 q4w or placebo) while on site. 
Subjects will continue to receive the daily dose of SL BPN or SL placebo that they received at 
the end of Phase 1. Based on their CAM2038 q1w (or SC placebo) dose at the end of Phase 1, 
subjects will be transitioned to the following doses of CAM2038 q4w or placebo SC injection in 
Phase 2:  
 16 mg CAM2038 q1w/placebo = 64 mg CAM2038 q4w/placebo  
 24 mg CAM2038 q1w/placebo = 96 mg CAM2038 q4w/placebo  
 32 mg CAM2038 q1w/placebo = 128 mg CAM2038 q4w/placebo  
Dosage adjustment will be allowed during Phase 2 at the monthly scheduled visits only, up to a 
maximum of 32 mg SL BPN (or placebo) and up to 160 mg CAM2038 q4w (or placebo), as 
outlined in Section 9.1.2.  
Subjects will return to the clinic for monthly trial visits during Phase 2. In addition to the 
monthly visits, subjects will return to the clinic to provide 3 random urine toxicology samples 
during Phase 2 of the trial. At each scheduled monthly visit, SL tablets (BPN or placebo) 
sufficient to last until the next visit will be dispensed. Subjects will also receive SC injections on 
site at the Week 13 (±2 days), 17 and 21 visits (±7 days). Urine toxicology samples will be taken 
at each scheduled or random visit for illicit testing of opiates/opioids and self-reports of illicit 
drug use will be collected in connection to the urine samplings. Other drugs of abuse will also be 
assessed. During Phase 2, a total of 6 urine toxicology samples will be collected; 3 at scheduled 
visits (1 per month) and 3 at random urine toxicology visits. COWS/SOWS and VAS will be 
performed at each scheduled trial visit. Other outcome measures and safety assessments are 
outlined in Table 4. 
Supplemental BPN: The trial provides dosing of BPN in both Group 1 and 2 that is expected to 
be adequate for suppression of withdrawal symptoms and progression in reductions on cravings 
and evidence of illicit opioid use. However, supplemental BPN may be needed during the trial.   
Supplemental BPN will be provided utilizing CAM2038 q1w 8 mg SC injection only in Phase 2. 
Supplemental BPN will be allowed at maximum of one SC injection per month (in between two 
scheduled clinic visits). SOWs, COWS and Desire/Need to Use VAS will be performed at this 


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visit. The reason for administering supplemental BPN will be recorded, in addition to SOWS, 
COWS, and Desire/Need to Use VAS. 
7.1.4. 
Follow-up Phase (Week 25 to Week 29) 
At Week 25, subjects will be transitioned to standard care (e.g., SL BPN). Assessment to be 
performed at this visit and additional assessments to be performed during Weeks 26 to 28 via 
telephone contact and at final in-clinic Follow-up visit at Week 29 are outlined in Table 4. 
7.2. 
Discussion of Trial Design 
The evaluation of the efficacy and safety of CAM2038 q1w and CAM2038 q4w will be 
performed using a randomized, double-blind, double-dummy, active-controlled parallel group 
trial, designed to evaluate the non-inferiority of CAM2038 compared to an existing standard of 
care (SL BPN) in treatment with BPN. Non-inferiority designs have been used for past clinical 
trials of maintenance treatment, including BPN products (13, 14). Given the availability of an 
effective existing treatment for opioid dependence, the use of a placebo-controlled trial was 
considered unethical due to the high risk of failure of these patients on placebo treatment, and the 
potential harms associated with treatment failure. In addition, because CAM2038 is an 
alternative dosage form of an already approved and widely used active substance, which delivers 
similar overall exposure to once daily SL BPN, a non-inferiority assessment was considered 
appropriate to confirm the efficacy of the product. Finally, the availability of appropriate 
placebos for each active treatment will enable a double-blind, double-dummy design, which will 
help prevent bias in the outcome variables. 


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8. 
SELECTION OF TRIAL POPULATION 
Approximately 380 subjects (190 subjects per arm) will be randomized. For sample size 
calculation, please refer to Section 12.5.   
This trial will enroll adult outpatients with opioid use disorder as defined by the Diagnostic and 
Statistical Manual of Mental Disorders – Fifth Edition (DSM-V) who are not currently being 
treated using opioid maintenance therapy.  
8.1. 
Inclusion Criteria 
Subjects must meet each one of the following inclusion criteria in order to be eligible for 
participation in the trial: 
1. Subject must provide written informed consent prior to the conduct of any trial-related 
procedures.  
2. Male or female, 18-65 years of age, inclusive.  
3. Diagnosis of moderate or severe opioid use disorder (DSM-V).  
4. Voluntarily seeking treatment for opioid use disorder. 
5. Have not received medication-assisted treatment for opioid use disorder within 60 days 
prior to randomization. 
6. Considered by the Investigator to be a good candidate for BPN treatment, based on 
medical and psychosocial history. 
7. Male and female subjects of childbearing potential must be willing to use a reliable 
method of contraception during the entire trial (Screening visit to Follow-up visit) 
(Section 10.1.6).  
8.2. 
Exclusion Criteria 
Subjects will not be eligible to participate in this trial if any one of the following exclusion 
criteria is met: 
1. Current diagnosis of Acquired Immune Deficiency Syndrome (AIDS).  
2. Current diagnosis of chronic pain requiring opioids for treatment. 
3. Current DSM-V diagnosis of moderate to severe substance use disorder on any other 
psychoactive substances other than opioids, caffeine or nicotine (e.g., alcohol, cocaine, 
sedatives) and the non-opioid substance use disorder(s) are considered primary or co-
primary, causing current (last 30 days) significant impairment and/or in the judgement 
of the Investigator would interfere with the efficacy and safety assessments. 
4. Pregnant or lactating or planning to become pregnant during the trial.   
5. Hypersensitivity or allergy to BPN or other opioids, naloxone or other opioid 
antagonists, or excipients of CAM2038 or SL BPN.  


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6. Requires current use of agents that are strong inhibitors or inducers of cytochrome P450 
3A4 (CYP3A4) such as some azole antifungals (e.g., ketoconazole), macrolide 
antibiotics (e.g., clarithromycin), or protease inhibitors (e.g., ritonavir, indinavir, and 
saquinavir).  
7. Subjects with active signs or symptoms of hepatitis and requiring treatment. Subjects 
with no acute signs of inflammation and no clinical necessity for therapy may be 
allowed at the discretion of the Investigator.  
8. Recent history of or current evidence of suicidal ideation or active suicidal behavior as 
based on the Columbia Suicide Severity Rating Scale (C-SSRS) (“Yes” responses to 
questions 4 or 5). 
9. Any pending legal action that could prohibit participation or compliance in the trial. 
10. Exposure to any investigational drug within the 4 weeks prior to Screening. 
11. Participants with a history of risk factors of Torsades de Pointes (e.g., heart failure, 
hypokalemia, family history of Long QT Syndrome) or an electrocardiogram (ECG) 
demonstrating a Fridericia's corrected QT interval (QTcF) >450 msec in males and 
QTcF >470 in females at screening. 
12. Aspartate aminotransferase (AST) levels >3 X the upper limit of normal, alanine 
aminotransferase (ALT) levels >3 X the upper limit of normal, total bilirubin >1.5 X the 
upper limit of normal, or creatinine >1.5 X upper limit of normal on the Screening 
laboratory assessments, or other clinically significant laboratory abnormalities, which 
in the opinion of the Investigator may prevent the subject from safely participating in 
trial.  
13. Significant symptoms, medical conditions, or other circumstances which, in the opinion 
of the Investigator, would preclude compliance with the protocol, adequate cooperation 
in the trial or obtaining informed consent, or may prevent the subject from safely 
participating in trial (including, but not limited to, the risks described as precautions, 
warnings, and contraindications in the current version of the Investigator’s Brochure for 
CAM2038). 
14. Is an employee of the Investigator or the trial site, with direct involvement in the 
proposed trial or other trials under the direction of the Investigator or trial site, or is a 
family member of an employee or of the Investigator. 
8.3. 
Removal of Subjects from Therapy or Assessment 
A subject is free to withdraw his/her consent and discontinue participation in the trial at any time 
for any reason. A subject’s participation must therefore be terminated immediately upon his/her 
request, and the reason(s) for discontinuation appropriately documented. 
A subject must be discontinued from the trial for any of the following reasons: 
 Safety reasons, including AEs or significant concomitant illness, injury, or urgent 
surgeries/procedures that would, in the judgment of the Investigator, affect assessments of 
clinical status to a significant extent, require discontinuation of trial drug, or both 


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 At the request of the Sponsor, regulatory agency, or Institutional Review Board (IRB) 
 Subject is lost to follow-up 
 Subject treatment allocation is unblinded (i.e., individual code break; Section 9.6) 
 Death of subject 
A subject may also be discontinued from the trial, at the discretion of the Investigator and/or 
Sponsor, for any of the following reasons:  
 Subject refuses or is unable to adhere to the trial protocol 
 Major protocol violation (e.g. violation of inclusion or exclusion criteria during the trial, 
failure to adhere to the treatment schedule) 
 Pregnancy 
 Requirement for continual use of opioid analgesics >7 days or requirement for general 
anesthesia for surgery 
The Investigator must maintain a record of all subjects who discontinue from the trial prior to 
completion; the reason(s) for trial discontinuation will be documented. In the event that a subject 
chooses to withdraw from the trial, the Investigator should make a reasonable attempt to obtain 
and record the reason(s) for withdrawal, if possible, although the subject is not obligated to 
provide such a reason.  
All efforts will be made to ensure that all subjects are briefed on the importance of the clinical 
trial and collection of data they provide. Emphasis should be made to subjects that it is more 
important to attend all visits and be truthful about their use of illicit opioids than to be “clean”.  
The subjects will be told that they will not be punished or discontinued from the trial for using 
illicit opioids and their truthful information on illicit opioid use will be an important component 
of the trial data collection.All efforts should be made by the Investigator to continue collection of 
urine samples at the protocol-defined trial visit intervals, concomitant medications, and AEs in 
subjects that discontinue trial drugs, unless the subject withdraws his/her consent at the time of 
early discontinuation. The Investigator should also ask the subject to return for the Follow-up 
assessments for Week 25 (EOT), provided that the subject has not withdrawn consent for those 
assessments. If a subject refuses to complete early termination procedures and/or Follow-up, this 
information will be recorded. 
 
 


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9. 
TREATMENTS 
9.1. 
Treatment Administration 
All trial drugs will be administered in a double-blind, double-dummy manner, such that subjects 
will receive both SL tablets (active BPN or Placebo) and SC injections (active CAM2038 
q1w/CAM2038 q4w or Placebo) throughout the trial. Subjects will receive treatment for up to 
24 weeks during the trial; 12 weeks during Phase 1 and 12 weeks during Phase 2. 
CAM2038/Placebo will be injected in the buttocks, abdomen, thighs and the upper back of the 
arms and the injection sites will be rotated such that no injections are administered into the same 
site. A total of 26 sites have been identified and a pictorial of potential injection sites will be 
provided in the trial Manual of Procedures (MOP). The following rules apply: 
 CAM2038 q1w/Placebo must not be administered into a previously injected site for at least 
8 weeks. 
 CAM2038 q4w/Placebo must not be administered in a sited previously injected with 
CAM2038 q4w/Placebo. 
 The Investigator will keep record of the injection site at each treatment visit.  
9.1.1. 
Phase 1 (Weekly Visits) 
Week 1: 
On Day 1, all subjects will have an ECG and vital signs recorded, and after confirmation of a 
mild state of withdrawal, a test dose containing 4 mg/1 mg BPN/naloxone (SL film) will be 
administered under observation. If tolerability to the test dose is shown, subjects will be 
randomized to Group 1 or Group 2 and will receive the following treatments in Week 1 during 
Phase 1:  
 Group 1:  
o On Day 1, the subjects will receive a total dose of 8 mg SL BPN (4 mg SL BPN film 
and 4 mg SL BPN tablets) and a total dose of 0.32 mL placebo CAM2038 (matching 
16 mg active CAM2038 q1w). 
o On Days 2 and 3, the subjects will receive a daily dose of 16 mg SL BPN. 
o On Day 4, the subjects will receive 16 mg SL BPN and an SC injection of 0.16 mL 
placebo CAM2038 (matching 8 mg active CAM2038 q1w). 
o On Days 5 to 7, the daily dose of SL BPN will be 16 to 24 mg and the subjects may 
receive an additional SC injection of 0.16 mL placebo CAM2038. 
o The total Week 1 dose of placebo CAM2038 must not exceed 0.64 mL (matching 32 
mg active CAM2038 q1w). 
 Group 2:  


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o On Day 1, the subjects will receive a total dose of 4 mg SL BPN (4 mg SL BPN film 
and 4 mg SL placebo tablets) and a total dose of 16 mg active CAM2038 q1w (0.32 
mL). 
o On Days 2 and 3, the subjects will receive a daily dose of 16 mg SL placebo. 
o On Day 4, the subjects will receive 16 mg SL placebo and an SC injection of 8 mg 
active CAM2038 q1w (0.16 mL). 
o On Days 5 to 7, the daily dose of SL placebo will be 16 to 24 mg and the subjects 
may receive an additional SC injection of 8 mg active CAM2038 q1w (0.16 mL). 
o The total Week 1 dose of active CAM2038 q1w must not exceed 32 mg (0.64 mL).  
Weeks 2 to 12: 
 Group 1: Daily SL BPN tablets (containing BPN and naloxone) up to a daily dose of 8 mg to 
24 mg (doses from 8 mg/2 mg to 24 mg/6 mg) and weekly SC injections of placebo 
CAM2038 of 0.32 mL, 0.48 mL or 0.64 mL (matching 16 mg, 24 mg and 32 mg doses of 
active CAM2038 q1w) per week. 
 Group 2: Daily SL placebo tablets (tablets matching 8 mg/2 mg to 24 mg/6 mg doses) and 
weekly SC injections of active CAM2038 q1w BPN at doses of 16 mg, 24 mg or 32 mg (0.32 
mL, 0.48 mL or 0.64 mL) per week. 
9.1.2. 
Phase 2 (Monthly Visits) 
Subjects will receive the following treatments during Phase 2 for 12 weeks: 
 Group 1: Daily SL BPN tablets (containing BPN and naloxone) up to a maximum daily dose 
of 32 mg (doses may range from 8 mg/2 mg to 32 mg/8 mg SL BPN daily) and monthly SC 
injections of placebo CAM2038 of 0.16 mL, 0.32 mL, 0.32 mL or 0.48 mL (near-matching 
64 mg, 96 mg, 128 mg and 160 mg active CAM2038 q4w doses) per month.  
 Group 2: Daily SL placebo tablets (tablets matching 8 mg/2 mg to 32 mg/8 mg doses) and 
monthly SC injections of active CAM2038 q4w BPN at total doses of 64 mg (0.18 mL), 
96 mg (0.27 mL), 128 mg (0.36 mL) or 160 mg (0.45 mL) per month.  
Dosage adjustment will be allowed during Phase 2 only at the monthly visits, up to a maximum 
of 32 mg SL BPN (or placebo) and up to 160 mg CAM2038 q4w (or placebo).   
Supplemental BPN: During Phase 2, supplemental BPN will be provided with CAM2038 q1w 
8 mg SC injection (0.16 mL), at a maximum of one SC injection per month. The reason for 
administering supplemental BPN will be recorded, in addition to SOWS, COWS, and 
Desire/Need to Use VAS. Supplemental BPN cannot be given once subject is on 32 mg SL BPN 
(or placebo) and 160 mg (0.45 mL) CAM2038 q4w. 
9.2. 
Identity of Investigational Products 
The following treatments will be used during the trial:  
 CAM2038 q1w (BPN FC Injection depot for once weekly administration), 50 mg/mL: 8, 16, 
24 and 32 mg (BPN base), 0.16, 0.32, 0.48 and 0.64 mL SC injection. 


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 CAM2038 q4w (BPN FC Injection depot for once monthly administration), 356 mg/mL: 64, 
96, 128 and 160 mg (BPN base), 0.18, 0.27, 0.36 and 0.45 mL SC injection.  
 CAM2038 placebo: 0.16, 0.32, 0.48 and 0.64 mL SC injection for once weekly or once 
monthly administration. 
 SL BPN: 2 mg/0.5 mg or 8 mg/2 mg BPN/naloxone tablets.  
 SL placebo: tablets matching 2 mg/0.5 mg and 8 mg/2 mg SL BPN doses.  
 SL BPN film (test dose on Day 1): 4 mg/1 mg BPN/naloxone film. 
Description of CAM2038 q1w, q4w, and placebo SC injection products: 
CAM2038 q1w will be supplied as pre-filled syringe with safety device and plunger containing 
the following: BPN, soybean phosphatidylcholine, glycerol dioleate, and ethanol. 
CAM2038 q4w will be supplied as pre-filled syringe with safety device and plunger containing 
the following: BPN, soybean phosphatidylcholine, glycerol dioleate, and N-Methyl-2-
pyrrolidone. 
Placebo SC injections will be supplied as matching for CAM2038 q1w or nearly matching (by 
volume and color) for CAM2038 q4w pre-filled syringes with safety devices and plungers 
containing the following: soybean phosphatidylcholine, glycerol dioleate, and ethanol. More 
information regarding the CAM2038 q1w, CAM2038 q4w and matching/near-matching 
CAM2038 placebo injections can be found in the Trial MOP.   
Description of SL BPN and placebo tablets: 
Subjects will be required to take daily SL BPN (BPN/naloxone) during the trial. These products 
will be supplied by the Sponsor or designee. Matching SL placebo tablets will be provided for 
each dosage strength. More information regarding the SL BPN and near-matching SL placebo 
products can be found in the Trial MOP.   
All containers/packages/boxes of trial drug will be clearly labeled with trial-specific information 
meeting all the applicable regulatory/institutional requirements. 
Description of SL BPN film (test dose): 
All subjects will receive a 4 mg test dose of BPN/naloxone on Day 1. The test dose consists of 
1 film of Suboxone® containing 4 mg BPN and 1 mg naloxone (Indivior UK Limited). Handling 
and storage of the product will be in accordance with the Suboxone Summary of Product 
Characteristics. 
9.2.1. 
Handling, Storage, and Accountability 
All trial drugs will be transported, received, stored, and handled strictly in accordance with the 
container or product label, the instructions provided to the research site, and applicable 
regulations.  
SL BPN should be stored in a secured area and in accordance with the product labeling (a copy is 
located in the Trial MOP) and all applicable laws, regulations, and local/institutional 
requirements. A description of storage conditions for CAM2038 is provided in the Trial MOP. 


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Detailed drug accountability records must be maintained, including the dates shipments are 
received, the quantity of material received, the dates dispensed and the running inventory. The 
unused quantities will be returned to the Sponsor’s drug supply vendor at the end of the trial. All 
unused supplies will be checked against the drug accountability records during the trial and/or at 
the end of the trial. Subjects will be instructed to return all unused trial drugs to the clinical site. 
The Investigator or designee must maintain an inventory record of all SL BPN dispensed to 
subjects for the purpose of treatment use. The drug accountability records for returned SL BPN 
and placebo tablets will be handled by the unblinded trial site personnel. Additional details are 
provided in the Trial MOP. 
BPN is a Schedule III controlled substance and trial drugs must be handled and stored strictly in 
accordance with restrictions related to controlled substances. Trial drugs must be kept securely 
locked with access limited to appropriate trial personnel, according to applicable regulations. 
9.2.2. 
Dispensing and Administration 
Only eligible subjects participating in the trial will receive the trial drug. Only authorized 
research site staff may supply or administer the trial drugs. Once dispensed, trial drug may not be 
relabeled or reassigned for use by other subjects. Subjects will be provided with a weekly 
(Phase 1) or monthly (Phase 2) supply of trial medications. 
Subjects will be instructed to place SL BPN or placebo tablets under the tongue until dissolved. 
For dosages requiring more than one SL tablet, tablets should be placed in different areas under 
the tongue at the same time. No more than two tablets should be placed under the tongue at one 
time.  
CAM2038 q1w, q4w, and placebo SC injections will be administered by designated healthcare 
professional at the investigational site. Detailed instructions for use will be provided in the Trial 
MOP. 
9.3. 
Method of Assigning Subjects to Treatment Groups 
Randomization will be used to avoid bias in the assignment of subjects to treatments, to increase 
the likelihood that known and unknown subject attributes (e.g., demographics, baseline 
characteristics) are evenly balanced across treatment groups, and to enhance the validity of 
statistical comparisons across treatment groups.  
Subjects who have provided written informed consent will be assigned a unique number in the 
screening process. This number will be used to identify the subject throughout the trial. 
Subjects who have met the eligibility criteria (Section 8) during the re-check on Day 1 and who 
have tolerated the 4 mg test dose will be randomized to one of the two treatment groups in a 1:1 
ratio (Group 1: Daily SL BPN plus SC placebo injections or Group 2: CAM2038 [q1w and q4w] 
SC injections plus SL placebo tablets). Due to the size of the trial, it is expected that subjects will 
be balanced for various other baseline factors, including age. 


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Once any subject number or randomization number is assigned, it cannot be reassigned to any 
other subject. This trial will use central randomization, through an Interactive Voice Response 
System and/or by an Interactive Web Response System managed by the Sponsor. 
9.4. 
Selection of Doses 
The trial will include a range of doses as used in clinical practice (i.e., 8 mg to 24 mg SL BPN 
per day in phase I and up to 32 mg SL BPN in Phase II), based on each subject’s individual 
needs. Doses of CAM2038 will deliver similar exposure to SL BPN doses. As in clinical 
practice, dose adjustments (increases in case of withdrawal effects or cravings or decreases for 
tolerability reasons) will be allowed during the trial at schedule trial visits during both Phase I 
and Phase II. 
9.5. 
Selection and Timing of Dose 
Subjects will be randomized to receive either CAM2038 or SL BPN at individualized doses. The 
dose levels will be sufficient to prevent withdrawal symptoms and cravings, as in clinical 
practice.   
No fasting or special dietary requirements are required for the trial; however, when taking the SL 
BPN or placebo tablets, subjects should be advised to not eat or drink anything for 20 minutes 
before and 20 minutes after the tablet(s) are completely dissolved. To ensure consistency in 
bioavailability, subjects should follow the same manner of dosing for the duration of the trial. 
9.6. 
Blinding 
In order to reduce the potential for bias in the trial, treatment group assignments will be double-
blinded. The subject, investigational site personnel, Sponsor, and Sponsor designees directly 
involved in the conduct and/or monitoring of this trial will not be aware of the treatment group 
assignments.  
SL BPN tablets used during the trial will have a nearly-matching placebo. Due to minor potential 
differences between active and placebo SL tablets, subjects will be told that clinical supplies of 
SL BPN have been specifically developed for this trial and may look or taste different than 
commercially available products that they may have been treated with previously. Subjects 
should not interpret these differences as indicative of whether they are receiving SL active or 
placebo tablets.  
There is a slight difference in color and fill volume between the placebo and active CAM2038 
q4w; however, the viscosity is the same. In order to maintain the blind given the differences in 
color and fill volume, the following will be implemented for both Phase 1 and Phase 2: 
 The Injecting Clinician and any other staff involved in the injection process will not 
participate in subject evaluations, nor discuss any information regarding the injections with 
the subjects or other trial staff. 


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 To keep the subjects blinded, appropriate steps will be taken to ensure that the subject is 
unable to view the syringe at any time. 
 The trial staff will not ask the Injecting Clinician or any other staff involved in the injection 
process for information regarding subject group assignment that might inadvertently unblind 
the trial staff. 
Designated site personnel will remain unblinded to maintain drug accountability records for all 
dispensed and returned SL BPN or SL placebo tablets. This unblinded site personnel must not 
participate in subject efficacy evaluations nor discuss with other trial staff any information 
regarding the SL tablets in reference to the subjects.   
Under normal circumstances, the blind will not be broken until all participants have completed 
treatment. In case of emergency, and only if the information is required by the Investigator to 
ensure subject’s safety in managing a medical condition, the treatment may be unblinded at the 
site by using a code break module.  The code break module will be provided by the Sponsor or 
designee. If possible, the Investigator should contact the Sponsor prior to unblinding and after 
any actions have been taken. Whenever a treatment sequence is prematurely unblinded, the 
reason, date and time of the unblinding, and the individual who broke the blind must be 
documented. Individual code breaks will result in withdrawal of the participant from the trial. 
9.7. 
Prior and Concomitant Therapy 
All non-trial medications, including prescription, over-the-counter, or herbal therapies, used by 
the subject will be documented for the 30 days prior to Screening and throughout the trial. The 
Investigator will determine if the prior/concomitant medication(s) affect the subject’s eligibility 
to participate or continue to participate in the trial. The following restrictions on concomitant 
medications will be in place during the trial:  
 Opioid receptors are likely to be occupied by BPN, which may reduce the analgesic effects of 
an opioid. The dissociation of BPN from the receptors may take several days following 
discontinuation of SL BPN treatment, or up to 2 weeks (for CAM2038 q1w) or at least 2 
months (for CAM2038 q4w) following the last CAM2038 injection. Therefore, subjects 
requiring analgesic emergency treatment or anesthesia for surgery should ideally be treated 
with a non-opioid analgesic. Opioids may be used with caution, but as higher doses may be 
required for analgesic effect, there may be a higher potential for toxicity with opioid 
administration. The clinical course should carefully evaluated and be fully documented for 
subjects who have a requirement for any opioid analgesic for >7 days continually or general 
anesthesia for surgery. 
 BPN is metabolized via CYP3A4. Because CYP3A4 inhibitors may increase plasma 
concentrations of BPN, if CYP3A4 inhibitors such as azole antifungals (e.g., ketoconazole), 
macrolide antibiotics (e.g., erythromycin), and HIV protease inhibitors (e.g., ritonavir, 
indinavir, and saquinavir) are required, the Medical Monitor must be consulted. Interactions 
with CYP 3A4 inducers have not been investigated; therefore it is recommended that the use 
of agents such as phenobarbital, carbamazepine, phenytoin and rifampicin be avoided in 
subjects receiving trial treatment. The Medical Monitor must be consulted prior to starting 
subjects on any of these agents. 


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 Concomitant use of other narcotic anesthetics, benzodiazepines, phenothiazines, other 
tranquilizers, or other central nervous system (CNS) depressants (including alcohol and 
sedative/hypnotics) may cause respiratory and CNS depression. Use of these substances 
should be minimized during treatment with CAM2038 or SL BPN. If these sedatives are 
required during the trial, the Medical Monitor must be consulted. Subjects should be advised 
of the danger of concomitant use of sedatives while participating in in the trial. Subjects 
should be explicitly advised of the danger of IV abuse of benzodiazepines and abuse of 
alcohol while under treatment with CAM2038 or SL BPN. 


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10. 
TRIAL PROCEDURES AND ASSESSMENTS 
All trial assessments will be performed at the visits and time points outlined in the Schedule of 
Assessments (Table 3 and Table 4); the following sections outline the details and procedures 
associated with the assessments. Additional details on the assessments, including copies of 
questionnaires, logs, manuals, and information sheets are provided in the Trial MOP.  


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Table 3 
Schedule of Assessments: Screening and Phase 1 (Weekly Visits) 
Trial Period/Phase:
Screening 
Phase 1 (Weekly Visits) 
Month:
-1 
M1 
M1-3 
Week:
-3 to -1 
W1 
W2-W11 
W12 
Day:
-21 to -1 
D1a 
D2 
D3 
D4 
D5-7 
D8 
Weeklyb 
- 
Informed Consentc 
X 
 
 
 
 
 
 
 
 
Eligibility Criteria Reviewd 
X 
X 
 
 
 
 
 
 
 
Demographic Data and Psychosocial History 
X 
 
 
 
 
 
 
 
 
Medical and Medication History/Substance Abuse and Treatment History 
(questionnaires) 
X 
 
 
 
 
 
 
 
 
DSM-V  
X 
 
 
 
 
 
 
 
 
Physical Examinatione 
X 
 
 
 
 
 
 
 
 
Weight, BMI 
X 
X 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
Vital Signsf 
X 
Xg 
 
 
X 
 
X 
Weekly 
X 
ECG 
X 
Xg 
 
 
 
 
X 
Weekly 
X 
Biohemistry, Hematology, Urinalysis and Coagulation Profile 
X 
X 
 
 
 
 
 
 
X 
Pregnancy Testh 
X 
X 
 
 
 
 
X 
Weekly 
X 
Hepatitis B/C, HIVi 
X 
 
 
 
 
 
 
 
 
Injection Site Examination 
 
X 
X 
 
X 
(X) 
X 
Weekly 
X 
 
a Subjects will be randomized to 1 of 2 treatment groups (SL BPN or CAM2038) after confirmation of eligibility ≥1 hour following a 4 mg SL BPN test dose.  
b A window of ±2 days will be allowed for weekly visits during Weeks 2 to 12, in addition to Week 13. 
c Subjects must voluntarily provide written informed consent prior to any trial-related procedures being performed. 
d Prior to randomization on Day 1, a review of the eligibility criteria will be made  
e A complete physical exam of all major body systems will be performed at the Screening visit. 
f Includes temperature, blood pressure, pulse rate, respiration rate. 
g Vital signs and ECG will be measured at approximately 15-30 minutes before the test dose and approximately 15-30 minutes after the CAM2038/SL BPN dose 
on Day 1 and approximately 15-30 minutes pre-dose at the other visits as indicated in the table (or during the visit if no dose is given).  
h A serum pregnancy test will be performed at Screening. An “in-office” urine pregnancy test will be required on Day 1 PRIOR to randomization and test dose 
administration  as well  weekly thereafter (for women of childbearing potential).   
i It is the Investigator’s responsibility to understand and comply with all laws and regulations that apply to HIV, Hepatitis B, and Hepatitis C and testing of blood.  
Hepatitis B/C and HIV testing is required unless a site’s IRB prohibits such testing. 


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Trial Period/Phase:
Screening 
Phase 1 (Weekly Visits) 
Month:
-1 
M1 
M1-3 
Week:
-3 to -1 
W1 
W2-W11 
W12 
Day:
-21 to -1 
D1a 
D2 
D3 
D4 
D5-7 
D8 
Weeklyb 
- 
Dispense Treatment Identification Card 
 
X 
 
 
 
 
 
 
 
Urine Toxicology 
X 
X 
 
 
 
 
X 
Weekly 
X 
Illicit Drug Use Self-Report  
X 
X 
 
 
 
 
X 
Weekly 
X 
SOWS, COWS, VASj 
X 
X 
X 
 
X 
(X) 
X 
Weekly 
X 
C-SSRSk 
X 
X 
X 
 
X 
(X) 
X 
Weekly 
X 
Measurement of Morning Desire to Use/Need to Use 
 
 
 
 
 
 
X 
Weekly 
X 
SL BPN or SL placebo dispensing 
 
X 
X 
 
X 
(X) 
X 
Weekly 
X 
SL BPN or SL placebo administrationl 
 
X 
X 
X 
X 
Daily 
X 
Daily 
X 
CAM2038 q1w or placebo SC injectionm 
 
X 
 
 
X 
(X) 
X 
Weekly 
X 
Psychosocial Counseling 
 
X 
 
 
 
 
X 
Weekly 
X 
Adverse Eventsn 
X 
X 
X 
 
X 
(X) 
X 
Weekly 
X 
Concomitant Medications/Procedures 
X 
X 
X 
 
X 
(X) 
X 
Weekly 
X 
On-site visits 
X 
X 
X 
 
X 
(X) 
X 
Weekly 
X 
Abbreviations: BMI=body mass index; BPN=buprenorphine; COWS=Clinical Opiate Withdrawal Scale; C-SSRS=Columbia Suicide Severity Rating Scale; 
D=day; DSM-V= Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition; ECG=electrocardiogram; HIV=human immunodeficiency virus; 
M=month; SC=subcutaneous; SL=sublingual; SOWS=Subjective Opiate Withdrawal Scale; VAS=visual analogue scale; W=week 
(X) indicates as needed based on the individual subject.
 
j SOWS/COWS/VAS will be completed each time the subject visits the clinic, as needed based on titration and dosage adjustment. On Day 1, COWS, SOWS and 
VAS will be completed before the test dose is administered (baseline). COWS will also be completed after the test dose on Day 1 to evaluate tolerability, and 
on Day 2. 
k Screening version at Visit 1 (Screening), Since Last Visit version at all subsequent visits. 
l Not to exceed 24 mg SL BPN (or placebo) per day, this administration will be done at home. 
m Not to exceed 32 mg CAM2038 q1w (or placebo) per week. 
n Any spontaneously reported adverse event will be recorded after the subject signs the informed consent form. In addition, adverse events will be elicited using a 
non-leading question each time the subject visits the clinic. 


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Table 4 
Schedule of Assessments: Phase 2 (Monthly Visits) and Follow-up 
Trial Period/Phase:
Phase 2 (Monthly Visits) 
Follow-up 
Month:
M4 
M5 
M6 
M7 
Week:a
W13 
W14-16
W17 
W18-20
W21 
W22-24 
(EOT)
W25 
W26-28
W29 
Weight and BMI 
X 
 
X 
 
X 
 
X 
 
 
Physical Examination 
 
 
 
 
 
 
X 
 
 
Vital Signsb,c 
X 
 
X 
 
X 
 
X 
 
 
ECGc 
X 
 
X 
 
X 
 
X 
 
 
Biochemistry, Hematology, Urinalysis and Coagulation Profile 
X 
 
X 
 
X 
 
X 
 
 
Pregnancy Testd 
X 
 
X 
 
X 
 
X 
 
 
Injection Site Examination 
X 
 
X 
 
X 
 
X 
 
X 
Urine Toxicology 
X 
 
X 
 
X 
 
X 
 
 
Illicit Drug Use Self-Report  
X 
 
X 
 
X 
 
X 
 
 
Random Urine Toxicology and Illicit Drug Use Self-Reporte 
3 x random urine toxicology 
 
 
 
SOWS, COWS, VAS 
X 
 
X 
 
X 
 
X 
 
X 
C-SSRSf 
X 
 
X 
 
X 
 
X 
 
X 
Measurement of Morning Desire to Use/Need to Use 
X 
 
X 
 
X 
 
X 
 
X 
SL BPN or SL Placebo Dispensing 
X 
 
X 
 
X 
 
 
 
 
SL BPN or SL Placebo Administrationg 
X 
Daily 
X 
Daily 
X 
Daily 
 
 
 
 
a Treatment Visits should be conducted within a window of ±7 days for monthly visits (other than Week 13, which will have a visit window of ±2 days). If a 
subject misses a visit or completes a visit early or late, the original schedule should be resumed at the subsequent visit such that the ensuing visits occur as 
originally scheduled, relative to Day 1.   
b Includes temperature, blood pressure, pulse rate, respiration rate. 
c Vital signs and ECG will be measured approximately 15-30 minutes pre-dose and approximately 15-30 minutes post-dose at Week 13. At the other visits, ECG 
will be measured approximately 15-30 minutes pre-dose as indicated in the table (or during the visit if no dose is given).  
d A serum pregnancy test will be performed at the End of Treatment visit (Week 25). An “in-office” urine pregnancy test will be required at Week 13, 17 and 21 
prior to injection being administered (for women of childbearing potential).   
e A total of 3 random urine toxicology visits during M4-M6, preferably once a month. Illicit drug use self-reports will also be completed by the subjects at these 
visits.  
f C-SSRS “Since Last Visit version” is to be used. 
g Not to exceed 32 mg/8 mg SL BPN (or placebo) per day. 


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Trial Period/Phase:
Phase 2 (Monthly Visits) 
Follow-up 
Month:
M4 
M5 
M6 
M7 
Week:a
W13 
W14-16
W17 
W18-20
W21 
W22-24 
(EOT)
W25 
W26-28
W29 
CAM2038 q4w or Placebo SC Injectionh 
X 
 
X 
 
X 
 
 
 
 
Transition to Standard Care 
 
 
 
 
 
 
X 
 
 
Psychosocial Counseling 
X 
 
X 
 
X 
 
X 
 
 
Adverse Eventsi 
X 
 
X 
 
X 
 
X 
X 
X 
Concomitant Medications/Procedures 
X 
 
X 
 
X 
 
X 
X 
X 
Scheduled On-site Visit 
X 
 
X 
 
X 
 
X 
 
X 
Telephone Contact 
 
 
 
 
 
 
 
Weekly 
 
Abbreviations: BMI=body mass index; BPN=buprenorphine; COWS=Clinical Opiate Withdrawal Scale; C-SSRS=Columbia Suicide Severity Rating Scale; 
ECG=electrocardiogram; M=month; SC=subcutaneous; SL=sublingual; SOWS=Subjective Opiate Withdrawal Scale; VAS=visual analogue scale; W=week.
 
h Subjects will receive the first CAM2038 q4w injection (active or placebo) at the beginning of Week 13 (±2 days). Not to exceed 160 mg CAM2038 q4w (or 
placebo) per month. Subjects will receive their last CAM2038 q4w dose at Week 21.  
i Any spontaneously reported adverse events will be recorded after the subject signs the informed consent form. In addition, adverse events will be elicited using 
a non-leading question each time the subject visits the clinic and during the telephone contacts in the Follow-up phase. 


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10.1. 
Demographics and Other Baseline Characteristics 
10.1.1. 
Informed Consent 
The nature of the trial and its risks and benefits will be explained to the subject by the 
Investigator or designated trial personnel. The subject must voluntarily provide written informed 
consent on an ethics-approved informed consent form (ICF), prior to performing any trial-related 
procedures. The subject’s medical records must document that the consent process has been 
completed and that written informed consent has been obtained from the subject prior to the 
initiation of any trial-specific procedures. Documentation that the subject was given adequate 
time to ask the Investigator (or designee) questions about their participation in the trial and that a 
signed and dated copy of the ICF was provided to the subject should also be included in the 
medical records or clinical chart. 
All subjects will be informed on the importance of visit attendance and truthful data on their self-
reported illicit opioid use. Subjects will be told that there will not be a bad consequence if there 
are evidence of opoid use and they will not be discontinued from the trial. Therefore, subjects 
should be as truthful as possible to provide accurate self-reported use data for this trial. A role 
induction form (included in the Trial MOP) will be completed at the time of providing informed 
consent. 
10.1.2. 
Demographics 
The following demographics will be recorded: age (birthdate), sex, race, and ethnicity. A 
complete psychosocial history will be obtained including education, employment status, 
marital/significant other status, residential status and legal status/arrest history.   
10.1.3. 
Medical History 
The complete medical history based on patient interview of 5 years prior to the screening visit 
and any clinically significant medical history greater than 5 years prior to the screening visit will 
be collected. These will include histories of acute, chronic, or infectious disease; surgical or 
oncologic histories; and any reported conditions affecting major body systems. All findings on 
medical history will be evaluated by the Investigator for clinical significance. 
10.1.4. 
Medication History  
All medications (prescription and non-prescription, herbal medications/natural health products, 
or investigational drugs) taken by the subjects during the 30 days prior to Screening will be 
recorded in the source documentation as medication history. Substance Abuse History and 
Treatments will be collected separately. 
10.1.5. 
Substance Use and Treatment History 
A complete history of previous and current illicit drug use, substance abuse/dependence, and 
treatments for any substance use disorders (pharmacologic as well as non-pharmacologic) will be 
obtained. This will include drugs used, type, frequency and patterns of abuse, routes, doses, drug 
preferences and concomitant medications, using questionnaires. Additional data to be collected 
include, previous episodes of BPN treatment, duration of BPN treatment for each episode, 


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previous illicit BPN use, and time since illicit BPN use at Screening. Detailed information on 
substance use and treatment history is provided in the Trial MOP.  
10.1.6. 
Contraceptive Requirements 
Both Male and female subjects of childbearing potential must be using and willing to continue 
using medically acceptable contraception during the trial. Examples of medically acceptable 
forms of contraception include true abstinence, hormonal contraceptives (combined oral pill, 
patch or vaginal ring, intrauterine device or system, progestin implant or injection), bilateral 
tubal ligation, or double-barrier methods (i.e., male condom in addition to a diaphragm or a 
contraceptive sponge).  
Female subjects of non-childbearing potential are not required to use contraception or undergo 
pregnancy tests; however, they must be surgically sterile (hysterectomy and/or bilateral 
oophorectomy/salpingo-oophorectomy, as determined by subject medical history) or 
congenitally sterile, or must be post-menopausal. Post-menopausal is defined as being 
amenorrheic for at least 2 years without another cause or amenorrheic for at least 1 year without 
another cause and a documented follicle stimulating hormone level ≥50 mIU/mL. Male subjects 
of non-childbearing potential are not required to use contraception, however they must be 
surgically sterile (Sterilisation with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate). 
10.2. 
Eligibility Review and Randomization 
At screening, the Investigator or designee must document that the subjects meet each individual 
criterion (as outlined in Section 8.1 and 8.2) via a signed note or eligibility and clinical stability 
checklist. Signatures on these documents must be dated on or before the date of randomization in 
Phase 1 (Day 1). Prior to randomization, a re-check of the eligibility criteria will be performed 
and tolerability of the 4 mg SL BPN test dose will be confirmed. 
10.3. 
Efficacy Assessments 
Details regarding primary, secondary and exploratory variables are provided in Section 10.6 
(Efficacy and Safety Variables); and the statistical analyses are discussed in Section 12 
(Statistical Analysis). The following sub-sections provide an overview of the efficacy 
assessments included in the trial. Additional details, such as the questionnaire items/scale text 
and additional instructions (where applicable) are provided in the Trial MOP.  
10.3.1. 
Urine Toxicology Samples for Opioids 
Urine toxicology samples will be collected at each visit (both scheduled and random, excluding 
Day 2, Day 4 and Follow-up) using a urine collection cup containing a temperature sensor. 
Specimen authenticity will be verified at the site using this sensor to measure the urine 
temperature immediately following collection. The temperature of a urine sample within 
4 minutes of voiding should fall within the range of 32.2 to 37.7 degrees Celsius (90 to 100 
degrees Fahrenheit). If test results are outside these ranges, the subject will be asked to 
immediately provide another urine sample. If this second sample is outside of the temperature 


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range, the sample will be counted as 'missing', and should not be sent for analysis (any such 
samples must be documented in the subject’s records). A direct observation approach to 
obtaining urine samples may be used if the Investigator deems it necessary. Urine samples will 
be logged and numbered and then sent to a central laboratory for analysis for the presence of 
opioids (e.g., morphine and metabolites, codeine, oxycodone, hydrocodone, hydromorphone, 
fentanyl, and methadone). In addition, it is recommended that the scheduled assessment visits 
take place preferably on Mondays to potentially improve detection of illicit opioid use that may 
have occurred over the weekend. 
There will be 3 random urine visits in Phase 2.  Sites should utilize their standard clinical process 
for scheduling the 3 random urine visits, however it is recommended that no more than one 
random urine test be conducted between two scheduled visits. Random urine visits should occur 
within 48 hours after speaking directly with the subject. 
10.3.2. 
Self-Reported Illicit Drug Use  
Subjects will be questioned about illicit drug use, including illicit or prescription opioids and 
other drugs of abuse, using a timeline follow-back type of interview at all visits when urine 
toxicology samples for opioids are taken (15). A copy of the Illicit Drug Use Self-Report form is 
provided in the Trial MOP.  
10.3.3. 
Measures of Desire and Need to Use 
Desire to Use and Need to Use will be administered using unipolar 100 mm VAS (“Since your 
last scheduled assessment visit, indicate your worst or strongest desire/need to use opioids, 
where 0 = No desire to use and 100 mm= Strongest possible desire, and from 0=No need to use 
and 100 mm=Strongest possible need, respectively”) outcome (16).  
Copies of these VASs are provided in the Trial MOP. NOTE: Only VAS copies provided by the 
Sponsor should be used with trial subjects; photocopies made locally may result in changes to 
the length of the scale, leading to inaccurate results.  
A separate VAS will be provided for each Desire to Use and Need to Use and measurements 
must be taken separately (i.e., separated in time or by other procedures). 
10.3.4. 
Measures of Withdrawal  
10.3.4.1. Subjective Opiate Withdrawal Scale (SOWS)  
Subjects will complete a self-assessment of withdrawal symptoms using the SOWS. This form 
contains 16 questions that rate the intensity of withdrawal from 0 (“Not at all”) to 4 
(“Extremely”). A copy of the SOWS is provided in the Trial MOP. 
10.3.4.2. Clinical Opiate Withdrawal Scale (COWS) 
Trial personnel will assess clinical observations indicative of withdrawal using the COWS. This 
scale consists of 11 common opiate withdrawal signs or symptoms, rated on a numeric scale and 
based on a timed period of observation of the subject by the rater. A copy of the COWS is 
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10.3.5. 
Urine Samples for Other Drugs of Abuse 
Urine will be tested for other drugs of abuse (e.g., cocaine, benzodiazepines, barbiturates, 
amphetamines, phencyclidine and cannabinoids [THC]) using qualitative methods. Positive 
results will not be confirmed using quantitative methods. Urine samples for testing other drugs of 
abuse will be taken at the same time points as the urine samples for toxicology tests for opioids.  
10.3.6. 
Unscheduled Visits, Medication and Counseling 
Subject-requested or physician-directed unscheduled visits, phone calls or additional counseling, 
temporary dosage adjustments, or other pharmacological interventions, along with the reason(s) 
for unscheduled visits, phone calls or additional counseling or other pharmacological 
interventions, will be recorded. 
10.3.7. 
Measures of Morning Desire to Use/Need to Use 
Starting on Day 8 (Week 2), subjects will be asked if they have felt desire or need to use opioids 
in the mornings since their last visit, and if so, how many mornings and how severe the 
desire/need has been (average severity of desire/need on a scale from 0 to 100). 
10.4. 
Safety Assessments 
Safety monitoring will be performed throughout the trial for all subjects. All AEs, regardless of 
causality or severity, will be recorded on the AE case report form (CRF). SL BPN treatment and 
CAM2038 injections may be discontinued as clinically indicated. 
10.4.1. 
Adverse Events and Serious Adverse Events 
The following definitions, developed in accordance with the United States Code of Federal 
Regulations (CFR) and the International Conference on Harmonisation (ICH) Clinical Safety 
Data Management Guidance for Industry, E2A, will be used for the purpose of identifying AEs 
in this clinical trial. 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
that does not necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (e.g., including an abnormal laboratory finding), symptom, 
or increase in severity of a preexisting abnormality, temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product. 
10.4.1.1. Adverse Event Reporting 
All AEs must be entered on the AE CRF, regardless of causality or severity. AEs include new 
AEs, worsening baseline conditions, clinically significant laboratory findings, disease-related 
signs and symptoms that were not present at baseline, and any events or findings that the 
Investigator considers clinically significant.  
Disease-related signs and symptoms that are present at baseline should not be recorded as AEs 
unless they worsen in severity or increase in frequency. 


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Information collected concerning AEs will include the following: 
 Name of the event 
 Onset date 
 Resolution date 
 Severity (i.e., mild, moderate, or severe) 
 Relationship to trial drug 
 Action and outcome 
 Seriousness of event 
All AEs will be documented and followed from the time the subject has signed the ICF until 
14 days after the Follow-up Visit at Week 29 or early termination. SAEs and AEs that have been 
designated as related to trial drug will be followed until resolution or stabilization. 
10.4.1.2. Serious Adverse Event (SAE) 
An SAE or reaction is any adverse drug experience occurring at any dose that results in any of 
the following outcomes: 
 Death 
 Is life-threatening (at the time of the event) 
 Requires inpatient hospitalization or prolongation of existing hospitalization, 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect (in an offspring) 
 An Important medical event that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
the event may jeopardize the subject and/or may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
All AEs requiring hospitalization or prolongation of a pre-existing hospitalization should be 
reported as SAEs unless they occur more than 14 days after the Follow-up Visit at Week 29 or 
30 days after early termination AND are not considered to be drug-related by the Investigator. 
Hospitalizations meeting the following criteria will not be reported as an SAE but must be 
recorded on the appropriate CRF: trial specified hospitalization, short-term administrative 
hospitalization for procedures, tests or treatments of conditions that would not otherwise 
constitute an SAE, elective hospitalizations. 
10.4.1.2.1. Serious Adverse Event Reporting 
SAEs must be reported to the Sponsor or designee within 24 hours of knowledge of the event. 
All SAEs that occur during the trial and within 14 days following the Follow-up Visit at Week 29 
(or 30 days following early termination) are reportable within 24 hours. During the follow-up 


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period beyond 14 days from Follow-up (or 30 days following early termination), only those 
SAEs that are considered to be possibly related to trial drug should be reported within 24 hours. 
The procedure for reporting an SAE is as follows: 
 Within 24 hours of knowledge of the event, the site must contact the Sponsor (or designee) 
by telephone or facsimile to report the event. 
 The initial report should include all information known at the time of the report (additional 
information can be reported as discovered). Do not delay the initial reporting in order to 
obtain resolution or follow-up information. 
 The site will enter into the electronic database (or fax using the SAE back-up form, if the 
database cannot be accessed for any reason) the following information, as available: 
o Subject ID 
o Basic demographic information (age, gender, weight) 
o Outcomes attributed to the event (death, life-threatening hospitalization [new or 
prolonged], disability, congenital anomaly, required medical intervention to prevent 
permanent impairment/damage, etc.) 
o Onset date and severity of the event 
o Brief description of the event including frequency and severity of symptoms leading 
to diagnosis 
o List of relevant test results and laboratory data 
o Any other relevant history 
o Dates and doses of temporary and unscheduled visit dosage adjustments 
o Whether the trial drug was discontinued 
o Whether the assigned treatment SL or injectable therapy was discontinued and/or 
dose titration discontinued, as applicable 
o Investigator’s assessment of causality 
The Medical Monitor or another representative of the Sponsor may contact the Investigator to 
request additional information regarding the event or to confirm information. All SAEs will be 
entered on the AE CRF. The same nomenclature should be used on both the SAE report and the 
AE CRF. 
Specific instructions for SAE reporting and a copy of an SAE report form are provided in the 
Trial MOP. 
The Investigator is responsible for the complete and timely reporting of all SAEs to the Sponsor 
(or designee), reporting pertinent follow-up information on the SAE, and notifying the 
appropriate IRB/Independent Ethics Committee (IEC) of the occurrence of and details 
surrounding the event. In the event there is a question as to whether the AE is serious, the event 
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10.4.1.2.2. Suspected Unexpected Serious Adverse Reactions (SUSAR) 
A suspected unexpected serious adverse reaction (SUSAR) is defined as an SAE and where: 
 There is a certain degree of probability that the event is harmful, and an undesirable, reaction 
to the medicinal product being research, regardless of the administered dosage. In other 
words, there is an adverse reaction. 
 The adverse reaction is unexpected. That is to say, the nature and severity of the adverse 
reaction are not in agreement with the reference safety information as recorded in the 
Investigator’s Brochure. 
A SUSAR has additional reporting requirements, as described below. 
 If the SUSAR is fatal or life-threatening, associated with the use of the investigational 
medicinal product, and unexpected, competent authorities and ethics committees will be 
notified within 7 calendar days after the Investigator learns of the event. Additional follow-up 
information (cause of death, autopsy report, hospital report) should be reported within an 
additional 8 days (15 days in total). 
 If the SUSAR is not fatal or life-threatening but is otherwise serious, associated with the use 
of the investigational medicinal product, and unexpected, competent authorities and ethics 
committees will be notified within 15 calendar days after the Investigator learns of the event. 
All Investigators will receive relevant information about SUSARs in a timely fashion. Follow-up 
information may be submitted if necessary. 
10.4.2. 
Pregnancy 
Pregnancies among trial participants or their partners should be reported to the Sponsor or 
designee as soon as possible after learning of the event. Subjects who become pregnant may 
withdraw their consent and discontinue the trial and be referred back to the care of their usual 
provider or continue in the trial after discussion with and documentation by the Principal 
Investigator or his/her designee. Follow-up information will be obtained where possible (with the 
consent of the participant or their partner) regarding the course and outcome of the pregnancy, 
including any post-natal sequelae in the infant. 
California participants: Subjects who become pregnant at anypoint during the study will be 
discontinued from the trial and be referred back to the care of their usual provider. Follow-up 
information will be obtained where possible (with the consent of the participant or their partner) 
regarding the course and outcome of the pregnancy including any post-natal sequelae in the 
infant. 
10.4.3. 
Clinical Laboratory Assessments 
All protocol-specified laboratory tests on blood and urine samples will be performed at a selected 
central laboratory, with the exception of urine pregnancy tests that are conducted at the trial site. 
The central lab will generate laboratory reports and forward them to the clinical site in a timely 
manner. It is the responsibility of the Investigator to review and sign all lab reports expeditiously, 
in order to document appropriate safety monitoring of trial subjects. The Investigator should sign 
and date each lab report concurrent with her or his review, and should indicate the clinical 


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significance of each abnormal/flagged value by noting “NCS” (not clinically significant) or “CS” 
(clinically significant). Notations indicating that a value is clinically significant should also 
include a brief description of the underlying disease or condition that is associated with the 
value, e.g., “CS/mild anemia.” In general, abnormal, clinically significant laboratory values are 
expected to be associated with an item recorded in medical history or with an AE. 
Blood and urine samples will be collected, processed, and shipped according to instructions from 
the safety laboratory. Additional laboratory samples may be taken at the discretion of the 
Investigator if the results of any tests fall outside reference ranges or clinical symptoms 
necessitate testing to ensure safety. Specific hematology, coagulation, biochemistry, and 
urinalysis assessments are listed in Table 5 and timing of the assessments is shown in Table 3 
(Screening and Phase 1) and Table 4 (Phase 2 and Follow-up). 
Table 5 
Clinical Laboratory Assessments  
Hematology 
Biochemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
Red blood cell (RBC) count  
RBC Morphology 
Mean corpuscular volume  
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration  
Total and differential (absolute) 
white blood cell count 
Platelets 
Sodium 
Potassium 
Magnesium  
Calcium  
Glucose (random) 
Bicarbonate  
Chloride  
Creatinine 
Total protein 
Blood urea nitrogen  
Albumin 
Total bilirubin 
Alanine transferase  
Aspartate transferase  
Lactic dehydrogenase  
Amylase  
Lipase 
Gamma-glutamyl transferase  
Alkaline phosphatase  
Creatine phosphokinase  
Total cholesterol (non-fasting) 
Color 
pH 
Specific gravity 
Ketones 
Protein 
Glucose 
Bilirubin 
Nitrite 
Urobilinogen 
Occult blood 
Microscopic examination of 
sediment, only if urinalysis 
dipstick results are abnormal 
 
 
Coagulation 
Prothrombin time (PT), 
International normalized ratio 
(INR) 
 
In addition to the clinical laboratory tests, a serum pregnancy test will be performed at the 
Screening Visit and End of Treatment visit (Week 25). An “in-office” urine pregnancy test will 
be required on Day 1 PRIOR  both test dose dispensation/ and confirmation of tolerability AND 


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randomization, and then at each scheduled visits (weekly for Weeks 1-12, monthly for Weeks 13-
24) (for women of childbearing potential). Results must be reviewed and confirmed to be 
negative prior to start of SL BPN and CAM2038 treatment (Day 1). 
A blood sample for a serology panel testing for hepatitis B surface antigen, anti-hepatitis C 
antibodies, and HIV will be performed for all subjects at Screening, unless a site’s IRB prohibits 
such testing. It is the Investigator’s responsibility to understand and comply with all laws and 
regulations that apply to the testing of blood for HIV and hepatitis B and C. These laws and 
regulations may include state laws related to written consent, separate from the ICF for this trial, 
and pre- and post-test counseling. 
10.4.4. 
Vital Signs 
Vital signs will consist of temperature, blood pressure (systolic and diastolic blood pressure, 
mmHg), pulse rate (beats per minute), and respiratory rate (breaths/min) collected while sitting, 
following a rest period of at least 3 minutes, at the time points indicated in Table 3 and Table 4. 
On Day 1, vital signs will be measured approximately 15-30 minutes before the subjects receive 
their SL BPN test dose and approximately 15-30 minutes after they have received their doses of 
blinded CAM2038 q1w/SL BPN (placebo or active). At Week 13, vital signs will be measured 
approximately 15-30 minutes pre-dose and approximately 15-30 minutes post-dose. At the other 
visits, vital signs will be measured approximately 15-30 minutes pre-dose (or during the visit if 
no dose is given). Clinically significant values will be recorded as AEs. 
10.4.5. 
12-Lead Electrocardiogram (ECG) 
12-Lead ECGs will be performed after the subject has been resting in a recumbent/supine 
position for at least 3 minutes, at the time points indicated in Table 3 and Table 4. On Day 1, an 
ECG will be performed approximately 15-30 minutes before the subjects receive their SL BPN 
test dose and approximately 15-30 minutes after they have received their doses of blinded 
CAM2038 q1w/SL BPN (placebo or active). At Week 13, ECGs will be performed 
approximately 15-30 minutes pre-dose and approximately 15-30 minutes post-dose. At the other 
visits, ECGs will be performed approximately 15-30 minutes pre-dose (or during the visit if no 
dose is given). The ECG variables will include ventricular heart rate and the PR, QRS, QT, QTcB 
and QTcF intervals. The ECGs will be signed and dated by a medically-qualified individual to 
confirm review of the ECG and verify whether any abnormalities are clinically significant. In 
general, abnormal, clinically significant ECGs are expected to be associated with an item 
recorded in medical history or with an AE.  
10.4.6. 
C-SSRS 
The C-SSRS will be used to assess both behavior and ideation. The C-SSRS tracks all suicidal 
events, and provides a summary of suicidal ideation and behavior. It assesses the lethality of 
attempts and other features of ideation (frequency, duration, controllability, reasons for ideation, 
and deterrents), all of which are significantly predictive of completed suicide.  
Two versions of the C-SSRS will be used in this trial: the Baseline/Screening version (6 months 
and lifetime history) and the Since Last Visit version. The Baseline/Screening version of the C-


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SSRS will be administered at Screening. The Since Last Visit version of the C-SSRS will be 
administered at all subsequent assessment times, as indicated in Table 3 and Table 4. 
The C-SSRS is to be administered by the Investigator or his/her certified designee.  The survey 
should be administered by the same assessor, where possible, throughout the trial. 
10.4.7. 
Physical Examination 
A complete physical examination including all major body systems (skin, head, eyes, ears, nose, 
respiratory, cardiovascular, gastrointestinal, endocrine metabolic, neurological, blood lymphatic 
and musculoskeletal) will be performed at Screening and Week 25 (EOT).  
Height, weight and body mass index (BMI) will be determined as described in Table 3 and 
Table 4.  
10.4.8. 
Injection Site Examination  
CAM2038 or placebo injections sites will be examined during each scheduled visits for any signs 
of adverse site reactions, including erythema, pruritus, edema, pain, etc. If needed, a photograph 
of the adverse site reactions wil be taken and shared with the medical monitor for review. The 
pain scale will be completed by the subjects within 10 minutes after each injection. The new 
injection site will also be examined within 15 minutes after each injection to determine if any site 
related AEs have occurred. Injection site evaluation form will be included in the Trial MOP. 
Subjects will also be queried specifically about local tolerability AEs in connection to the 
examinations. Injection site examination can only be performed by the blinded site personnel. 
10.4.9. 
Psychosocial Counseling 
All subjects will receive manual-guided drug counseling during the trial on a weekly basis during 
Phase 1 and on a monthly basis during Phase 2, as described in more detail in the Individual 
Drug Counseling Manual (provided in the Trial MOP) (17). Additional counseling can be 
provided as clinically indicated; however, all additional counseling, visits or phone calls must be 
recorded. 
10.4.10. 
Treatment Identification Card 
Subjects will receive a wallet card indicating that they are receiving BPN as part of the trial. This 
card should be presented to health care providers by the subject in the event of an emergency or 
if medications such as opioid analgesics are required (see Section 9.7). Sample wallet cards will 
be provided for IRB submission. 
10.4.11. 
Other Safety Considerations 
BPN may impair the mental and physical abilities required for performance of potentially 
dangerous tasks. Subjects will be instructed to avoid operating heavy machinery and to exercise 
caution in performing activities requiring alertness such as driving a car during the first few days 
after the first dose or until such time that they are reasonably certain that their ability to engage 
in such activities is not adversely affected. 


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10.5. 
Appropriateness of Measures 
The primary endpoint was selected to provide an objective assessment of efficacy of the trial 
medications (i.e., RR based on urine toxicology results for illicit opioids). The most direct 
method to ascertain the frequency and amount of illicit opioid use would be through the use of 
patient self-reports. However, these reports may not always be reliable or accurate (18). Thus, the 
analysis of urine samples for specific drugs or drug metabolites is typically used as an objective 
criterion for assessing illicit drug use. Urine toxicology has been used in many efficacy 
assessments of BPN and will be used together with self-reported illicit drug use as to define the 
primary RR endpoint in this trial.  
Retention in treatment, one secondary outcome measure in this trial, is commonly used for 
determining the efficacy of opioid maintenance treatment in pivotal clinical trials and provides 
an overall measure of treatment success (13, 14, 19). Additional secondary outcome measures 
were selected as a series of measures and scales to provide a complete assessment of the efficacy 
of CAM2038 compared to SL BPN, including investigator- and subject-reported withdrawal and 
subject-reported cravings. Standard and widely used measures of withdrawal will be included in 
this trial (COWS and SOWS) (20, 21) in order to ensure that subject’s withdrawal symptoms are 
adequately controlled by CAM2038 as compared to SL BPN. Desire to Use and Need to Use 
VASs were selected versus typical Craving VAS because the latter term is ambiguous and may 
have different meaning to different individuals, while the Desire/Need to Use VAS more directly 
assesses the potential behavioral outcome (16).  
10.6. 
Efficacy and Safety Variables 
10.6.1. 
Primary Efficacy Variable 
The primary outcome measure will be RR, where a responder is defined for Phase 1 as: the 
subject must have no evidence of illicit opioids use at Week 13 and have no evidence of illicit 
opioids use for at least 2 out of the three weeks from Week 10 to Week 12. To be a responder for 
Phase 2, the subject must have no evidence of illicit opioids use at Month 6 (last illicit opioids 
use assessment in Month 6 or Week 25) and have no evidence of illicit opioids use in 5 out of the 
6 illicit opioids use assessments in Phase 2. To be a responder for the study, the subject must be a 
responder for both Phases 1 and 2.  
A total of 18 scheduled urine toxicology samples will be collected during the treatment period, 
whereof 12 samples will be collected in Phase 1 and 6 will be collected in Phase 2 (3 scheduled 
and 3 random).  
10.6.2. 
Secondary Efficacy Variables 
The secondary efficacy variables are: 
 Percentage of urine samples negative for illicit opioids (This variable will be defined in the 
manner per EMA’s request.  This variable will serve as the primary efficacy variable for 
EMA NDA and will not be applicable for US NDA submission) 


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 Cumulative distribution function (CDF) of percent samples that are negative for illicit 
opioids (Week 5-24) 
 Time to sustained abstinence of opioid use 
 Percent of subjects remaining in the trial (retention rate) 
10.6.3. 
Exploratory Efficacy Variables 
Exploratory efficacy variables in the trial are: 
 RR for Phase 1  
 RR for Phase 2 
 Percent negative urine samples in Phase 1 
 Percent negative urine samples in Phase 2 
 Percent of subjects with evidence of no illicit opioid use by time point 
 Cumulative percentage of subjects with evidence of no illicit opioid use by time point 
 Percent of subjects with no self-reported illicit opioid use by time point 
 Percentage of subjects meeting criteria of stability at Week 13 
 Measures of opioid craving: 
o Desire to Use VAS  
o Need to Use VAS 
 Measures of opioid withdrawal:  
o COWS 
o SOWS 
 Percentage of subjects without evidence of using other drugs of abuse by time point 
 Supplemental BPN use  
 Additional supplemental counseling  
 Measures of morning need to use/desire to use 
 Quantity of illicit opioid use 
10.6.4. 
Safety Variables 
Safety variables include AEs, clinical laboratory parameters, ECG, physical and injection site 
examinations, concomitant medications, vital signs and C-SSRS.  


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11. 
DATA QUALITY ASSURANCE 
This trial will be conducted under Good Clinical Practice (GCP) and all applicable regulatory 
requirements. To ensure compliance, the Sponsor or designee may conduct a quality assurance 
audit, as outlined in Section 11.2.  
Actions to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate trial centers; the review of protocol procedures with the 
Investigator and trial personnel prior to trial start; the design of suitable source documents with 
appropriate instructions for use (where applicable); the internal audit of source data according to 
GCP and internal procedures to ensure their accuracy, completeness, and verifiability; as well as 
the periodic site monitoring by the Sponsor. The Sponsor or designee will review source 
documents for accuracy and completeness during on-site monitoring visits and after their return 
to the Sponsor; any discrepancies will be resolved with the Investigator, as appropriate.  
Significant and/or repeated non-compliance will be investigated and remedial action instituted 
when appropriate. Failure to comply with remedial actions may result in investigational site 
termination and regulatory authority notification. 
11.1. 
Data Collection  
Source documents include but are not limited to original documents, data and records such as 
hospital/medical records (including electronic health records), clinic charts, lab results, 
participant diaries, data recorded in automated instruments, microfilm or magnetic media, and 
pharmacy records, etc. This trial will use electronic data capture (EDC). At a minimum, all data 
required by the protocol should have supporting source documentation for entries in the EDC 
system. 
All CRFs will be completed by the site staff prior to review by the Sponsor’s monitor or 
designated representative. The Sponsor’s monitor or designated representative will review all 
source records on-site and compare them to the data collected on the CRF.  All entries, 
corrections, and alterations will be made by the Investigator or other authorized trial personnel. 
All data entries will be verified for accuracy and correctness by independent monitors. The EDC 
system maintains a full audit trail.  
11.2. 
Trial Auditing and Monitoring 
Monitoring of the trial site (including, but not limited to, reviewing CRFs for accuracy and 
completeness) will be performed by the Sponsor’s designated monitor(s). The extent, nature, and 
frequency of on-site visits will be based on such considerations as the trial objectives and/or 
endpoints, the purpose of the trial, trial design complexity, and enrollment rate. By signing the 
protocol, the Investigator agrees that, within local regulatory restrictions and institutional and 
ethical considerations, authorized representatives of the Sponsor, a regulatory authority, and/or 
an IRB may visit the site to perform audits or inspections, including the drug storage area, trial 
drug stocks, drug accountability records, participant charts and source documents, and other 


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records related to trial conduct. The purpose of the Sponsor audit or inspection is to 
systematically and independently examine all trial-related activities and documents to determine 
whether the trial-related activities were conducted, and data recorded, analyzed, and accurately 
reported according to the protocol, the site’s standard operating procedures, GCP guidelines of 
the ICH, and any applicable regulatory requirements. The Investigator should contact the 
Sponsor immediately if contacted by a regulatory agency regarding an inspection. 


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12. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
12.1. 
Statistical and Analytical Plans 
Complete details of the statistical analyses to be performed will be documented in a statistical 
analysis plan (SAP), which will be completed prior to unblinding of the trial data. This document 
will include more detail of analysis populations, summary strategies, and any amendments to the 
proposed analyses listed here, if necessary. Any changes to the SAP will be outlined in the final 
trial report. A separate document will describe the testing procedure to address the requirements 
from the European Medicines Agency (EMA) and will only be used for the purpose of an 
application in the European Union.  
12.2. 
Analysis Populations 
 Intent-to-Treat (ITT) Population: All subjects who have been randomized to a 
treatment group. Analyses based on this population will group subjects according to the 
treatment they were randomized to receive, regardless of actual treatment received. The 
primary efficacy analysis will be based on this ITT population. 
 Modified Intent-to-Treat (mITT) Population: All subjects who have been randomized 
to a treatment group and have received at least one dose of SL BPN/placebo or SC 
CAM2038/placebo in the treatment phase.  
 Safety Population: All subjects who are randomized and treated who received any dose 
of SL BPN/placebo or CAM2038/placebo injections in the treatment phase. Analyses 
based on this population will group subjects according to the treatment they actually 
received regardless of the treatment they were randomized to receive. All safety analyses 
will use the safety population. 
 Per Protocol Population: All subjects in the mITT population with no major protocol 
violations. Major protocol violation criteria will be established prior to the database lock. 
12.3. 
Planned Analyses 
12.3.1. 
Demographics and Other Baseline Characteristics 
Disposition for all enrolled subjects will be summarized. Reasons for discontinuation will be 
tabulated. 
Demographic data and baseline psychosocial characteristics will be summarized.  
Tabular summaries and/or listings will be provided for baseline clinical characteristics, such as 
illicit drug and treatment use history, medical and psychiatric history, inclusion/exclusion 
criteria, and medication history. 


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12.3.2. 
Analysis of Efficacy Measures 
12.3.2.1. Analysis of the Primary Efficacy Endpoint 
The responder definition will be derived based on urine samples obtained from Weeks 10, 11, 12 
and 13 in Phase 1 and samples obtained at Weeks 17 (Month 1), 21 (Month 2) and 25 (Month 3) 
and at the 3 random samples in Phase 2.  
To be a responder for Phase 1, the subject must have no evidence of illicit opioids use at Week 13 
and have no evidence of illicit opioids use for at least 2 out of the three weeks from Week 10 to 
Week 12. To be a responder for Phase 2, the subject must have no evidence of illicit opioids use 
at Month 6 (last illicit opioids use assessment in Month 6 or Week 25) and have no evidence of 
illicit opioids use in 5 out of the 6 illicit opioids use assessments in Phase 2. To be a responder 
for the study, the subject must be a responder for both Phases 1 and 2. Evidence of illicit opioid 
use is defined as a positive opioid urine toxicology result or a self-reported illicit opioid use. 
The primary efficacy variable will be RR.  The proportion of responders will be calculated in 
both treatment arms.  
An analysis of non-inferiority in the primary efficacy variable between the two treatments arms 
will be performed using a  margin of 13.5% point.  
Non-inferiority will be concluded if the two-sided 95% confidence interval for the difference 
between the probabilities of response (Active- Control) is above –0.135. The 95% confidence 
interval, (LB, UB), will be derived using normal approximation: 
LB = (PT-PC) – 1.96*(1/NT*PT*(1-PT)+ 1/NC*PC*(1-PC))0.5 , and 
UB = (PT-PC) + 1.96*(1/NT*PT*(1-PT)+ 1/NC*PC*(1-PC))0.5, where 
PT and PC are observed proportions of the responders for the treatment and the control, 
respectively, and NT and NC are the sample sizes for the treatment and the control, respectively. 
12.3.2.2. Handling of Dropouts or Missing Data 
Imputation methods to handle dropouts and/or missing data will be detailed in the trial SAP. 
Varieties of sensitivity analyses will be considered, including the analysis treating missing as 
evidence of opioids use. 
12.3.2.3. Sensitivity Analyses 
Sensitivity analyses based on various missing imputation methods will be performed and 
described in the trial SAP. 
12.3.2.4. Analysis of Secondary Efficacy Endpoints 
Percentage of Urine Samples Negative for Illicit Opioids 
This variable will be defined in the manner per EMA’s request.  This variable will serve as the 
primary efficacy variable for EMA NDA and will not be applicable for US NDA submission. 


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Percent negative urine samples will be derived after applying missing value imputation. This 
variable will be analyzed via an analysis of variance (ANOVA) model with treatment effects. 
The difference between the two treatments in percent negative urine samples will be obtained 
from this model and the two-sided 95% confidence interval for the treatment difference will be 
presented.  
An analysis of non-inferiority in the primary efficacy variable between the two treatments arms 
will be performed using a margin of 11% point.  
Non-inferiority will be concluded if the two-sided 95% confidence interval for the difference 
between the percent negative urine samples (Active- Control) is above –0.11. 
Cumulative Distribution Function (CDF) of Percent Samples that are Negative for Illlicit 
Opioid (Week 5-24) 
Percent negative samples from 14 samples (8 weekly assessments obtained from Weeks 6 to 13, 
plus 3 monthly assessments obtained at Weeks 17, 21, and 25 and plus 3 random samples) will 
be calculated for each subject.  Missing samples will be imputed as positive before the 
percentage is derived.   
The null hypothesis of no difference in the CDF of the percent of urine samples that are negative 
for illicit opioids over Weeks 5-24 will be tested at the 5% significance level using Wilcoxon 
Rank-Sum test. The empirical CDF plot will be presented.   
Time to Sustained Abstinence of Opioid Use 
For the purpose of deriving time to sustained abstinence of opioid use (i.e., no opioid use through 
the rest of treatment period for at least 2 months), the time will be define as: 
 If the sustained abstinence is obtained during the scheduled visit, time is the number of days 
between randomization day to the scheduled visit day. For example, if first sustained 
abstinence is obtained at the Week 8 visit, the time would be 56. 
 If the first sustained abstinence is obtained during a random test, time is the number of days 
between randomization day to the day that random sample is obtained (Random Sample Date 
– Randomization Date).   
Definition for evidence of illicit opioid use and rules for missing value imputation will be 
outlined in the SAP.  
Time to sustained abstinence of opioid use will be analyzed via a log-rank model with treatment 
effects. Time to event “Survival” curve will be presented using Kaplan-Meier method. Median 
time to event and the 95% confidence interval of the median times will be presented, if 
estimable. In this time to event analyses, subjects who do not have any opioid-positive results 
during the entire study and who do not have any opioid-positive results before discontinuing 
from the study will be censored at Day 175 (Week 25 day), the day when the last sample will be 
obtained. 


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Retention Rate 
The secondary endpoint retention rate will be analyzed using a chi square test. The percentages 
for each treatment and between treatment percentage differences will be estimated. The 95% 
confidence intervals of the estimated treatment differences, based on a normal approximation, 
will be presented.  
12.3.2.5. Analysis of Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints will include RR during weeks on CAM2038 q1w (Phase 1) 
and during months on CAM2038 q4w (Phase 2). RR for Phase 1 and Phase 2 will be analyzed 
using chi square test. The percentages of negative urine samples in Phase 1 and Phase 2 will also 
be analyzed using chi square test. The 95% confidence intervals of the estimates will be 
presented using normal approximation. 
Additionally, the following exploratory efficacy variables will be analyzed: 
• Percent of subjects with evidence of no illicit opioid use by time point; 
• Cumulative percentage of subjects with evidence of no illicit opioid use by time point; 
• Percent of subjects with no self-reported illicit opioid use by time point 
• Percent of subjects meeting criteria of stability at Week 13 
• Changes from baseline in Desire to Use VAS, Need to Use VAS, COWS and SOWS over 
time. 
• Percent of subjects without evidence of using other drugs of abuse by time point 
• Supplemental BPN use  
• Additional supplemental counseling  
• Measures of morning need to use/desire to use 
• Quantity of illicit opioid use 
 
For the exploratory efficacy variables based on the percentages, the percentages, the differences 
of percentages (based on normal approximation) and 95% confidence intervals of the differences 
will be presented. Change from baseline variables will be analyzed via Analysis of Covariance 
(ANCOVA) model with treatment and baseline effects. Treatment effects and treatment 
differences will be estimated. The two-sided 95% confidence intervals of the between- and 
within-treatment differences will be presented. 
Details of additional measures of efficacy and their analysis will be described prospectively, 
prior to final database lock and unblinding, in the SAP for this trial. 


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12.3.2.6. Handling of Multiplicity 
This protocol has defined one primary endpoint and four secondary endpoints. The primary 
endpoint will be used to address the regulatory requirements as outlined by the US Food and 
Drug Administration (FDA). The two secondary endpoints percent negative urine samples and 
retention rate will be used to address the regulatory requirements as recommended by EMA.  
The method for protecting the overall significance level, when drawing the conclusions based on 
the primary endpoint and the secondary endpoints, will be described in the associated SAP.  
12.4. 
Analysis of Safety  
Exposure will be summarized by treatment group. 
Adverse events will be coded by primary system organ class (SOC) and preferred term according 
to the Medical Dictionary for Regulatory Activities (MedDRA), and summarized by number and 
percent of subjects in each primary SOC and preferred term. Summaries of these AE subsets will 
be presented for relationship to trial drug, intensity, seriousness, AEs or SAEs leading to 
discontinuation and AEs occurring in 5% or greater of any treatment group (by preferred term). 
Frequencies for deaths and hospitalizations will also be summarized by treatment group and 
overall. 
Data for clinical laboratory tests, ECG, vital signs, and physical and injection site examinations 
will be summarized using standard descriptive and change from baseline statistics. Shift tables 
and tabular summaries of abnormalities will be provided, where appropriate.  
Medications will be coded using the World Health Organization Drug dictionary and summarized 
using descriptive statistics.  
By-subject listings will be provided for all safety data. 
12.5. 
Determination of Sample Size 
The primary efficacy variable is based on data from Week 2 to Week 25. Approximately 380 
subjects (190 subjects per arm) will be randomized. 
The sample size of 190 subjects per treatment arm (380 total) was selected to achieve 
approximately 82% power to establish non-inferiority based on the primary efficacy variable, RR 
(Week 12-25). In the sample size calculation, it is assumed that both arms have a 70% RR, and 
that the non-inferiority margin is 13.5%.  
Choice of non-inferiority margin for the primary endpoint 
The proposed 13.5% margin is appropriate from a scientific validity perspective as well as 
meeting the FDA guidelines for non-inferiority selection (24). The FDA draft guidance on non-
inferiority trials suggest 50% of the benefit of the control arm relative to a placebo or no care 
would be a reasonable approach. The following information provides additional credence to the 
rationale: 


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1. In the study by Rosenthal et al (27), the RR between open-label SL BPN/naloxone and 
placebo was found to be approximately 33% and 6%, a difference of 27% (lower limit of 
a two-sided confidence interval for the difference; 17%, using an approximate 95% 
confidence level ) over 24 weeks of treatment (data derived from Fig 2 in Rosenthal et 
al).  The expectation, based on this, is that a hypothetical placebo arm in this trial, HS-11-
421, would be worse than the SL BPN control arm by at least a 17% difference in RR. 
Note that using the suggested 50% of the benefit of the control arm in this trial will imply 
a non-inferiority margin of 13.5%. Thus, using 13.5% as the non-inferiority margin 
should be viewed as conservative as the lower limit of the associated confidence interval 
for the difference is 17%.  
2. In addition, the FDA Draft Guidance (24) notes that circumstances might support a 
conservative choice for the margin, including: 
a.  Pharmacologic properties of the test drug that are very similar to those of the 
active control – CAM2038 is an alternative dosage form of the same active entity 
with the expectation of similar overall average plasma concentrations to the SL 
BPN arm; 
b. Use of a persuasive biomarker – responder definition in this trial will include the 
standard and well-accepted objective urine toxicology results to confirm treatment 
success with with respect to drug use; 
c. If the test drug were shown to have some important advantage (e.g., on public 
health, potential to reduce misuse and abuse) – the misuse, abuse and accidental 
pediatric exposure are well known; the Drug Abuse Warning Network confirmed 
an increasing trend in adverse medical outcomes associated with SL BPN abuse 
(26) CAM2038 has the potential to reduce misuse/abuse associated with SL BPN 
and to have a significant positive public health impact in addition to potentially 
increasing adherence 
The choice of non-inferiority margin for the secondary variable percent negative urine is based 
on the outcome of the Rosenthal study  where a comparison was evaluated over 24 weeks 
between SL BPN (n=119) and placebo (n=54) for the outcome variable percent negative urine 
samples. The reported values from the analysis of variance is 35.1% and 14.4%, respectively 
(difference = 20.7%, p=0.81). This translates to an approximate 95% confidence interval for the 
diffence of (11.5%, 29.9%). The power calculation is based on the the lower limit of this 
confidence interval representing a level of effect that can be viewed as clinically relevant, and 
can represent a hypothetical placebo arm in this trial.  
A sample size of 190 subjects per treatment arm will provide over 90% power to establish the 
non-inferiority with 11% point for the percent of urine samples negative for illicit opioids. In the 
sample size calculation it was assumed that the percentage of samples negative for illicit opioids 
is the same for the two treatment groups and the standard deviation was 30%.  
In summary, the sample size of approximately 190 subjects per treatment arm (380 total) will 
provide approximately 82% power to establish non-inferiority for the primary efficacy variable 
at a two-sided significance level of 0.05. 
  


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13. 
TRIAL ADMINISTRATION AND INVESTIGATOR 
RESPONSIBILITIES 
Additional details may be outlined in the Clinical Study Agreement (CSA) between the sponsor 
and the investigational site.  
13.1. 
Regulatory and Ethical Considerations 
13.1.1. 
Ethical Conduct of the Trial 
The Investigator will conduct the trial in accordance with GCP and all applicable regulations, 
including, where applicable, the Declaration of Helsinki. The trial will also be carried out in 
keeping with applicable national and local laws and regulations. This may include an inspection 
by the Sponsor’s representatives and/or regulatory authority’s representatives at any time. 
13.1.2. 
Ethics Approval 
The investigational site’s IRB must meet all relevant regulatory requirements. The trial protocol 
and ICF will be reviewed by the IRB prior to enrolling participants into the trial; written 
approval from the committee must be received by the Sponsor before drug will be released to the 
Investigator. The Investigator is responsible for submitting all protocol or ICF changes and SAE 
reports to the IRB according to local procedures. At a minimum, all SAEs requiring an 
investigational new drug safety report must be immediately reported. 
In accordance with applicable local regulatory requirements, the Investigator may be obligated to 
provide periodic safety updates on the conduct of the trial at his or her research site and 
notification of trial closure to the IRB. Such periodic safety updates and notifications are the 
responsibility of the Investigator and not of the Sponsor. The Sponsor will be provided with 
copies of all notifications sent to the IRB. 
All relevant correspondence from the IRB will be forwarded by the respective trial site to the 
Sponsor in a timely fashion. 
13.1.3. 
Subject Informed Consent 
The Investigator (or authorized designee) will ensure that the participant (or the participant’s 
legal representative) is given full and adequate oral and written information about the nature, 
purpose, potential and possible risks and benefits of the trial. Each prospective subject will 
receive an IRB-approved ICF that summarizes the pertinent trial information and will be given 
ample time to read the form and ask questions about the trial. All information is to be provided in 
a language understandable to the participant and must not include any language that waives the 
participant’s legal rights. Prospective participants must also be informed of their right to 
withdraw consent without prejudice at any time during the trial. If the participant chooses to 
participate, he/she must sign the ICF before any trial-related procedures are performed.  
Significant changes to the protocol or product safety information may require a revision of the 
ICF, which must be reviewed and signed by all applicable trial participants. 


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The time that informed consent is obtained must be documented. The Investigator must maintain 
the original, signed ICF in the participant’s source documents. A copy of the signed ICF must be 
given to the trial participant. 
13.2. 
Privacy and Confidentiality 
The Investigator is responsible for complying with applicable privacy regulations, per his or her 
jurisdiction. Only information identified in this protocol will be collected. The information 
collected will only be used for the purposes identified in this protocol. 
To ensure anonymity and to limit disclosure, participants will be assigned a unique identifier at 
their first assessment. This identifier will be cross-referenced in the participant’s chart. The 
identifier will not contain any potentially identifiable information. An identifier log will be 
maintained, linking each participant’s name to the corresponding identifier. This log will be 
stored at the research site in a secure location. 
The knowledge gained through this trial is the property of the Sponsor. The Sponsor, 
representatives and affiliated companies of the Sponsor, the IRB, and regulatory agencies (such 
as the United States FDA) may inspect medical records related to the trial to check the validity 
and accuracy of the data gathered in this trial. Participant medical records (with participant’s 
initials and/or date of birth) may be copied. Confidentiality of participant records will be 
maintained except where release of information is required by law.  
The results of this trial will be reported in such a manner that participants will not be identifiable 
in any way. Published reports or presentations will refer to grouped data or coded individual data 
and not to any identifiable individuals. Trial reports sent to the Sponsor or drug regulatory 
agencies will not include participant names. 
By signing the ICF, the participant consents to the collection, access, use, and disclosure of his or 
her information as described in the ICF document. If a participant withdraws consent, some of 
the subject’s information may still be collected, used, and disclosed by those involved in this 
trial, per applicable laws.  
By signing this protocol, the Investigator affirms that he or she will maintain in confidence 
information furnished to him or her by the Sponsor and will divulge such information to his or 
her respective IRB or IEC under an appropriate understanding of confidentiality with such board. 
All data will be considered the sole property of the Sponsor. Please refer to the CSA for details. 
13.3. 
Trial and Site Closure 
Upon completion of the trial, all trial data will be provided to the Sponsor following review of 
site trial records for completeness, and data clarifications and resolutions. Accounting, 
reconciliation, and final disposition of used and unused trial drugs, treatment codes, and 
emergency code break envelopes will be performed, as applicable. 
In addition, the Sponsor reserves the right to temporarily suspend or prematurely discontinue this 
trial at any time and for any reason. If such action is taken, the Sponsor will discuss this with the 


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Investigator (including the reasons for taking such action) at that time. The Sponsor will 
promptly inform any other investigators and/or institutions conducting the trial, if the trial is 
suspended or terminated for safety reasons and will inform the regulatory authorities of the 
suspension or termination of the trial and the reason(s) for the action. If required by applicable 
regulations, the Investigator will inform the IRB promptly and provide the trial participants with 
the reason for the suspension or termination. If the trial is prematurely discontinued, all trial data 
will be returned to the Sponsor.  
13.4. 
Regulatory Documents and Records Retention 
The Investigator is responsible for creating and/or maintaining all trial documentation required 
by 21 CFR 50, 54, 56 and 312, ICH E6 section 8, as well as any other documentation defined in 
the protocol or CSA. The Investigator must provide key documents to the Sponsor prior to the 
start of the trial. A complete list of required regulatory documents will be supplied by the 
Sponsor or its representative. 
Federal and local regulations require that the Investigator retain a copy of all regulatory 
documents and records that support the data for this trial for whichever of the following is the 
longest period of time: 
 A period of 2 years following the final date of approval by the FDA or other regulatory 
agency of the trial drug for the purposes that were the subject of the investigation; or 
 A period of 5 years following the date on which the results of the investigation were 
submitted to the FDA or other regulatory agency in support of, or as part of, an application 
for a research or marketing permit for the trial drug for the purposes that were the subject of 
the investigation. 
The Sponsor will notify investigators once one of the above 2 timeframes has been satisfied. 
If the investigation does not result in the submission of the data in support of, or as part of, an 
application for a research or marketing permit, records must be retained for a period of 2 years 
following notification by the Sponsor that the entire clinical investigation (not merely the 
Investigator’s portion) is completed, terminated, or discontinued or 2 years following withdrawal 
of the Investigational New Drug application/Clinical Trial Authorization or request for marketing 
approval (New Drug Application/Marketing Authorization Application).  
If the Investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the trial records, custody must be transferred to a person who will accept the 
responsibility. The Sponsor must be notified in writing of the name and address of the new 
custodian. Trial records should not be destroyed without consultation with the Sponsor. 
13.5. 
Delegation of Responsibilities and Adequate Resources 
The Investigator should have adequate time to conduct the trial properly and should have an 
adequate number of qualified staff to assist with the conduct of the trial.  


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The term “Investigator” used throughout this protocol refers to the principal investigator and/or 
qualified sub-investigators. However, the Investigator may delegate responsibilities to other 
investigational site personnel. The Investigator shall delegate tasks only to individuals qualified 
by education, training and experience to perform the delegated tasks. The Investigator shall have 
direct oversight of all delegated activities and shall document delegation of responsibilities. The 
Investigator is responsible for ensuring all delegated staff has been properly trained on the 
protocol and their assigned trial responsibilities. A delegation log identifying all delegated duties 
and the individual to whom they have been delegated will be maintained at the investigational 
site.  
13.6. 
Protocol Amendments 
Approval of a protocol amendment by the Investigator’s IRB must be obtained before 
implementation of the protocol amendment, unless a change is necessary to eliminate an 
apparent immediate hazard to the participant or when the change involves logistical or 
administrative aspects of the trial. The protocol amendment must be signed and dated by both the 
Sponsor and the Investigator. The Sponsor or designee will submit protocol amendments to the 
appropriate regulatory authorities, if required. 
13.7. 
Financial Disclosure 
Clinical Investigators are required to provide financial disclosure information for the submission 
of certification or disclosure statements required under 21 CFR § 54. As defined in 21 CFR § 
54.2, a Clinical Investigator is a listed or identified Investigator or Sub-investigator who is 
directly involved in the treatment or evaluation of research participants. The term also includes 
the spouse and each dependent child of the Investigator. In addition, Investigators must promptly 
update financial disclosure information if any relevant changes occur during the course of the 
investigation and for 1 year following completion of the trial. 


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14. 
SPONSOR APPROVAL PAGE 
A Phase III, Randomized, Double-Blind, Active-Controlled, Parallel Group, 
Multi-center Trial Assessing the Efficacy and Safety of a Once-Weekly and 
Once-Monthly, Long-Acting Subcutaneous Injectable Depot of 
Buprenorphine (CAM2038) in Treatment of Adult Outpatients with Opioid 
Use Disorder 
Version: v 6.0  
Date: 03-Nov-2016 
Braeburn Pharmaceuticals 
 
 
 
 
Sonnie Kim, PharmD 
VP, Clinical Development & Medical Affairs         
 
 
 
 
 
 
03-Nov-2016 
 
Sponsor Representative 
Full Title               
 
Date 
(DD-MMM-YYYY) 
 


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15. 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
A Phase III, Randomized, Double-Blind, Active-Controlled, Parallel Group, 
Multi-center Trial Assessing the Efficacy and Safety of a Once-Weekly and 
Once-Monthly, Long-Acting Subcutaneous Injectable Depot of 
Buprenorphine (CAM2038) in Treatment of Adult Outpatients with Opioid 
Use Disorder 
Version: v 6.0 
Date: 03-Nov-2016 
I have read this protocol and I agree to conduct the trial in accordance with the protocol and with 
all applicable government regulations and International Conference on Harmonisation/Good 
Clinical Practice guidances. 
 
Principal Investigator’s 
Name 
 
(please print or type) 
 
 
 
 
Principal Investigator’s Signature 
 
Date (DD-MMM-YYYY) 
 
 
 


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15. 
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about urges or desires. Addict Behav. 1989;14(4):443-5. 
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Zanis DA, McLellan AT, Randall M. Can you trust patient self-reports of drug use during 
treatment? Drug Alcohol Depend. 1994;35(2):127-32. 
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Mattick RP, Ali R, White JM, O'Brien S, Wolk S, Danz C. Buprenorphine versus 
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dependent patients. Addiction. 2003;98(4):441-52. 
20. 
Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubinstein KJ, Kanof PD. Two new 
rating scales for opiate withdrawal. Am J Drug Alcohol Abuse. 1987;13(3):293-308. 
21. 
Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive 
Drugs. 2003;35(2):253-9. 
22. 
Fiellin DA, Pantalon MV, Chawarski MC, Moore BA, Sullivan LE, O'Connor PG, et al. 
Counseling plus buprenorphine-naloxone maintenance therapy for opioid dependence. N 
Engl J Med. 2006;355(4):365-74. 
23. 
Fareed A, Vayalapalli S, Casarella J, Drexler K. Effect of buprenorphine dose on 
treatment outcome. J Addict Dis. 2012;31(1):8-18. 
24. 
FDA. Guidance for Industry Non-Inferiority Clinical Trials. March 2010. Available from: 
http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-
gen/documents/document/ucm202140.pdf. 
25. 
Weiss RD, Potter JS, Fiellin DA, Byrne M, Connery HS, Dickinson W, et al. Adjunctive 
counseling during brief and extended buprenorphine-naloxone treatment for prescription 
opioid dependence: a 2-phase randomized controlled trial. Arch Gen Psychiatry. 
2011;68(12):1238-46. 
26. 
US Department of Health and Human Services SAaMHSA, Center for Behavioral Health 
Statistics and Quality. Drug Abuse Warning Network; National Estimates of Drug-
Related Emergency Department Visits 2011. Available from: 
http://www.samhsa.gov/data/sites/default/files/DAWN2k11ED/DAWN2k11ED/DAWN2
k11ED.pdf. 
27. 
Rosenthal RN, Ling W, Casadonte P, Vocci F, Bailey GL, Kampman K, et al. 
Buprenorphine implants for treatment of opioid dependence: randomized comparison to 
placebo and sublingual buprenorphine/naloxone. Addiction. 2013;108(12):2141-9. 
 

SAP_000.pdf: 
HS-­‐11-­‐421	  
Phase	  III	  
	  
A	  Phase	  III,	  Randomized,	  Double-­‐Blind,	  Active-­‐Controlled,	  Parallel	  
Group,	  Multi-­‐center	  Trial	  Assessing	  the	  Efficacy	  and	  Safety	  of	  a	  Once-­‐
Weekly	  and	  Once-­‐Monthly,	  Long-­‐Acting	  Subcutaneous	  Injectable	  
Depot	  of	  Buprenorphine	  (CAM2038)	  in	  Treatment	  of	  Adult	  
Outpatients	  with	  Opioid	  Use	  Disorder	  
	  
Statistical	  Analysis	  Plan	  (SAP)	  
	  
	  
Sponsor	  
BRAEBURN	  PHARMACEUTICALS	  
47	  Hulfish	  Street,	  Suite	  441	  
Princeton,	  NJ	  08542	  
Tel:	  (609)	  751-­‐5375	  
Fax:	  (609)	  921-­‐2156	  
	  
	  
Final	  Version	  1.01	  
	  
4	  Nov,	  2016	  
	  
	  
	  


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SPONSOR	  APPROVAL	  
	  
The	  undersigned	  have	  reviewed	  the	  format	  and	  content	  of	  this	  prospective	  statistical	  analysis	  plan	  (SAP)	  
and	  have	  approved	  it	  for	  use	  to	  analyze	  the	  HS-­‐11-­‐421	  data.	  
	  
	  
BRAEBURN	  PHARMACEUTICALS	  	  
	  
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Nov	  4,	  2016	  
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Signature	  
	  
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STATISTICIAN	  
	  
Michael	  Chen	  
	  
	  
	  
Nov	  4,	  2016	  
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TABLE	  OF	  CONTENTS	  
1.0	  
DOCUMENT	  HISTORY	  ...........................................................................................................................	  5	  
2.0	  
LIST	  OF	  ABBREVIATIONS	  ....................................................................................................................	  5	  
3.0	  
INTRODUCTION	  ......................................................................................................................................	  6	  
4.0	  
STUDY	  DESCRIPTION	  ............................................................................................................................	  6	  
4.1	  
Study	  Objectives	  ......................................................................................................................	  6	  
4.2	  
Study	  Treatments	  ....................................................................................................................	  7	  
4.3	  
Study	  Design	  ..............................................................................................................................	  7	  
4.4	  
Randomization	  and	  Blinding	  ...............................................................................................	  8	  
5.0	  
ANALYSIS	  POPULATIONS	  ....................................................................................................................	  8	  
5.1	  
Safety	  Population	  ....................................................................................................................	  8	  
5.2	  
Intent-­‐‑to-­‐‑Treat	  Population	  ..................................................................................................	  9	  
5.3	  
modified	  intent-­‐‑to-­‐‑treat	  population	  .................................................................................	  9	  
5.4	  
per	  protocol	  Population	  ........................................................................................................	  9	  
6.0	  
GENERAL	  CONVENTIONS	  .....................................................................................................................	  9	  
6.1	  
Definition	  of	  Baseline	  .............................................................................................................	  9	  
6.2	  
Software	  ......................................................................................................................................	  9	  
6.3	  
Changes	  to	  Planned	  Analyses	  ..............................................................................................	  9	  
7.0	  
DESCRIPTION	  OF	  THE	  STUDY	  POPULATIONS	  ............................................................................	  10	  
7.1	  
Disposition	  ...............................................................................................................................	  10	  
7.2	  
Demographic	  and	  Baseline	  Characteristics	  ..................................................................	  10	  
7.3	  
Medical	  History	  ......................................................................................................................	  10	  
8.0	  
PRIOR	  AND	  CONCOMITANT	  MEDICATIONS	  ................................................................................	  10	  
9.0	  
EFFICACY	  ANALYSES	  ...........................................................................................................................	  11	  
9.1	  
Primary	  Efficacy	  VARIABLE	  –	  Responder	  rate	  .............................................................	  11	  
9.1.1	  
derivation	  of	  response	  rate	  ................................................................................................	  11	  
9.1.2	  
Primary	  Analysis	  .....................................................................................................................	  12	  
9.1.3	  
missing	  value	  imputation	  ....................................................................................................	  12	  
9.2	  
Secondary	  Efficacy	  VARIABLES	  .........................................................................................	  12	  
9.2.1	  
Cumulative	  distribution	  function	  (CDF)	  of	  percent	  samples	  that	  are	  negative	  
for	  illicit	  opioids	  (Weeks	  5-­‐‑25)	  .........................................................................................	  13	  
9.2.2	  
time	  to	  sustained	  abstinence	  of	  opioid	  use	  .................................................................	  13	  
9.2.3	  
Percent	  of	  subjects	  remaining	  in	  the	  study	  (Retention	  Rate)	  ..............................	  13	  
9.3	  
EXPLORATORY	  Efficacy	  VARIABLES	  ...............................................................................	  13	  
9.3.1	  
Response	  rate	  (RR)	  for	  phase	  1	  ........................................................................................	  14	  
9.3.2	  
Response	  rate	  (RR)	  for	  phase	  2	  ........................................................................................	  14	  
9.3.3	  
percentage	  negative	  urine	  samples	  in	  phase	  1	  (weeks	  3-­‐‑13)	  .............................	  14	  
9.3.4	  
percentage	  negative	  urine	  samples	  in	  phase	  2	  (weeks	  14-­‐‑25)	  ...........................	  14	  
9.3.5	  
Percent	  of	  Subjects	  with	  no	  Illicit	  Opioid	  Use	  by	  time	  point	  ................................	  14	  


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9.3.6	  
Cumulative	  Percentage	  of	  SUBJECTS	  with	  Evidence	  of	  No	  Illicit	  Opioid	  Use	  by	  
time	  point	  after	  2	  months	  of	  treatment	  ........................................................................	  15	  
9.3.7	  
Percent	  of	  Subjects	  with	  No	  Self-­‐‑Reported	  Illicit	  opioid	  Use	  by	  time	  point	  ..	  15	  
9.3.8	  
Percent	  of	  subjects	  meeting	  criteria	  of	  stability	  by	  time	  point	  ...........................	  15	  
9.3.9	  
Measures	  of	  craving	  (VAS)	  ..................................................................................................	  16	  
9.3.10	   Measures	  of	  withdrawal	  SYMPTOMS	  .............................................................................	  16	  
9.3.11	   Percent	  of	  subjects	  without	  evidence	  of	  using	  other	  drugs	  of	  abuse	  by	  time	  
point	  ..............................................................................................................................................	  17	  
9.3.12	   Supplemental	  BPN	  use	  .........................................................................................................	  17	  
9.3.13	   Additional	  supplemental	  counseling	  ..............................................................................	  17	  
9.3.14	   Measures	  of	  morning	  need	  to	  use/desire	  to	  use	  (VAS)	  ..........................................	  17	  
9.4	  
Interim	  Analyses	  ....................................................................................................................	  17	  
9.5	  
Adjustments	  for	  Multiplicity	  .............................................................................................	  17	  
9.6	  
Power	  and	  Sample	  Size	  Justification	  ...............................................................................	  18	  
10.0	  
SUMMARIES	  OF	  MEASURES	  OF	  SAFETY	  ........................................................................................	  18	  
10.1	  
Extent	  of	  Exposure	  ................................................................................................................	  18	  
10.2	  
Adverse	  Events	  .......................................................................................................................	  18	  
10.3	  
Laboratory	  Assessments	  .....................................................................................................	  19	  
10.4	  
Vital	  Signs	  .................................................................................................................................	  20	  
10.5	  
Physical	  Examination	  ...........................................................................................................	  20	  
10.6	  
12-­‐‑Lead	  Electrocardiogram	  (ECG)	  ...................................................................................	  20	  
10.7	  
injection	  Site	  Examination	  .................................................................................................	  21	  
11.0	  
IDENTIFICATION	  AND	  SUMMARY	  OF	  PROTOCOL	  DEVIATIONS	  ...........................................	  21	  
12.0	  
DATA	  QUALITY	  ASSURANCE	  ............................................................................................................	  21	  
13.0	  
REFERENCES	  ..........................................................................................................................................	  21	  
14.0	  
APPENDICES	  ..........................................................................................................................................	  22	  
14.1	  
Appendix	  A	  -­‐‑	  Imputation	  Algorithm	  for	  Partial	  and	  Missing	  Dates	  ......................	  22	  
14.2	  
Appendix	  B	  –	  List	  of	  tables,	  listings,	  and	  figures	  .........................................................	  23	  
	  


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1.0  
DOCUMENT	  HISTORY	  
Version	  
Date	  	  
Changes	  made	  since	  previous	  version	  
0.01	  
27	  Jan,	  2016	  
First	  draft	  
1.00	  
20	  October,	  2016	  
Final	  after	  receiving	  FDA’s	  comments	  dated	  on	  01	  Sept	  2016	  
1.01	  
4	  November,	  2016	  
Due	   to	   differences	   in	   analyses	   requested	   by	   the	   FDA	   and	   EMA	  
and	  to	  avoid	  confusion,	  as	  stated	  in	  the	  protocol,	  two	  SAPs	  will	  
be	   prepared,	   one	   for	   FDA	   submission	   and	   one	   for	   the	   EMA	  
submission.	   	   Additionally,	   this	   version	   incorporates	   FDA’s	  
comments	  dated	  on	  04	  Nov	  2016.	  Version	  1.00	  was	  revised	  to	  
reflect	  statistical	  analysis	  plan	  for	  the	  US	  FDA	  submission.	  	  The	  
EMA	   specific	   variables	   are	   removed	   from	   Version	   1.00.	   	   No	  
analysis	  methodologies	  are	  changed	  from	  Version	  1.00.	  
	  
2.0  
LIST	  OF	  ABBREVIATIONS	  
Abbreviation	  
Definition	  
AE	  
Adverse	  Event	  
ANCOVA	  
Analysis	  of	  Covariance	  
ANOVA	  
Analysis	  of	  Variance	  
BMI	  
Body	  Mass	  Index	  	  
BPN	  
Buprenorphine	  or	  Buprenorphine/Naloxone	  
CDF	  
Cumulative	  Distribution	  Function	  
COWS	  
Clinical	  Opiate	  Withdrawal	  Scale	  
CRF	  
Case	  Report	  Form	  (may	  include	  electronic	  data	  capture	  systems	  or	  paper	  forms)	  
FID	  
First	  Injection	  Date	  
ICH	  
International	  Council	  for	  Harmonisation	  
ITT	  
Intent-­‐to-­‐Treat	  
LD	  
Last	  Date	  in	  the	  study	  
LOCF	  
Last	  Observation	  Carried	  Forward	  
MedDRA	  
Medical	  Dictionary	  for	  Regulatory	  Activities	  
mg	  
Milligram	  
mITT	  
Modified	  Intent-­‐to-­‐Treat	  
PT	  
MedDRA	  Preferred	  Term	  
RR	  
Response	  Rate	  
SAE	  	  
Serious	  Adverse	  Event	  
SAP	  
Statistical	  Analysis	  Plan	  
SC	  
Subcutaneous	  
SD	  
Standard	  Deviation	  
SL	  
Sublingual	  	  
SOC	  
MedDRA	  System	  Organ	  Class	  
SOWS	  
Subjective	  Opiate	  Withdrawal	  Scale	  
TEAE	  
Treatment-­‐Emergent	  Adverse	  Event	  
VAS	  
Visual	  Analog	  Scale	  
	  


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3.0  
INTRODUCTION	  
This	  statistical	  analysis	  plan	  (SAP)	  is	  based	  on	  Protocol	  HS-­‐11-­‐421	  Amendment	  5,	  dated	  on	  November	  3,	  
2016.	  
The	  purpose	  of	  this	  document	  is	  to	  provide	  details	  on	  study	  populations	  and	  on	  how	  the	  variables	  will	  be	  
derived,	  how	  missing	  data	  will	  be	  handled,	  as	  well	  as	  details	  on	  statistical	  methodologies	  to	  be	  used	  to	  
analyze	  the	  safety	  and	  efficacy	  data	  from	  the	  study.	  	  	  
	  
The	  document	  may	  evolve	  over	  time,	  for	  example,	  to	  reflect	  the	  requirements	  of	  protocol	  amendments	  
or	  regulatory	  requests.	  	  However,	  the	  final	  SAP	  must	  be	  finalized,	  approved	  by	  the	  Sponsor,	  and	  placed	  
on	  file	  before	  database	  is	  locked	  and	  treatment	  codes	  are	  unblinded.	  	  Deviations	  from	  the	  approved	  
plan	  will	  be	  noted	  in	  the	  clinical	  study	  report.	  
	  
The	  primary	  endpoint	  response	  rate	  will	  be	  used	  to	  address	  the	  regulatory	  requirements	  as	  outlined	  by	  
the	   US	   Food	   and	   Drug	   Administration	   (FDA).	   Specifically,	   the	   FDA	   requested	   an	   alternative	   primary	  
efficacy	   responder	   definition	   on	   September	   1,	   2016,	   which	   have	   been	   incorporated	   in	   this	   final	   SAP.	  
Additionally,	  the	  FDA	  provided	  comments	  on	  November	  4,	  2016	  and	  recommended	  a	  NI	  margin	  of	  10%	  
points	  to	  be	  reasonable	  NI	  margin	  for	  the	  study.	  This	  change	  is	  reflected	  in	  this	  final	  SAP.	  	  	  
	  
The	   European	   Medical	   Agency	   (EMA)	   has	   requested	   percent	   negative	   urine	   samples	   as	   the	   primary	  
endpoint	  and	  retention	  rate	  as	  key	  secondary	  endpoint.	  These	  requests	  are	  addressed	  in	  a	  separate	  SAP	  
for	  EMA	  submission.	  	  The	  variables	  related	  to	  the	  percentage	  of	  urine	  sample	  negative	  (EMA	  specific	  
variables)	  are	  removed	  from	  Version	  1.01	  that	  is	  for	  FDA	  submission.	  
	  
	  
4.0  
STUDY	  DESCRIPTION	  
4.1  
STUDY	  OBJECTIVES	  
The	  primary	  objective	  of	  the	  study	  is	  to	  demonstrate	  non-­‐inferiority	  of	  the	  CAM2038	  buprenorphine	  
(BPN)	  treatment	  arm	  as	  compared	  to	  the	  sublingual	  (SL)	  BPN	  treatment	  arm	  in	  treating	  adult	  
outpatients	  with	  opioid	  use	  disorder,	  as	  measured	  by	  the	  primary	  efficacy	  measure	  of	  response	  rate	  
(RR).	  
The	  secondary	  objectives	  of	  the	  study	  are:	  
•  
To	  evaluate	  the	  efficacy	  of	  CAM2038	  compared	  to	  SL	  BPN	  in	  adult	  outpatients	  with	  opioid	  use	  
disorder,	  as	  measured	  by	  cumulative	  distribution	  function	  of	  percent	  negative	  urines	  (supported	  
by	  self-­‐reported	  opioid	  use	  results)	  between	  Weeks	  5	  and	  24.	  
•  
To	  evaluate	  the	  efficacy	  of	  CAM2038	  compared	  to	  SL	  BPN	  in	  adult	  outpatients	  with	  opioid	  use	  
disorder,	  as	  measured	  by	  the	  secondary	  efficacy	  measure	  of	  time	  to	  sustained	  abstinence	  from	  
illicit	  opioid	  use.	  
•  
To	  evaluate	  the	  efficacy	  of	  CAM2038	  compared	  to	  SL	  BPN	  in	  adult	  outpatients	  with	  opioid	  use	  
disorder,	  as	  measured	  by	  the	  secondary	  efficacy	  measure	  retention	  rate.	  
•  
To	  evaluate	  the	  efficacy	  of	  CAM2038	  compared	  to	  SL	  BPN	  in	  adult	  outpatients	  with	  opioid	  use	  
disorder,	  as	  measured	  by	  the	  exploratory	  efficacy	  measures.	  


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•  
To	  evaluate	  the	  safety	  of	  CAM2038	  in	  adult	  outpatients	  with	  opioid	  use	  disorder.	  
	  
4.2  
STUDY	  TREATMENTS	  	  
In	  this	  double-­‐blind	  and	  double-­‐dummy	  study,	  subjects	  will	  be	  randomized	  to	  one	  of	  two	  treatment	  
groups	  in	  a	  1:1	  ratio:	  
Treatment	  Group	  1:	  SL	  BPN	  tablets	  +	  placebo	  subcutaneous	  (SC)	  injections	  
Treatment	  Group	  2:	  CAM2038	  SC	  injections	  +	  SL	  placebo	  tablets	  
4.3  
STUDY	  DESIGN	  
This	  is	  a	  randomized,	  double-­‐blind,	  double-­‐dummy,	  active-­‐controlled,	  parallel	  group	  multi-­‐center	  trial,	  
designed	  to	  evaluate	  the	  non-­‐inferiority	  of	  CAM2038	  compared	  to	  an	  existing	  standard	  of	  care	  (SL	  BPN)	  
in	  initiation	  and	  maintenance	  treatment	  with	  BPN.	  The	  trial	  will	  involve	  4	  phases:	  Screening,	  Phase	  1	  
(weekly	  visits),	  Phase	  2	  (monthly	  visits),	  and	  Follow-­‐up.	  
	  
Following	  Screening	  and	  confirmation	  of	  eligibility,	  subjects	  will	  be	  randomized	  to	  one	  of	  two	  treatment	  
groups	  in	  a	  1:1	  ratio:	  	  
	  
•  
Group	  1:	  SL	  BPN	  tablets	  +	  placebo	  SC	  injections	  
•  
Group	  2:	  CAM2038	  SC	  injections	  +	  SL	  placebo	  tablets	  
	  
Following	   randomization,	   subjects	   will	   undergo	   initiation	   of	   BPN	   treatment	   with	   either	   SL	   BPN	   or	   SC	  
CAM2038	  q1w,	  and	  participate	  in	  weekly	  visits	  for	  12	  weeks	  (Phase	  1).	  After	  Week	  12,	  subjects	  will	  be	  
transitioned	  to	  Phase	  2	  with	  monthly	  visits.	  During	  Phase	  2,	  subjects	  in	  Group	  1	  will	  continue	  treatment	  
with	  monthly	  dispensing	  of	  daily	  SL	  BPN	  treatment	  and	  monthly	  placebo	  SC	  injections,	  and	  subjects	  in	  
Group	   2	   (receiving	   CAM2038	   q1w)	   will	   be	   transferred	   to	   monthly	   injections	   of	   CAM2038	   q4w	   and	  
monthly	   dispensing	   of	   daily	   SL	   placebo.	   Subjects	   will	   participate	   in	   6	   visits	   during	   the	   12	   weeks	   of	  
Phase	  2;	   3	   scheduled	   monthly	   visits	   and	   3	   random	   urine	   toxicology	   visits.	   At	   each	   random	   urine	  
toxicology	   visit,	   subject’s	   self-­‐reported	   illicit	   use	   will	   be	   collected.	   After	   Phase	   2,	   subjects	   will	   be	  
followed-­‐up	  for	  4	  weeks.	  
	  
A	  total	  of	  18	  opioid	  urine	  toxicology	  samples	  will	  be	  collected	  during	  Phase	  1	  and	  Phase	  2	  of	  the	  trial,	  
whereof	  12	  samples	  will	  be	  collected	  at	  the	  scheduled	  weekly	  visits	  during	  Phase	  1.	  A	  total	  of	  6	  opioid	  
urine	  toxicology	  samples	  will	  be	  collected	  during	  the	  12	  weeks	  of	  Phase	  2	  (3	  at	  the	  scheduled	  monthly	  
visits	   and	   3	   at	   random	   urine	   toxicology	   visits).	   A	   self-­‐report	   of	   drug	   use	   will	   accompany	   every	   urine	  
toxicology	  test.	  
	  
Subjects	  who	  complete	  the	  24	  weeks	  of	  treatment	  (i.e.,	  Phase	  1	  and	  Phase	  2)	  will	  be	  transitioned	  to	  
standard	  of	  care	  (e.g.,	  SL	  BPN)	  and	  be	  followed	  up	  for	  4	  weeks.	  
	  
All	  subjects	  will	  be	  blinded	  to	  their	  treatment	  group	  assignment,	  as	  will	  all	  trial	  staff	  with	  the	  exception	  
of	  the	  clinician(s)/staff	  performing	  the	  SC	  injections	  and	  designated	  personnel	  who	  will	  be	  responsible	  
for	  drug	  accountability	  (i.e.,	  counting	  the	  active	  and	  placebo	  SL	  BPN	  returned	  tablets).	  
	  	  


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To	  ensure	  adequate	  enrollment	  and	  address	  potential	  inconvenience	  to	  subjects,	  all	  subjects	  (regardless	  
of	  randomized	  group)	  will	  receive	  appropriate	  compensation	  for	  time	  and	  travel	  expenses	  related	  to	  
attendance	  at	  trial	  visits.	  All	  costs	  of	  study	  related	  medications	  and	  counseling	  will	  also	  be	  covered.	  
Investigators	   will	   be	   instructed	   to	   use	   manual-­‐guided	   psychosocial	   counseling	   for	   trial	   subjects	  
throughout	  the	  trial	  period.	  	  	  
4.4  
RANDOMIZATION	  AND	  BLINDING	  
Randomization	   will	   be	   used	   to	   avoid	   bias	   in	   the	   assignment	   of	   subjects	   to	   treatment	   sequences,	   to	  
increase	   the	   likelihood	   that	   known	   and	   unknown	   subject	   attributes	   (e.g.,	   demographics,	   baseline	  
characteristics)	  are	  evenly	  balanced	  across	  treatment	  groups,	  and	  to	  enhance	  the	  validity	  of	  statistical	  
comparisons	  across	  treatment	  groups.	  
Subjects	   who	   have	   provided	   written	   informed	   consent	   will	   be	   assigned	   a	   unique	   number	   in	   the	  
screening	  process.	  This	  number	  will	  be	  used	  to	  identify	  the	  subject	  throughout	  the	  study.	  
Subjects	  who	  have	  met	  the	  eligibility	  criteria	  (outlined	  in	  Section	  8	  of	  the	  clinical	  trial	  protocol)	  will	  be	  
randomized	   to	   one	   of	   the	   2	   treatment	   groups	   in	   a	   1:1	   ratio	   (Treatment	   Group	   1:	   SL	   BPN	   tablets	   +	  
placebo	  SC	  injections	  or	  Treatment	  Group	  2:	  CAM2038	  SC	  injections	  +	  SL	  placebo	  tablets).	  Due	  to	  the	  
size	  of	  the	  study,	  it	  is	  expected	  that	  subjects	  will	  be	  balanced	  for	  various	  other	  baseline	  factors,	  including	  
age.	  
Once	  any	  subject	  number	  or	  randomization	  number	  is	  assigned,	  it	  cannot	  be	  reassigned	  to	  any	  other	  
subject.	  This	  study	  will	  use	  central	  randomization,	  as	  described	  in	  Section	  10.2	  of	  the	  protocol.	  
In	   order	   to	   reduce	   the	   potential	   for	   bias	   in	   the	   study,	   treatment	   group	   assignments	   will	   be	   double-­‐
blinded.	  The	  subject,	  investigational	  site	  personnel,	  Sponsor,	  and	  Sponsor	  designees	  directly	  involved	  in	  
the	   conduct	   and/or	   monitoring	   of	   this	   study	   will	   not	   be	   aware	   of	   the	   treatment	   group	   assignments.	  
Sublingual	  BPN	  tablets	  used	  during	  the	  study	  will	  have	  a	  nearly-­‐matching	  placebo.	  	  
Under	   normal	   circumstances,	   the	   blind	   will	   not	   be	   broken	   until	   all	   participants	   have	   completed	  
treatment.	  In	  case	  of	  emergency,	  and	  only	  if	  the	  information	  is	  required	  by	  the	  Investigator	  to	  ensure	  
subject’s	  safety	  in	  managing	  a	  medical	  condition,	  the	  treatment	  may	  be	  unblinded	  at	  the	  site	  by	  using	  a	  
code	  break	  module.	  The	  code	  break	  module	  will	  be	  provided	  by	  the	  Sponsor	  or	  designee.	  If	  possible,	  the	  
Investigator	   should	   contact	   the	   Sponsor	   prior	   to	   unblinding	   and	   after	   any	   actions	   have	   been	   taken.	  
Whenever	  a	  treatment	  sequence	  is	  prematurely	  unblinded,	  the	  reason,	  date	  and	  time	  of	  the	  unblinding,	  
and	   the	   individual	   who	   broke	   the	   blind	   must	   be	   documented.	   Individual	   code	   breaks	   will	   result	   in	  
withdrawal	  of	  the	  participant	  from	  the	  study.	  	  
5.0  
ANALYSIS	  POPULATIONS	  
5.1  
SAFETY	  POPULATION	  
The	   safety	   population	   will	   include	   all	   subjects	   who	   have	   any	   dose	   of	   SL	   BPN/placebo	   or	   SC	  
CAM2038/placebo	   injection.	   Analyses	   based	   on	   this	   population	   will	   group	   subjects	   according	   to	   the	  
treatment	   they	   actually	   received	   regardless	   of	   the	   treatment	   they	   were	   randomized	   to	   receive.	   All	  
safety	  analyses	  will	  use	  the	  safety	  population.	  


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5.2  
INTENT-­‐‑TO-­‐‑TREAT	  POPULATION	  
The	  Intent-­‐to-­‐Treat	  (ITT)	  population	  will	  consist	  of	  all	  randomized	  subjects.	  The	  primary	  efficacy	  analyses	  
will	  be	  based	  on	  the	  ITT	  population.	  
5.3  
MODIFIED	  INTENT-­‐‑TO-­‐‑TREAT	  POPULATION	  
The	  modified	  Intent-­‐to-­‐Treat	  (mITT)	  population	  will	  consist	  of	  all	  randomized	  subjects	  who	  received	  any	  
SL	  BPN/placebo	  or	  SC	  CAM2038/placebo	  injection.	  	  It	  is	  expected	  that	  the	  ITT	  and	  mITT	  population	  will	  
be	  nearly	  identical.	  	  The	  results	  for	  the	  mITT	  population	  will	  not	  be	  presented	  if	  the	  two	  populations	  are	  
differed	  by	  less	  than	  five	  (5)	  subjects	  as	  in	  this	  case	  the	  conclusions	  based	  on	  the	  two	  populations	  should	  
be	  identical.	  
5.4  
PER	  PROTOCOL	  POPULATION	  
The	   Per	   Protocol	   population	   will	   include	   all	   subjects	   in	   the	   ITT	   population	   with	   no	   major	   protocol	  
violations.	   Major	   protocol	   violation	   criteria	   will	   be	   established	   prior	   to	   the	   data	   base	   lock.	   Protocol	  
deviations	  will	  be	  presented	  in	  the	  clinical	  study	  report.	  Efficacy	  analyses	  may	  also	  be	  performed	  based	  
on	  the	  per	  protocol	  population.	  	  	  
	  
6.0  
GENERAL	  CONVENTIONS	  
Unless	   otherwise	   stated,	   all	   analyses	   will	   be	   performed	   using	   SAS	   Version	   9.2	   or	   higher	   and	   all	  
hypothesis	  tests	  will	  be	  conducted	  at	  a	  two-­‐sided	  significance	  level	  of	  0.05.	  P-­‐values	  will	  be	  presented	  
with	  3	  decimals	  and	  p-­‐values	  that	  are	  less	  than	  0.001	  will	  be	  presented	  as	  <0.001.	  
	  
Continuous	   (non	   survival	   related)	   data	   will	   be	   summarized	   using	   descriptive	   statistics:	   number	   of	  
observations	   (n),	   mean,	   standard	   deviation	   (SD),	   median,	   minimum,	   and	   maximum.	   Frequencies	   and	  
percentages	  will	  be	  used	  to	  summarize	  categorical	  (discrete)	  data.	  Presentations	  of	  categorical	  data	  will	  
generally	   suppress	   percentages	   for	   items	   where	   the	   count	   is	   zero	   in	   order	   to	   draw	   attention	   to	   the	  
nonzero	  counts.	  In	  general,	  mean,	  standard	  deviation,	  median,	  minimum,	  maximum,	  and	  percentages	  
will	  be	  presented	  with	  one	  decimal.	  
	  
Unless	   otherwise	   stated,	   confidence	   intervals,	   when	   presented,	   will	   be	   constructed	   at	   the	   two-­‐sided	  
95%	  level.	  For	  binomial	  variables,	  the	  95%	  confidence	  intervals	  will	  be	  constructed	  using	  the	  normal	  
approximation	  without	  continuity	  correction.	  
	  
Data	  listings	  will	  present	  all	  data	  collected	  on	  case	  report	  forms	  (CRFs)	  by	  study	  drug,	  center,	  and	  subject	  
number.	  Unless	  otherwise	  stated	  data	  will	  be	  presented	  by	  treatment	  and	  overall.	  
6.1  
DEFINITION	  OF	  BASELINE	  
Unless	  otherwise	  stated,	  the	  last	  observed	  measurement	  prior	  to	  or	  on	  the	  date	  of	  randomization	  will	  
be	   considered	   the	   baseline	   measurement.	   If	   multiple	   observations	   are	   made	   during	   baseline,	   the	  
baseline	  will	  be	  defined	  as	  average	  of	  the	  observations	  obtained	  during	  the	  baseline	  phase.	  
6.2  
SOFTWARE	  
Analyses	  will	  be	  conducted	  using	  SAS	  Version	  9.2	  or	  higher.	  	  	  
6.3  
CHANGES	  TO	  PLANNED	  ANALYSES	  


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HS-­‐‑11-­‐‑421	  Final	  SAP	  
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Draft	  versions	  of	  the	  SAP	  will	  be	  numbered	  sequentially	  as	  Version	  0.0i.	  The	  final	  approved	  version	  will	  
be	  numbered	  as	  Version	  1.00.	  Revisions	  after	  the	  “Final”	  version	  will	  be	  numbered	  as	  Version	  1.0x.	  The	  
Clinical	   Study	   Report	   will	   document	   any	   changes	   made	   after	   the	   final	   version	   approved	   before	  
unblinding.	  
	  
7.0  
DESCRIPTION	  OF	  THE	  STUDY	  POPULATIONS	  
All	   tables,	   figures,	   and	   listings	   must	   include	   a	   population	   descriptor	   (e.g.,	   ITT	   population,	   mITT	  
population,	  safety	  population,	  or	  per	  protocol	  population)	  in	  the	  title.	  
7.1  
DISPOSITION	  
Subject	   disposition	   summaries	   will	   be	   presented	   by	   treatment	   arm	   and	   will	   include	   the	   number	   of	  
subjects	  randomized,	  the	  number	  and	  percentage	  of	  randomized	  subjects	  in	  the	  safety,	  ITT,	  mITT	  and	  
per	  protocol	  (if	  applicable)	  populations,	  as	  well	  as	  the	  number	  and	  percentage	  of	  subjects	  who	  complete	  
the	  study.	  The	  summaries	  will	  also	  include	  the	  reasons	  for	  early	  discontinuation	  from	  the	  study.	  	  	  
	  
Disposition	   summaries	   will	   be	   presented	   for	   safety,	   ITT,	   mITT,	   and	   per	   protocol	   populations	   (if	  
applicable)	  separately.	  
7.2  
DEMOGRAPHIC	  AND	  BASELINE	  CHARACTERISTICS	  
A	  summary	  of	  demographics	  and	  baseline	  characteristics	  will	  be	  presented	  by	  treatment	  arm	  and	  overall	  
for	  the	  ITT	  and	  safety	  populations.	  The	  demographic	  characteristics	  will	  consist	  of	  age,	  sex,	  ethnicity,	  
and	  race	  using	  descriptive	  statistics.	  
	  
Demographic	  data	  including	  age,	  race,	  ethnicity,	  and	  gender,	  as	  well	  as	  baseline	  clinical	  characteristics	  
will	  be	  summarized.	  Age	  will	  be	  calculated	  based	  on	  the	  following	  conditional	  algorithm:	  	  
•  
Has	  the	  patient	  had	  his/her	  birthday	  this	  year?	  
o   Yes,	  then	  AGE	  =	  (year	  of	  informed	  consent)	  –	  (year	  of	  birth).	  
o   No,	  then	  AGE	  =	  (year	  of	  informed	  consent)	  –	  (year	  of	  birth)	  –	  1.	  
	  
Clinical	   baseline	   characteristics	   (including	   height,	   weight	   and	   body	   mass	   index	   [BMI]),	   psychosocial	  
history,	  and	  substance	  abuse	  treatment	  history	  will	  be	  summarized	  by	  treatment	  group	  and	  overall.	  
7.3  
MEDICAL	  HISTORY	  
Medical	  history	  will	  be	  coded	  using	  MedDRA	  dictionary	  Version	  18.	  Medical	  history	  will	  be	  presented.	  	  	  
	  
8.0  
PRIOR	  AND	  CONCOMITANT	  MEDICATIONS	  
All	  medications	  recorded	  on	  the	  CRFs	  will	  be	  coded	  using	  the	  WHO	  DRUG	  Dictionary	  Enhanced	  March	  
2015.	  Prior	  and	  concomitant	  medications	  will	  be	  summarized	  by	  treatment	  arm	  in	  the	  safety	  population	  
by	  anatomical	  therapeutic	  chemical	  Class	  Level	  4	  and	  WHO	  Drug	  base	  substance	  preferred	  name.	  
	  
Prior	   medications	   are	   defined	   as	   medications	   with	   stop	   dates	   occurring	   before	   the	   date	   of	   first	  
administration	  of	  any	  study	  treatment	  component.	  Concomitant	  medications	  are	  defined	  as	  medications	  
with	  start	  dates	  occurring	  on	  or	  after	  the	  date	  of	  first	  administration	  of	  any	  study	  treatment	  component	  
and	  no	  more	  than	  30	  days	  after	  the	  last	  administration	  of	  any	  study	  treatment	  component.	  Medications	  


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with	  start	  and	  stop	  dates	  that	  bracket	  the	  date	  of	  first	  administration	  of	  any	  study	  treatment	  component	  
will	  be	  summarized	  as	  both	  prior	  and	  concomitant	  medications.	  
	  
Medications	  that	  clearly	  stopped	  prior	  to	  date	  of	  first	  administration	  of	  any	  study	  treatment	  component	  
will	  be	  included	  in	  the	  prior	  medications	  table,	  and	  medications	  that	  clearly	  started	  on	  or	  after	  date	  of	  
first	  administration	  of	  any	  study	  treatment	  component	  will	  be	  included	  in	  the	  concomitant	  medications	  
table.	  All	  other	  medications	  will	  be	  included	  in	  both	  the	  prior	  and	  concomitant	  medications	  tables.	  
	  
Prior	  and	  concomitant	  medication	  will	  be	  summarized	  for	  the	  safety	  population.	  
	  
9.0  
EFFICACY	  ANALYSES	  
9.1  
PRIMARY	  EFFICACY	  VARIABLE	  –	  RESPONDER	  RATE	  
The	  responder	  definition	  will	  be	  derived	  based	  on	  urine	  samples	  obtained	  from	  Weeks	  10,	  11,	  12	  and	  13	  
in	  Phase	  1	  and	  samples	  obtained	  at	  Weeks	  17	  (end	  of	  Month	  1	  of	  Phase	  2),	  21	  (end	  of	  Month	  2	  of	  Phase	  
2)	  and	  25	  (end	  of	  Month	  3	  of	  Phase	  2)	  and	  at	  the	  3	  random	  samples	  in	  Phase	  2.	  	  
	  
To	  be	  a	  responder	  for	  Phase	  1,	  the	  subject	  must	  have	  no	  evidence	  of	  illicit	  opioids	  use	  at	  Week	  13	  and	  
have	  no	  evidence	  of	  illicit	  opioids	  use	  for	  at	  least	  2	  out	  of	  the	  three	  weeks	  from	  Week	  10	  to	  Week	  12.	  To	  
be	  a	  responder	  for	  Phase	  2,	  the	  subject	  must	  have	  no	  evidence	  of	  illicit	  opioids	  use	  at	  Month	  6	  and	  have	  
no	  evidence	  of	  illicit	  opioids	  use	  in	  5	  out	  of	  the	  6	  illicit	  opioids	  use	  assessments	  in	  Phase	  2.	  To	  be	  a	  
responder	  for	  the	  study,	  the	  subject	  must	  be	  a	  responder	  for	  both	  Phases	  1	  and	  2.	  	  
	  
Please	   note	   that	   EMA	   requested	   percent	   negative	   urine	   samples	   as	   the	   primary	   endpoint	   for	   their	  
evaluation.	  	  Percent	  negative	  urine	  samples	  is	  the	  first	  secondary	  endpoint	  (see	  Section	  9.2.1)	  for	  this	  
study.	  
9.1.1   DERIVATION	  OF	  RESPONSE	  RATE	  
For	  the	  purpose	  of	  deriving	  the	  RR,	  the	  following	  rules	  will	  be	  used:	  
	  
Time	  Windows	  for	  Illicit	  Opioid	  Use	  Assessment	  
For	  easy	  discussion,	  unless	  otherwise	  stated	  a	  window	  denoted	  as	  Week	  (x+,	  y)	  for	  efficacy	  assessment	  
is	  a	  window	  that	  covers	  a	  period	  between	  Week	  x	  +1	  day	  to	  Week	  y	  day	  (exclusive	  of	  Week	  x	  day	  but	  
inclusive	   of	   Week	   y	   day).	   A	   window	   denoted	   as	   Weeks	   x-­‐y	   for	   efficacy	   assessment	   is	   a	   window	   that	  
covers	  a	  period	  between	  Week	  x	  day	  to	  Week	  y	  day	  (inclusive	  of	  Week	  x	  day	  and	  Week	  y	  day).	  	  	  
	  
Subjects	  will	  receive	  12	  weekly	  injections	  from	  Week	  1	  (Day	  1	  Week	  1)	  through	  Week	  12.	  	  Subjects	  will	  
then	  receive	  three	  monthly	  injections	  at	  Week	  13,	  Week	  17,	  and	  Week	  21.	  	  Since	  the	  last	  weekly	  dosing	  
will	  occur	  at	  Week	  12,	  the	  efficacy	  assessments	  collected	  at	  Week	  13	  reflected	  effects	  of	  weekly	  dosing	  
in	  Phase	  1.	  	  The	  Phase	  1	  window	  is	  Week	  (1+,	  13).	  	  Since	  the	  last	  monthly	  dosing	  will	  occur	  at	  Week	  21	  
Phase	  2	  efficacy	  window	  will	  be	  Week	  (13+,	  25).	  
	  
Due	  to	  visit	  date	  deviation,	  the	  actual	  days	  in	  Phase	  1	  and	  Phase	  2	  may	  not	  be	  exactly	  equal	  to	  91	  days	  
(13	  weeks)	  and	  84	  days	  (12	  weeks),	  respectively.	  Similarly,	  for	  analysis	  purpose,	  weekly	  and	  monthly	  
windows	  will	  be	  based	  on	  the	  visit	  windows,	  instead	  of	  exact	  7-­‐day	  and	  exact	  30-­‐day	  windows.	  


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Evidence	  of	  Illicit	  Opioid	  Use	  within	  a	  Window	  
Subject	   response	   for	   Phase	   1	   will	   be	   based	   on	   the	   12	   scheduled	   weekly	   post-­‐baseline	   urine	   samples	  
collected	   from	   Weeks	   2-­‐13.	   Subject	   response	   for	   Phase	   2	   will	   be	   based	   on	   the	   3	   scheduled	   monthly	  
urine	  samples	  collected	  at	  Weeks	  17,	  21,	  and	  Week	  25	  and	  the	  3	  random	  samples.	  Evidence	  of	  illicit	  
opioid	  use	  within	  a	  window	  is	  defined	  as	  a	  positive	  opioid	  urine	  toxicology	  result	  or	  self-­‐reported	  illicit	  
opioid	  use	  within	  that	  window,	  including	  the	  results	  from	  random	  urine	  toxicology	  samples	  (in	  Phase	  2)	  
obtained	   within	   that	   window.	   Therefore,	   there	   is	   evidence	   of	   illicit	   opioid	   use,	   if	   self-­‐reported	   illicit	  
opioid	  use	  is	  present,	  regardless	  of	  the	  opioid	  urine	  toxicology	  result	  is	  positive	  or	  negative.	  	  	  
	  
If	   urine	   toxicology	   samples	   are	   missing,	   for	   example,	   due	   to	   missing	   scheduled	   visit,	   early	  
discontinuation	  of	  the	  study,	  or	  subject’s	  refusal	  to	  provide	  the	  samples	  (scheduled	  or	  random	  samples),	  
the	   results	   will	   be	   imputed	   as	   positive	   according	   to	   the	   Missing	   Value	   Imputation	   rules	   discussed	   in	  
Section	  9.1.3	  of	  the	  SAP.	  	  	  
9.1.2   PRIMARY	  ANALYSIS	  
The	  primary	  analysis	  of	  RR	  will	  be	  performed	  based	  on	  the	  ITT	  population.	  	  	  
	  
An	  analysis	  of	  non-­‐inferiority	  in	  the	  primary	  efficacy	  variable	  between	  the	  two	  treatments	  arms	  will	  be	  
performed	  using	  a	  margin	  of	  10%	  point.	  	  
	  
Non-­‐inferiority	  will	  be	  concluded	  if	  the	  two-­‐sided	  95%	  confidence	  interval	  for	  the	  difference	  between	  
the	  probabilities	  of	  response	  (Active-­‐	  Control)	  is	  above	  –0.10.	  The	  95%	  confidence	  interval,	  (LB,	  UB),	  will	  
be	  derived	  using	  normal	  approximation:	  
	  
LB	  =	  (PT-­‐PC)	  –	  1.96*(1/NT*PT*(1-­‐PT)+	  1/NC*PC*(1-­‐PC))0.5	  ,	  and	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  UB	  =	  (PT-­‐PC)	  +	  1.96*(1/NT*PT*(1-­‐PT)+	  1/NC*PC*(1-­‐PC))0.5,	  where	  	  	  	  
	  
PT	  and	  PC	  are	  observed	  proportions	  of	  the	  responders	  for	  the	  treatment	  and	  the	  control,	  respectively,	  
and	  NT	  and	  NC	  are	  the	  sample	  sizes	  for	  the	  treatment	  and	  the	  control,	  respectively.	  
9.1.3   MISSING	  VALUE	  IMPUTATION	  
Unless	  otherwise	  stated	  the	  following	  procedures	  will	  be	  used	  to	  handle	  missing	  values	  for	  urine	  
toxicology.	  	  	  
	  
All	  missing	  urine	  toxicology	  samples	  (scheduled	  or	  random	  samples),	  regardless	  of	  reasons,	  will	  be	  
imputed	  as	  positive.	  	  
	  
Unless	  otherwise	  stated	  all	  other	  missing	  values	  will	  not	  be	  imputed.	  
9.2  
SECONDARY	  EFFICACY	  VARIABLES	  
Secondary	  efficacy	  variables	  will	  include:	  	  
	  
•  
Cumulative	  Distribution	  Function	  (CDF)	  of	  percent	  urine	  samples	  negative	  for	  illicit	  opioids	  
(supported	  by	  self-­‐reported	  illicit	  opioids	  use	  results)	  based	  on	  Weeks	  5-­‐25;	  


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•  
Time	  to	  sustained	  abstinence	  of	  opioid	  use	  (supported	  by	  self-­‐reported	  illicit	  opioids	  use	  
results);	  	  
•  
Percent	  of	  subjects	  remaining	  in	  the	  study	  (retention	  rate);	  
	  	  	  
9.2.1   CUMULATIVE	  DISTRIBUTION	  FUNCTION	  (CDF)	  OF	  PERCENT	  SAMPLES	  
THAT	  ARE	  NEGATIVE	  FOR	  ILLICIT	  OPIOIDS	  (WEEKS	  5-­‐‑25)	  
Percent	  negative	  samples	  from	  15	  samples	  (9	  weekly	  assessments	  obtained	  from	  Weeks	  5	  to	  13,	  plus	  3	  
monthly	  assessments	  obtained	  at	  Weeks	  17,	  21,	  and	  25	  and	  plus	  3	  random	  samples)	  will	  be	  calculated	  
for	  each	  subject.	  	  Missing	  samples	  will	  be	  imputed	  as	  positive	  before	  the	  percentage	  is	  derived.	  	  	  
	  
The	  null	  hypothesis	  of	  no	  difference	  in	  the	  CDF	  of	  the	  percent	  of	  urine	  samples	  that	  are	  negative	  for	  
illicit	  opioids	  over	  Weeks	  5-­‐25	  will	  be	  tested	  at	  the	  5%	  significance	  level	  using	  Wilcoxon	  Rank-­‐Sum	  test.	  
The	  empirical	  CDF	  plot	  will	  be	  presented.	  	  	  
9.2.2   TIME	  TO	  SUSTAINED	  ABSTINENCE	  OF	  OPIOID	  USE	  	  
For	  the	  purpose	  of	  deriving	  time	  to	  sustained	  abstinence	  of	  opioid	  use	  (i.e.,	  no	  opioid	  use	  through	  the	  
rest	  of	  treatment	  period	  for	  at	  least	  two	  months),	  the	  time	  will	  be	  defined	  as:	  
	  
•  
If	  the	  sustained	  abstinence	  is	  obtained	  during	  the	  scheduled	  visit,	  time	  is	  the	  number	  of	  days	  
between	   randomization	   day	   to	   the	   scheduled	   visit	   day.	   	   For	   example,	   if	   first	   sustained	  
abstinence	  is	  obtained	  at	  the	  Week	  8	  visit,	  the	  time	  would	  be	  56.	  
•  
If	  the	  first	  sustained	  abstinence	  is	  obtained	  during	  a	  random	  test,	  time	  is	  the	  number	  of	  days	  
between	  randomization	  day	  to	  the	  day	  that	  random	  sample	  is	  obtained	  (Random	  Sample	  Date	  –	  
Randomization	  Date).	  	  	  
	  
The	  same	  definition	  for	  evidence	  of	  illicit	  opioid	  use	  (see	  Section	  9.1.1)	  and	  the	  same	  rules	  for	  missing	  
value	  imputation	  (see	  Section	  9.1.3)	  will	  be	  used	  in	  the	  calculation.	  	  
	  
Time	  to	  sustained	  abstinence	  of	  opioid	  use	  will	  be	  analyzed	  via	  a	  log-­‐rank	  model	  with	  treatment	  effects.	  
Time	  to	  event	  “Survival”	  curve	  will	  be	  presented	  using	  Kaplan-­‐Meier	  method.	  Median	  time	  to	  event	  and	  
the	  95%	  confidence	  interval	  of	  the	  median	  times	  will	  be	  presented,	  if	  estimable.	  In	  this	  time	  to	  event	  
analyses,	  subjects	  who	  do	  not	  have	  any	  opioid-­‐positive	  results	  during	  the	  entire	  study	  and	  who	  do	  not	  
have	  any	  opioid-­‐positive	  results	  before	  discontinuing	  from	  the	  study	  will	  be	  censored	  at	  Day	  175	  
(Week	  25	  day),	  the	  day	  when	  the	  last	  sample	  will	  be	  obtained.	  
9.2.3   PERCENT	  OF	  SUBJECTS	  REMAINING	  IN	  THE	  STUDY	  (RETENTION	  RATE)	  
The	  percentages	  for	  each	  treatment	  and	  between	  treatment	  percentage	  differences	  will	  be	  estimated.	  
The	  95%	  confidence	  intervals	  of	  the	  estimated	  treatment	  differences,	  based	  on	  a	  normal	  approximation,	  
will	  be	  presented.	  In	  addition,	  the	  retention	  rate	  will	  be	  analyzed	  using	  a	  chi	  square	  test.	  	  
	  
An	  analysis	  of	  non-­‐inferiority	  in	  this	  variable	  between	  the	  two	  treatments	  arms	  will	  be	  performed	  using	  
a	  margin	  of	  15%	  point.	  Non-­‐inferiority	  will	  be	  concluded	  if	  the	  two-­‐sided	  95%	  confidence	  interval	  for	  the	  
difference	  in	  retention	  rate	  (Active-­‐	  Control)	  is	  above	  15%.	  
9.3  
EXPLORATORY	  EFFICACY	  VARIABLES	  


BRAEBURN	  PHARMACEUTICALS	   CONFIDENTIAL	  
Version	  1.01—4	  November,	  2016	  
HS-­‐‑11-­‐‑421	  Final	  SAP	  
Page	  14	  of	  27	  
	  
	  
Exploratory	  efficacy	  variables	  will	  include:	  
•  
Primary	  endpoint	  RR	  for	  Phase	  1;	  
•  
Primary	  endpoint	  RR	  for	  Phase	  2;	  
•  
Percentage	  negative	  urine	  samples	  in	  Phase	  1;	  	  
•  
Percentage	  negative	  urine	  samples	  in	  Phase	  2;	  
•  
Percent	  of	  subjects	  with	  evidence	  of	  no	  illicit	  opioid	  use	  by	  time	  point;	  
•  
Cumulative	  percentage	  of	  subjects	  with	  evidence	  of	  no	  illicit	  opioid	  use	  after	  two	  months	  of	  
treatment	  by	  time	  point	  (from	  Week	  9	  to	  Week	  25);	  
•  
Percent	  of	  subjects	  with	  no	  self-­‐reported	  illicit	  opioid	  use	  by	  time	  point;	  
•  
Percent	  of	  subjects	  meeting	  criteria	  of	  stability	  at	  Week	  13;	  
•  
Measures	  of	  craving:	  Desire	  to	  Use	  visual	  analog	  scale	  (VAS)	  and	  Need	  to	  Use	  VAS;	  
•  
Measures	  of	  withdrawal:	  Clinical	  Opiate	  Withdrawal	  Scale	  (COWS)	  and	  Subjective	  Opiate	  
Withdrawal	  Scale	  (SOWS);	  	  
•  
Percent	  of	  subjects	  without	  evidence	  of	  using	  other	  drugs	  of	  abuse	  by	  time	  point;	  
•  
Supplemental	  BPN	  use;	  
•  
Additional	  supplemental	  counseling;	  
•  
Measures	  of	  morning	  need	  to	  use/desire	  to	  use	  
9.3.1   RESPONSE	  RATE	  (RR)	  FOR	  PHASE	  1	  	  
The	  treatment	  differences	  in	  RR	  based	  on	  the	  primary	  responder	  definition	  and	  based	  on	  responder	  for	  
Phase	   1	   will	   be	   analyzed	   using	   chi	   square	   test.	   The	   percentages	   for	   each	   treatment	   and	   between	  
treatment	  percentage	  differences	  will	  be	  estimated.	  The	  95%	  confidence	  intervals	  of	  the	  estimates	  will	  
be	  presented	  using	  normal	  approximation.	  
9.3.2   RESPONSE	  RATE	  (RR)	  FOR	  PHASE	  2	  	  
The	  treatment	  differences	  in	  RR	  based	  on	  the	  primary	  responder	  definition	  for	  Phase	  2	  will	  be	  analyzed	  
using	   chi	   square	   test.	   The	   percentages	   for	   each	   treatment	   and	   between	   treatment	   percentage	  
differences	   will	   be	   estimated.	   The	   95%	   confidence	   intervals	   of	   the	   estimates	   will	   be	   presented	   using	  
normal	  approximation.	  
9.3.3   PERCENTAGE	  NEGATIVE	  URINE	  SAMPLES	  IN	  PHASE	  1	  (WEEKS	  3-­‐‑13)	  
The	  percentages	  for	  each	  treatment	  and	  between	  treatment	  percentage	  differences	  will	  be	  estimated	  
for	  Phase	  1.	  The	  95%	  confidence	  intervals	  of	  the	  estimated	  treatment	  differences,	  based	  on	  a	  normal	  
approximation,	  will	  be	  presented.	  In	  addition,	  the	  percentage	  negative	  urine	  samples	  will	  be	  analyzed	  
using	  a	  chi	  square	  test.	  
9.3.4   PERCENTAGE	  NEGATIVE	  URINE	  SAMPLES	  IN	  PHASE	  2	  (WEEKS	  14-­‐‑25)	  
The	  percentages	  for	  each	  treatment	  and	  between	  treatment	  percentage	  differences	  will	  be	  estimated	  
for	  Phase	  2.	  The	  95%	  confidence	  intervals	  of	  the	  estimated	  treatment	  differences,	  based	  on	  a	  normal	  
approximation,	  will	  be	  presented.	  In	  addition,	  the	  percentage	  negative	  urine	  samples	  will	  be	  analyzed	  
using	  a	  chi	  square	  test.	  
9.3.5   PERCENT	  OF	  SUBJECTS	  WITH	  NO	  ILLICIT	  OPIOID	  USE	  BY	  TIME	  POINT	  	  
For	  the	  purpose	  of	  deriving	  percent	  of	  subjects	  with	  no	  illicit	  opioid	  use	  by	  month,	  the	  same	  definitions	  
for	  monthly	  window	  and	  evidence	  of	  illicit	  opioid	  use	  (see	  Section	  9.1.1)	  and	  the	  same	  rules	  for	  missing	  
value	  imputation	  (see	  Section	  9.1.3)	  will	  be	  used	  in	  the	  calculation.	  


BRAEBURN	  PHARMACEUTICALS	   CONFIDENTIAL	  
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Page	  15	  of	  27	  
	  
	  
The	   treatment	   differences	   in	   these	   by	   month	   variables	   will	   be	   analyzes	   using	   chi	   square	   tests.	   The	  
percentages	  for	  each	  treatment	  and	  between	  treatment	  percentage	  differences	  will	  be	  estimated.	  The	  
95%	  confidence	  intervals	  of	  the	  estimates	  will	  be	  presented	  using	  normal	  approximation.	  	  	  
	  
The	  overall	  treatment	  difference	  will	  be	  tested	  via	  Wei	  and	  Lachin	  procedure.	  In	  this	  analysis,	  missing	  
values	  were	  not	  imputed.	  
9.3.6   CUMULATIVE	  PERCENTAGE	  OF	  SUBJECTS	  WITH	  EVIDENCE	  OF	  NO	  
ILLICIT	  OPIOID	  USE	  BY	  TIME	  POINT	  AFTER	  2	  MONTHS	  OF	  TREATMENT	  
The	  cumulative	  percentage	  of	  evidence	  of	  no	  illicit	  opioid	  use	  will	  be	  calculated	  for	  all	  post	  baseline	  
scheduled	   visits	   after	   two	   months	   of	   treatment	   (from	   Week	   9	   to	   Week	   25).	   The	   same	   definition	   for	  
evidence	  of	  illicit	  opioid	  use	  (see	  Section	  9.1.1)	  and	  the	  same	  rules	  for	  missing	  value	  imputation	  (see	  
Section	  9.1.3)	  will	  be	  used	  in	  the	  calculation.	  As	  the	  percentage	  is	  derived	  on	  a	  cumulative	  basis,	  subject	  
will	  be	  included	  in	  the	  numerator	  (i.e.,	  users)	  at	  a	  given	  scheduled	  visit,	  if	  the	  subjects	  have	  evidence	  of	  
use	  at	  any	  prior	  visits	  or	  at	  the	  current	  visit.	  
	  
The	  cumulative	  percentages	  by	  month	  will	  be	  analyzed	  using	  chi	  square	  tests.	  The	  percentages	  for	  each	  
treatment	   and	   between	   treatment	   percentage	   differences	   will	   be	   estimated.	   The	   95%	   confidence	  
intervals	  of	  the	  estimated	  treatment	  differences	  will	  be	  presented.	  	  	  
	  
The	   overall	   treatment	   difference	   will	   be	   also	   tested	   via	   Wei	   and	   Lachin	   procedure.	   	   In	   this	   analysis,	  
missing	  values	  were	  not	  imputed.	  
9.3.7   PERCENT	  OF	  SUBJECTS	  WITH	  NO	  SELF-­‐‑REPORTED	  ILLICIT	  OPIOID	  USE	  
BY	  TIME	  POINT	  
Percent	  of	  subjects	  with	  No	  Self-­‐Reported	  Illicit	  Drug	  Use	  by	  time	  points	  (by	  scheduled	  post	  baseline	  
visit)	   will	   be	   analyzed	   using	   chi	   square	   tests.	   The	   percentages	   for	   each	   treatment	   and	   between	  
treatment	   percentage	   differences	   will	   be	   estimated.	   The	   95%	   confidence	   intervals	   of	   the	   estimated	  
treatment	  differences	  will	  be	  presented.	  
9.3.8   PERCENT	  OF	  SUBJECTS	  MEETING	  CRITERIA	  OF	  STABILITY	  BY	  TIME	  
POINT	  
At	   each	   weekly	   visit,	   starting	   at	   Week	   5,	   the	   subjects	   will	   be	   evaluated	   with	   regard	   to	   the	   following	  
stability	  criteria:	  
•  
Has	  the	  subject	  been	  on	  a	  stable	  dose	  of	  CAM2038	  q1w/Placebo	  SC	  injections	  without	  any	  
fluctuations	  in	  doses	  for	  the	  last	  4	  weeks?	  
•  
Does	  the	  subject	  exhibit	  minimal	  subjective	  and	  no	  objective	  withdrawal	  symptoms,	  based	  on	  
SOWS	  ≤7	  and	  COWS	  <5?	  
•  
Does	  the	  subject	  exhibit	  diminished	  desire/need	  to	  use,	  based	  on	  VAS	  scores	  (defined	  as	  at	  least	  
50%	  reduction	  from	  baseline	  in	  the	  VAS	  score)?	  
•  
Does	  the	  subject	  exhibit	  diminished	  use	  of	  illicit	  opioids,	  according	  to	  the	  Investigator’s	  
discretion?	  
	  
Percent	  of	  subjects	  meeting	  criteria	  of	  stability	  by	  time	  point	  (by	  scheduled	  post	  baseline	  visit)	  will	  be	  
analyzed	  using	  chi	  square	  tests.	  The	  Week	  13	  will	  be	  the	  primary	  time	  point.	  The	  percentages	  for	  each	  


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Page	  16	  of	  27	  
	  
treatment	   and	   between	   treatment	   percentage	   differences	   will	   be	   estimated.	   The	   95%	   confidence	  
intervals	  of	  the	  estimated	  treatment	  differences	  will	  be	  presented.	  Additionally,	  for	  the	  primary	  time	  
point	  (Week	  13),	  sensitivity	  analysis	  will	  be	  performed	  quantifying	  the	  number	  of	  subjects	  with	  at	  least	  
25%	  reduction	  in	  positive	  urine	  test	  performed	  at	  Weeks	  10-­‐13	  compared	  to	  Weeks	  2-­‐5.	  	  
	  
The	  overall	  treatment	  difference	  will	  be	  also	  tested	  via	  Wei	  and	  Lachin	  procedure.	  
9.3.9   MEASURES	  OF	  CRAVING	  (VAS)	  
Measures	  of	  craving	  include	  Desire	  to	  Use	  VAS	  and	  Need	  to	  Use	  VAS,	  will	  be	  administered	  using	  unipolar	  
100	  mm	  VAS	  (“In	  the	  past	  week/month,	  how	  intense	  has	  been	  your	  average	  desire/need	  to	  use	  “drug	  
name?”,	  where	  0	  =	  No	  desire	  to	  use	  and	  100	  mm=	  Strongest	  possible	  desire,	  and	  from	  0=No	  need	  to	  use	  
and	   100	   mm=Strongest	   possible	   need,	   respectively).	   	   They	   will	   be	   measured	   at	   baseline	   and	   some	  
selected	   post	   baseline	   visits	   (For	   more	   detail,	   please	   refer	   to	   Table	   3,	   Schedule	   of	   Assessments,	   in	  
Section	  10	  of	  the	  protocol,	  TRIAL	  PROCEDURES	  AND	  ASSESSMENTS).	  	  
	  
Changes	  from	  baseline	  in	  the	  above	  VASs	  will	  be	  derived	  by	  subtracting	  the	  baseline	  values	  from	  the	  
post-­‐baseline	  values,	  thus,	  negative	  changes	  are	  indicative	  of	  improvement.	  Changes	  from	  baseline	  in	  
measurements	  of	  craving	  will	  be	  analyzed	  via	  Analysis	  of	  Covariance	  (ANCOVA)	  model	  with	  treatment	  
and	  baseline	  effects.	  Treatment	  effects	  and	  treatment	  differences	  will	  be	  estimated.	  The	  two-­‐sided	  95%	  
confidence	  intervals	  the	  treatment	  differences	  will	  be	  presented.	  In	  this	  primary	  analysis,	  missing	  values	  
will	  be	  imputed	  using	  Last	  Observation	  Carried	  Forward	  (LOCF)	  method.	  
9.3.10  MEASURES	  OF	  WITHDRAWAL	  SYMPTOMS	  
Measures	  of	  withdrawal	  include	  COWS	  and	  SOWS.	  The	  COWS	  is	  comprised	  of	  11	  items	  each	  with	  a	  score	  
of	  0	  through	  4.	  Higher	  scores	  are	  associated	  with	  greater	  withdrawal	  symptoms.	  The	  items	  are	  meant	  to	  
be	   objective	   (e.g.,	   resting	   pulse	   rate)	   measures	   of	   patient’s	   withdrawal	   symptoms.	   The	   SOWS	   is	  
comprised	   of	   16	  items	   each	   with	   a	   score	   of	   0	   through	   4.	   Higher	   scores	   are	   associated	   with	   greater	  
withdrawal	  symptoms.	  The	  items	  are	  statements	  which	  are	  evaluated	  by	  the	  patient	  and	  are	  there	  for	  
subjective	  (e.g.,	  I	  feel	  anxious,	  0	  =	  not	  at	  all,	  1	  =	  a	  little,	  2	  =	  moderately,	  3	  =	  quite	  a	  bit,	  4	  =	  extremely).	  	  
Both	  COWS	  and	  SOWS	  will	  be	  measured	  at	  baseline	  and	  some	  selected	  post	  baseline	  visits	  (For	  more	  
detail,	   please	   refer	   to	   Table	   3,	   Schedule	   of	   Assessments,	   in	   Section	   10	   of	   the	   protocol,	   TRIAL	  
PROCEDURES	  AND	  ASSESSMENTS).	  	  	  
	  
If	  there	  are	  >=3	  (i.e.,	  >=20%)	  missing	  items	  in	  the	  COWS	  scale	  at	  a	  given	  visit	  or	  >=4	  (i.e.,	  >20%)	  
missing	  items	  in	  the	  SOWS	  scale	  at	  a	  given	  visit,	  the	  COWS/SOWS	  score	  for	  that	  visit	  will	  be	  missing.	  If	  
there	  are	  1	  or	  2	  missing	  items	  for	  the	  COWS	  assessment	  then	  the	  total	  of	  the	  non-­‐missing	  items	  will	  be	  
calculated	  and	  the	  product	  of	  the	  calculated	  total	  and	  11/(11-­‐	  #	  missing)	  will	  be	  used	  for	  the	  COWS	  
score	  for	  that	  visit.	  If	  3	  or	  fewer	  items	  are	  missing	  for	  the	  SOWS	  score	  then	  the	  total	  of	  the	  non-­‐missing	  
items	  will	  be	  calculated	  and	  the	  product	  of	  the	  calculated	  total	  and	  16/(16	  -­‐	  #	  missing)	  will	  be	  used	  for	  
the	  SOWS	  score.	  Missing	  total	  scores	  or	  scores	  with	  more	  than	  two	  missing	  components	  in	  COWS,	  or	  
more	  than	  3	  missing	  components	  in	  SOWS,	  will	  be	  imputed	  using	  LOCF	  method.	  	  
	  
Changes	  from	  baseline	  in	  COWS	  and	  SOWS	  will	  be	  derived	  by	  subtracting	  the	  baseline	  values	  from	  the	  
post-­‐baseline	  values,	  thus,	  negative	  changes	  are	  indicative	  of	  improvement.	  Changes	  from	  baseline	  in	  
measurements	  of	  withdrawal	  will	  be	  analyzed	  via	  ANCOVA	  model	  with	  treatment	  and	  baseline	  effects.	  
Treatment	  effects	  and	  treatment	  differences	  will	  be	  estimated.	  The	  two-­‐sided	  95%	  confidence	  intervals	  


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of	  the	  treatment	  differences	  will	  be	  presented.	  In	  this	  primary	  analysis,	  missing	  values	  will	  be	  imputed	  
using	  LOCF	  method.	  
9.3.11  PERCENT	  OF	  SUBJECTS	  WITHOUT	  EVIDENCE	  OF	  USING	  OTHER	  DRUGS	  
OF	  ABUSE	  BY	  TIME	  POINT	  
The	   list	   of	   drugs	   of	   abuse	   will	   include	   cocaine,	   benzodiazepines,	   barbiturates,	   amphetamines,	  
phenycyclidine,	  and	  THC.	  Percent	  of	  subjects	  without	  using	  each	  of	  the	  above	  drugs	  by	  time	  point	  (by	  
scheduled	   post	   baseline	   visit)	   will	   be	   analyzed	   using	   chi	   square	   tests.	   The	   percentages	   for	   each	  
treatment	   and	   between	   treatment	   percentage	   differences	   will	   be	   estimated.	   The	   95%	   confidence	  
intervals	  of	  the	  estimated	  treatment	  differences	  will	  be	  presented.	  
9.3.12  SUPPLEMENTAL	  BPN	  USE	  
Supplemental	   BPN	   will	   be	   provided	   utilizing	   CAM2038	   q1w	   8	   mg	   SC	   injection	   only	   in	   Phase	   2.	  
Supplemental	   BPN	   will	   be	   allowed	   at	   maximum	   of	   one	   SC	   injection	   per	   month	   (in	   between	   two	  
scheduled	  clinic	  visits).	  	  
	  
Percentages	  of	  subjects	  who	  require	  supplemental	  uses	  and	  total	  number	  of	  supplemental	  use	  episodes	  
will	  be	  summarized.	  
9.3.13  ADDITIONAL	  SUPPLEMENTAL	  COUNSELING	  
Percentages	   of	   subjects	   who	   required	   additional	   unscheduled	   visits	   to	   obtain	   counseling	   to	   manage	  
withdrawal	  symptoms	  or	  desire	  to	  use	  illicit	  opioids	  during	  each	  of	  the	  two	  phases	  as	  well	  as	  during	  the	  
study	  will	  be	  summarized.	  In	  addition,	  number	  of	  unscheduled	  visit	  to	  obtain	  such	  counseling	  during	  
each	  of	  the	  two	  phases	  as	  well	  as	  during	  the	  study	  will	  also	  be	  summarized.	  
	  
9.3.14  MEASURES	  OF	  MORNING	  NEED	  TO	  USE/DESIRE	  TO	  USE	  (VAS)	  
Measures	   of	   VAS	   scores	   include	   Morning	   Desire	   to	   Use	   VAS	   and	   Morning	   Need	   to	   Use	   VAS,	   will	   be	  
administered	  using	  unipolar	  100	  mm	  VAS	  (“In	  the	  past	  week/month,	  how	  intense	  has	  been	  your	  average	  
desire/need	  to	  use	  “drug	  name?”,	  where	  0	  =	  No	  desire	  to	  use	  and	  100	  mm=	  Strongest	  possible	  desire,	  
and	  from	  0=No	  need	  to	  use	  and	  100	  mm=Strongest	  possible	  need,	  respectively).	  	  They	  will	  be	  measured	  
at	  baseline	  and	  some	  selected	  post	  baseline	  visits	  (For	  more	  detail,	  please	  refer	  to	  Table	  3,	  Schedule	  of	  
Assessments,	  in	  Section	  10	  of	  the	  protocol,	  TRIAL	  PROCEDURES	  AND	  ASSESSMENTS).	  	  
	  
Changes	  from	  baseline	  in	  the	  above	  VASs	  will	  be	  derived	  by	  subtracting	  the	  baseline	  values	  from	  the	  
post-­‐baseline	  values,	  thus,	  negative	  changes	  are	  indicative	  of	  improvement.	  Changes	  from	  baseline	  in	  
measurements	  of	  craving	  will	  be	  analyzed	  via	  Analysis	  of	  Covariance	  (ANCOVA)	  model	  with	  treatment	  
and	  baseline	  effects.	  Treatment	  effects	  and	  treatment	  differences	  will	  be	  estimated.	  The	  two-­‐sided	  95%	  
confidence	  intervals	  the	  treatment	  differences	  will	  be	  presented.	  In	  this	  primary	  analysis,	  missing	  values	  
will	  be	  imputed	  using	  Last	  Observation	  Carried	  Forward	  (LOCF)	  method.	  
9.4  
INTERIM	  ANALYSES	  
No	  interim	  analyses	  will	  be	  performed.	  
9.5  
ADJUSTMENTS	  FOR	  MULTIPLICITY	  


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There	  are	  a	  number	  of	  hypothesis	  testings	  that	  will	  be	  performed	  for	  this	  study.	  To	  control	  overall	  Type	  I	  
error	   rate	   at	   5%,	   a	   closed	   testing	   procedure	   will	   be	   employed	   (Dmitrienko	   2004,	   Dmitrienko,	   Offen,	  
Westfall	  2003).	  Specifically,	  the	  following	  ordered	  hypotheses	  will	  be	  tested:	  
	  
1.   Superiority	  for	  CDF	  of	  percent	  samples	  that	  are	  negative	  for	  illicit	  opioids	  (Weeks	  5-­‐25);	  	  
2.   Superiority	  for	  the	  primary	  efficacy	  variable,	  RR	  (Weeks	  2-­‐25);	  
3.   Superiority	  of	  active	  treatment	  over	  the	  control	  for	  time	  to	  sustained	  abstinence	  after	  8	  weeks	  
of	  treatment;	  
4.   Non-­‐inferiority	  with	  margin	  of	  15%	  for	  retention	  rate;	  
5.   Superiority	  of	  active	  treatment	  over	  the	  control	  for	  retention	  rate.	  	  
	  
In	   this	   procedure,	   a	   comparison	   will	   be	   eligible	   for	   non-­‐inferiority	   or	   superiority	   testing	   only	   if	   all	  
previous	  comparisons,	  if	  any,	  were	  successfully	  established	  at	  the	  two-­‐sided	  5%	  significance	  level.	  	  	  
9.6  
POWER	  AND	  SAMPLE	  SIZE	  JUSTIFICATION	  
The	  sample	  size	  of	  approximately	  190	  per	  treatment	  arm	  (380	  total)	  will	  provide	  approximately	  82%	  
power	   to	   establish	   the	   non-­‐inferiority	   with	   a	   13.5%	   non-­‐inferiority	   margin	   for	   the	   primary	   efficacy	  
variable,	  RR	  Weeks	  2-­‐25.	  In	  the	  sample	  size	  calculation,	  it	  was	  assumed	  that	  the	  proportion	  of	  response	  
in	  both	  the	  active	  treatment	  arm	  and	  control	  treatment	  arm	  is	  70%.	  
	  
10.0   SUMMARIES	  OF	  MEASURES	  OF	  SAFETY	  
Safety	   analyses	   will	   be	   performed	   for	   the	   safety	   population.	   Safety	   evaluations	   will	   be	   based	   on	   the	  
incidence,	  intensity,	  and	  type	  of	  adverse	  events	  (AEs),	  as	  well	  as	  on	  clinically	  significant	  changes	  in	  the	  
subject’s	  physical	  examination,	  vital	  signs,	  and	  clinical	  laboratory	  results,	  Injection	  site	  examination	  and	  
wound	  care.	  	  Safety	  variables	  will	  be	  tabulated	  and	  presented	  by	  study	  drug	  actually	  received.	  
	  
Because	  there	  is	  no	  pre-­‐specified	  safety	  outcome	  defined	  in	  terms	  of	  AEs,	  clinically	  relevant	  laboratory	  
parameters,	  or	  vital	  signs,	  any	  formal	  comparisons	  between	  the	  treatment	  arms	  with	  respect	  to	  specific	  
safety	  parameters	  will	  be	  post-­‐hoc.	  
10.1   EXTENT	  OF	  EXPOSURE	  
Summary	  statistics	  (number	  and	  percentage)	  of	  weeks	  of	  exposure	  to	  study	  drug	  (i.e.	  from	  date	  of	  initial	  
injection	  to	  4	  weeks	  after	  the	  last	  injection)	  will	  be	  tabulated	  by	  treatment	  group.	  	  
10.2   ADVERSE	  EVENTS	  
Each	  AE	  and	  serious	  adverse	  event	  (SAE)	  term	  recorded	  on	  the	  CRFs	  will	  be	  mapped	  to	  a	  primary	  system	  
organ	  class	  (SOC)	  and	  a	  preferred	  term	  using	  the	  MedDRA	  dictionary.	  The	  investigator	  will	  assess	  AE	  
severity	  and	  relationship	  to	  the	  study	  treatment.	  
	  
Columbia	  Suicide	  Severity	  Rating	  Scale	  (C-­‐SSRS)	  will	  be	  summarized.	  
	  
A	  treatment-­‐emergent	  adverse	  event	  (TEAE)	  is	  defined	  as	  any	  AE	  with	  an	  onset	  date	  on	  or	  after	  date	  of	  
randomization,	  or	  any	  ongoing	  event	  on	  the	  date	  of	  first	  dose	  that	  worsens	  in	  severity	  after	  date	  of	  
randomization.	  Only	  TEAEs	  with	  an	  onset	  date	  prior	  to	  date	  of	  last	  dose	  +	  30	  days	  will	  be	  tabulated	  in	  


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summary	   tables.	   For	   the	   purpose	   calculating	   treatment	   emergence	   and	   inclusion	   in	   summary	   tables,	  
incomplete	  onset	  dates	  will	  be	  imputed	  as	  detailed	  in	  Appendix	  A.	  	  	  
	  
TEAEs	  will	  be	  summarized	  by	  the	  number	  and	  percent	  of	  subjects	  in	  each	  primary	  SOC	  and	  preferred	  
term.	   	   Patients	   will	   be	   counted	   only	   once	   for	   each	   primary	   SOC	   and	   each	   preferred	   term.	   Summary	  
tables	  of	  TEAEs	  by	  primary	  SOC,	  preferred	  term	  and	  intensity	  will	  be	  provided.	  If	  a	  subject	  has	  more	  than	  
one	  AE	  coded	  to	  the	  same	  preferred	  term,	  the	  subject	  will	  be	  counted	  only	  once	  for	  that	  preferred	  term	  
by	   using	   the	   event	   with	   the	   highest	   intensity.	   Similarly,	   if	   a	   subject	   has	   more	   than	   one	   AE	   within	   a	  
primary	  SOC	  category,	  the	  subject	  will	  be	  counted	  only	  once	  in	  that	  SOC	  category	  by	  using	  the	  event	  
with	  the	  highest	  intensity.	  AEs	  by	  primary	  SOC,	  preferred	  term	  and	  relationship	  to	  study	  drug	  will	  be	  
provided	  as	  well.	  If	  a	  subject	  has	  more	  than	  one	  AE	  coded	  to	  the	  same	  preferred	  term,	  the	  subject	  will	  
be	  counted	  only	  once	  for	  that	  preferred	  term	  by	  using	  the	  most	  related	  event.	  Similarly,	  if	  a	  subject	  has	  
more	  than	  one	  AE	  within	  a	  primary	  SOC	  category,	  the	  subject	  will	  be	  counted	  only	  once	  in	  that	  primary	  
SOC	  category	  by	  using	  the	  most	  related	  event.	  In	  addition,	  SAEs	  by	  primary	  SOC	  and	  preferred	  term	  will	  
be	  provided.	  Deaths	  and	  SAEs	  will	  be	  summarized	  similarly	  to	  AEs.	  All	  TEAE	  tables	  will	  also	  include	  the	  
total	  number	  of	  events,	  counting	  multiple	  events	  per	  patient.	  
	  
Injection	  related	  AEs,	  other	  (non-­‐injection	  related)	  AEs	  as	  well	  as	  all	  AEs	  will	  be	  presented	  by	  treatment	  
group	  and	  overall.	  Summaries	  of	  these	  AE	  subsets	  will	  be	  presented	  for	  the	  following	  categories:	  
	  
•  
Study	  drug	  related	  
•  
Intensity	  
•  
Relationship	  to	  injection	  
•  
Possibly	  study	  drug	  related	  by	  intensity	  
•  
Reasonably	  injection	  related	  by	  intensity	  
•  
Serious	  
•  
AEs	  which	  led	  to	  discontinuation	  of	  treatment	  
•  
SAEs	  which	  led	  to	  discontinuation	  of	  treatment	  
•  
AEs	  occurring	  in	  5%	  or	  greater	  of	  any	  treatment	  group	  (by	  preferred	  term)	  
	  
In	  the	  AE	  summary,	  preferred	  terms	  within	  each	  SOC	  will	  appear	  in	  alphabetical	  order.	  	  	  
	  
Frequencies	  for	  deaths	  and	  hospitalizations	  will	  also	  be	  summarized	  by	  treatment	  group	  and	  overall.	  
	  
To	  assess	  the	  AE	  profile	  during	  the	  first	  week	  of	  treatment	  (first	  week	  after	  the	  randomization),	  TEAEs	  
that	  occur	  within	  the	  first	  week	  of	  treatment	  will	  be	  presented.	  	  
	  
Other	  safety	  analyses	  will	  be	  performed	  as	  appropriate	  
10.3   LABORATORY	  ASSESSMENTS	  
Chemistry,	   hematology,	   urinalysis	   and	   coagulation	   profile	   will	   be	   assessed	   at	   Screening,	   Week	   1	  
(baseline),	  Week	  12,	  Week	  13,	  Week	  17,	  Week	  21	  and	  Week	  25	  (see	  Section	  10.4.3	  in	  the	  clinical	  trial	  
protocol	  for	  a	  complete	  list	  of	  parameters	  to	  be	  assessed).	  Summary	  statistics	  for	  these	  parameters	  will	  
be	  presented	  by	  visit	  for	  the	  actual	  value	  and	  change	  from	  baseline	  for	  each	  test	  in	  each	  laboratory	  
category	  (hematology,	  chemistry,	  urinalysis,	  and	  coagulation	  profile).	  Shift	  tables	  will	  be	  presented	  for	  


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shifts	  from	  baseline	  lab	  categories	  to	  end	  of	  study	  laboratory	  category.	  The	  three	  laboratory	  categories	  
will	  be:	  L	  (below	  lower	  bound	  of	  normal	  range),	  N	  (within	  normal	  range),	  and	  H	  (above	  higher	  bound	  of	  
normal	  range).	  	  	  	  
The	   number	   and	   percent	   of	   subjects	   experiencing	   a	   value	   greater	   than	   2x	   and	   3x	   the	   upper	   limit	   of	  
normal	  (ULN)	  for	  ALT	  and	  AST	  will	  also	  be	  presented	  for	  each	  visit	  and	  overall	  (at	  any	  visit).	  	  	  
If	  applicable,	  a	  listing	  will	  also	  be	  provide	  for	  all	  subjects	  experiencing	  a	  value	  greater	  than	  3x	  the	  upper	  
limit	  of	  normal	  (ULN)	  for	  ALT	  or	  AST	  and	  a	  doubling	  of	  baseline	  total	  bilirubin	  occurring	  on	  the	  same	  
visit.	  	  
If	  a	  lab	  value	  is	  reported	  using	  a	  non-­‐numeric	  qualifier	  (e.g.,	  less	  than	  (<)	  a	  certain	  value,	  or	  greater	  than	  
(>)	  a	  certain	  value),	  the	  given	  numeric	  value	  will	  be	  used	  in	  the	  summary	  statistics,	  ignoring	  the	  non-­‐
numeric	  qualifier.	  
If	  a	  subject	  has	  repeated	  laboratory	  values	  for	  a	  given	  time	  point,	  the	  value	  from	  the	  first	  evaluation	  at	  
that	  time	  point	  will	  be	  used	  for	  summarization	  purposes.	  For	  the	  purpose	  of	  determining	  baseline,	  the	  
last	  non-­‐missing	  observation	  on	  or	  prior	  to	  randomization	  will	  be	  used.	  The	  Week	  25	  values	  will	  be	  the	  
last	  post-­‐baseline	  value	  on	  or	  prior	  to	  Week	  25.	  
10.4   VITAL	  SIGNS	  
Vital	  signs	  will	  consist	  of	  blood	  pressure	  (systolic	  and	  diastolic	  blood	  pressure,	  mmHg),	  pulse	  rate	  (beats	  
per	  minute),	  and	  respiratory	  rate	  (breaths/min),	  and	  body	  temperature	  collected	  while	  sitting,	  following	  
a	  rest	  period	  of	  at	  least	  3	  minutes.	  Vital	  sign	  values	  and	  change	  from	  baseline	  in	  the	  vital	  signs	  will	  be	  
summarized	  for	  each	  treatment	  group.	  
10.5   PHYSICAL	  EXAMINATION	  
Number	  and	  percent	  of	  subjects	  with	  abnormal	  physical	  examination	  findings	  at	  Screening	  and	  Week	  25	  
will	  be	  summarized	  by	  body	  system	  for	  each	  treatment	  group	  and	  overall.	  Physical	  examination	  data	  for	  
each	  subject	  will	  also	  be	  presented	  in	  a	  listing.	  
10.6   12-­‐‑LEAD	  ELECTROCARDIOGRAM	  (ECG)	  
12-­‐Lead	  ECGs	  will	  be	  performed	  at	  screening,	  Day	  1,	  Day	  8,	  and	  all	  subsequent	  scheduled	  visits	  through	  
Week	  25	  after	  the	  subject	  has	  been	  resting	  in	  a	  recumbent/supine	  position	  for	  at	  least	  3	  minutes.	  The	  
ECG	  variables	  will	  include	  ventricular	  heart	  rate	  and	  the	  PR,	  QRS,	  QT,	  QTcB	  and	  QTcF	  intervals.	  The	  ECGs	  
will	   be	   signed	   and	   dated	   by	   a	   medically-­‐qualified	   individual	   to	   confirm	   review	   of	   the	   ECG	   and	   verify	  
whether	  any	  abnormalities	  are	  clinically	  significant.	  	  
	  
Number	   and	   percent	   of	   subjects	   in	   each	   ECG	   finding	   category	   (normal,	   abnormal	   not	   clinically	  
significant,	  and	  abnormal	  and	  clinically	  significant),	  will	  be	  summarized	  for	  each	  visit	  by	  each	  treatment	  
group	  and	  overall.	  Summary	  statistics	  will	  be	  presented	  for	  the	  actual	  value	  and	  change	  for	  each	  ECG	  
parameter.	  
	  
The	  number	  and	  percent	  of	  subjects	  with	  QT,	  QTcB	  and	  QTcF	  intervals	  <	  450	  msec,	  450	  to	  <480,	  480	  to	  
<500	  and	  greater	  than/equal	  to	  500	  msec	  at	  each	  visit	  and	  overall	  (at	  any	  visit)	  will	  be	  summarized.	  
Additionally,	  the	  number	  and	  percentage	  of	  subjects	  with	  changes	  in	  these	  parameters	  of	  <30	  msec,	  30	  


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to	  <60	  msec	  and	  greater	  than/equal	  to	  60	  msec	  will	  be	  summarized	  at	  each	  visit	  and	  overall	  (at	  any	  
visit).	  
10.7   INJECTION	  SITE	  EXAMINATION	  
Injection	  site	  reactions	  can	  occur	  with	  injection	  of	  CAM2038	  or	  placebo.	  The	  injection	  site	  will	  be	  visually	  
inspected	  for	  evidence	  of	  erythema,	  edema,	  itching,	  pain,	  infection,	  bleeding,	  abnormal	  healing	  and	  any	  
other	  abnormalities.	  	  Summaries	  of	  all	  injection	  site	  reactions	  as	  well	  as	  of	  clinically	  significant	  injection	  
site	  reactions	  will	  be	  presented.	  
	  
All	  AEs,	  AEs	  that	  are	  associated	  with	  injection	  procedures,	  and	  other	  AEs	  (not	  associated	  with	  injections)	  
will	  be	  summarized.	  
	  
11.0   IDENTIFICATION	  AND	  SUMMARY	  OF	  PROTOCOL	  DEVIATIONS	  
Major	  protocol	  deviations	  from	  entry	  criteria	  and	  treatment	  compliance	  will	  be	  summarized	  as	  far	  as	  
they	  can	  be	  extracted	  from	  numeric	  or	  coded	  study	  data.	  
	  
12.0   DATA	  QUALITY	  ASSURANCE	  
Accurate	  and	  reliable	  data	  collection	  will	  be	  ensured	  by	  verification	  and	  cross	  check	  of	  the	  CRFs	  against	  
the	  investigator’s	  records	  by	  the	  study	  monitor	  (source	  document	  verification)	  and	  by	  the	  maintenance	  
of	  a	  drug–dispensing	  log	  by	  the	  investigator.	  	  Collected	  data	  will	  be	  entered	  into	  a	  computer	  database	  
and	  subject	  to	  electronic	  and	  manual	  quality	  assurance	  procedures.	  
	  
13.0   REFERENCES	  
	  
1.   L.	  J.	  Wei	  and	  J.	  M.	  Lachin,	  Sept	  1984,	  “Two-­‐Samples	  Asymptotically	  Distribution-­‐Free	  Tests	  for	  
Incomplete	  Multivariate	  Observations,”	  Journal	  of	  the	  American	  Statistical	  Association,	  Vol.	  79,	  
No.	  387	  (Sep.,	  1984),	  pp.	  653-­‐661	  
2.   Dmitrienko,	  Offen,	  Westfall	  2003,	  “Gatekeeping	  strategies	  for	  clinical	  trials	  that	  do	  not	  require	  
all	  primary	  effects	  to	  be	  significant,”	  	  Statistics	  in	  Medicine,	  22:	  2387-­‐2400	  


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14.0   APPENDICES	  
14.1   APPENDIX	  A	  -­‐‑	  IMPUTATION	  ALGORITHM	  FOR	  PARTIAL	  AND	  MISSING	  
DATES	  	  
This	  section	  describes	  missing	  date	  imputation	  methods.	  
	  
For	  Adverse	  Events	  
	  
If	  onset	  date	  is	  completely	  missing,	  onset	  date	  is	  set	  to	  date	  of	  randomization.	  
If	  (year	  is	  present	  and	  month	  and	  day	  are	  missing)	  or	  (year	  and	  day	  are	  present	  and	  month	  is	  missing):	  
•  
If	  year	  =	  year	  of	  randomization,	  then	  set	  month	  and	  day	  to	  month	  and	  day	  of	  randomization	  
•  
If	  year	  <	  year	  of	  randomization,	  then	  set	  month	  and	  day	  to	  December	  31.	  
•  
If	  year	  >	  year	  of	  randomization,	  then	  set	  month	  and	  day	  to	  January	  1.	  
If	  month	  and	  year	  are	  present	  and	  day	  is	  missing:	  
•  
If	  year=year	  of	  randomization	  and	  	  
•  
If	  month	  =	  month	  of	  randomization	  then	  set	  day	  to	  day	  of	  first	  dose	  
•  
If	  month	  <	  month	  of	  first	  dose	  then	  set	  day	  to	  last	  day	  of	  month	  
•  
If	  month	  >	  month	  of	  first	  dose	  then	  set	  day	  to	  first	  day	  of	  month	  
•  
If	  year	  <	  year	  of	  randomization	  then	  set	  day	  to	  last	  day	  of	  month	  
•  
If	  year	  >	  year	  of	  randomization	  then	  set	  day	  to	  first	  day	  of	  month	  
	  
For	  all	  other	  cases,	  set	  onset	  date	  to	  date	  of	  randomization.	  
	  
Concomitant	  Medications/Medical	  History	  
For	  start	  date	  
•  
If	  start	  date	  is	  completely	  missing,	  start	  date	  will	  not	  be	  imputed.	  
•  
If	  (year	  is	  present	  and	  month	  and	  day	  are	  missing)	  or	  (year	  and	  day	  are	  present	  and	  month	  
is	  missing),	  set	  month	  and	  day	  to	  January	  1.	  
•  
If	  year	  and	  month	  are	  present	  and	  day	  is	  missing,	  set	  day	  to	  1st	  day	  of	  month.	  
	  
For	  end	  date	  
•  
If	  end	  date	  is	  completely	  missing,	  end	  date	  will	  not	  be	  imputed.	  
•  
If	  (year	  is	  present	  and	  month	  and	  day	  are	  missing)	  or	  (year	  and	  day	  are	  present	  and	  month	  
is	  missing),	  set	  month	  and	  day	  to	  December	  31.	  
•  
If	  year	  and	  month	  are	  present	  and	  day	  is	  missing,	  set	  day	  to	  last	  day	  of	  the	  month.	  
	  
Note:	  that	  if	  both	  start	  and	  end	  dates	  are	  missing	  then	  the	  medication	  will	  be	  classified	  as	  concomitant.	  


BRAEBURN	  PHARMACEUTICALS	   CONFIDENTIAL	  
Version	  1.01—4	  November,	  2016	  
HS-­‐‑11-­‐‑421	  Final	  SAP	  
Page	  23	  of	  27	  
	  
	  
14.2   APPENDIX	  B	  –	  LIST	  OF	  TABLES,	  LISTINGS,	  AND	  FIGURES	  	  
	  
List	  of	  Tables	  
Number	  
Title	  
TABLE	  14.1.1.1	  
Summary	  of	  Disposition	  of	  Patients	  (ITT	  Population)	  	  
TABLE	  14.1.1.2	  
Summary	  of	  Disposition	  of	  Patients	  (Safety	  Population)	  
TABLE	  14.1.1.3	  
Summary	  of	  Disposition	  of	  Patients	  (mITT	  Population)	  
TABLE	  14.1.1.4	  
Summary	  of	  Disposition	  of	  Patients	  (Per	  Protocol	  Population)	  
TABLE	  14.1.2.1	  
Summary	  of	  Demographics	  and	  Baseline	  Characteristics	  (Safety	  Population)	  
TABLE	  14.1.2.2	  
Summary	  of	  Demographics	  and	  Baseline	  Characteristics	  (ITT	  Population)	  
TABLE	  14.1.2.3	  
Summary	  of	  Demographics	  and	  Baseline	  Characteristics	  (Per	  Protocol	  
Population)	  
TABLE	  14.1.4	  
Summary	  of	  Psychiatric	  History	  (Safety	  Population)	  
TABLE	  14.1.5.1	  
Summary	  of	  Prior	  Medications	  (Safety	  Population)	  
TABLE	  14.1.5.2	  
Summary	  of	  Concomitant	  Medications	  (Safety	  Population)	  
TABLE	  14.1.6	  
Summary	  of	  Substance	  Abuse	  Treatment	  History	  (Safety	  Population)	  
TABLE	  14.2.1.1	  
Analysis	  Results	  for	  Primary	  Efficacy	  Variable	  Responder	  Rate	  (ITT	  Population)	  
TABLE	  14.2.1.2	  
Analysis	  Results	  for	  Primary	  Efficacy	  Variable	  Responder	  Rate	  (Per	  Protocol	  
Population)	  
TABLE	  14.2.2.1	  
Analysis	  Results	  for	  CDF	  of	  Percentage	  of	  Urine	  Samples	  Negative	  for	  Illicit	  
Opioids	  Supported	  by	  Self-­‐reported	  	  Illicit	  Opioid	  Use	  Results	  Over	  Weeks	  5-­‐25	  
(ITT	  Population)	  
TABLE	  14.2.2.2	  
Analysis	  Results	  for	  CDF	  of	  Percentage	  of	  Urine	  Samples	  Negative	  for	  Illicit	  
Opioids	  Supported	  by	  Self-­‐reported	  	  Illicit	  Opioid	  Use	  Results	  Over	  Weeks	  5-­‐25	  
(Per	  Protocol	  Population)	  
TABLE	  14.2.3.1	  
Analysis	  Results	  for	  Time	  to	  Sustained	  Abstinence	  of	  Opioid	  Use	  (ITT	  Population)	  
TABLE	  14.2.3.2	  
Analysis	  Results	  for	  Time	  to	  Sustained	  Abstinence	  of	  Opioid	  Use	  (Per	  Protocol	  
Population)	  
TABLE	  14.2.4.1	  
Analysis	  Results	  for	  Percent	  of	  Subjects	  Remaining	  in	  the	  Study	  (Retention	  Rate)	  
(ITT	  Population)	  
TABLE	  14.2.4.2	  
Analysis	  Results	  for	  Percent	  of	  Subjects	  Remaining	  in	  the	  Study	  (Retention	  Rate)	  
(Per	  Protocol	  Population)	  
TABLE	  14.2.5.1	  
Analysis	  Results	  for	  Response	  Rate	  in	  Phase	  1	  Based	  on	  Primary	  Responder	  
Definition	  (ITT	  Population)	  
TABLE	  14.2.5.2	  
Analysis	  Results	  for	  Response	  Rate	  in	  Phase	  2	  Based	  on	  Primary	  Responder	  
Definition	  (ITT	  Population)	  
TABLE	  14.2.6.1	  
Analysis	  of	  Percentage	  Negative	  Urine	  Samples	  in	  Phase	  1	  (ITT	  Population)	  
TABLE	  14.2.6.2	  
Analysis	  of	  Percentage	  Negative	  Urine	  Samples	  in	  Phase	  2	  (ITT	  Protocol	  
Population)	  
TABLE	  14.2.7	  
Analysis	  Results	  for	  Percent	  of	  Subjects	  with	  Evidence	  of	  No	  Illicit	  Opioid	  Use	  by	  
Time	  Point	  (ITT	  Population)	  
TABLE	  14.2.8	  
Analysis	  Results	  for	  Cumulative	  Percentage	  of	  Subjects	  with	  Evidence	  of	  No	  


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HS-­‐‑11-­‐‑421	  Final	  SAP	  
Page	  24	  of	  27	  
	  
Urine	  Illicit	  Opioid	  Use	  after	  2	  Month	  of	  Treatment	  by	  Time	  Point	  from	  Week	  9	  
to	  Week	  25	  (ITT	  Population)	  
TABLE	  14.2.9	  
Analysis	  Results	  for	  Percent	  of	  Subjects	  with	  No	  Self-­‐Reported	  Illicit	  Drug	  Use	  by	  
Time	  Point	  (ITT	  Population)	  
TABLE	  14.2.10	  
Analysis	  Results	  for	  Percent	  of	  Subjects	  Meeting	  Criteria	  of	  Stability	  by	  Time	  
Point	  (ITT	  Population)	  
TABLE	  14.2.11.1	  
Analysis	  Results	  for	  Change	  from	  Baseline	  in	  Measures	  of	  Craving:	  Desire	  to	  Use	  
VAS	  (ITT	  Population)	  
TABLE	  14.2.11.2	  
Analysis	  Results	  for	  Change	  from	  Baseline	  in	  Measures	  of	  Craving:	  Need	  to	  Use	  
VAS	  (ITT	  Population)	  
TABLE	  14.2.12	  
Analysis	  Results	  for	  Change	  from	  Baseline	  in	  Measures	  of	  withdrawal:	  Clinical	  
Opiate	  Withdrawal	  Scale	  (COWS)	  (ITT	  Population)	  
TABLE	  14.2.13	  
Analysis	  Results	  for	  Change	  from	  Baseline	  in	  Measures	  of	  withdrawal:	  Subjective	  
Opiate	  Withdrawal	  Scale	  (SOWS)	  (ITT	  Population)	  
TABLE	  14.2.14	  
Analysis	  Results	  for	  Percent	  of	  Subjects	  without	  Evidence	  of	  Using	  Other	  Drugs	  
of	  Abuse	  by	  Time	  Point	  (ITT	  Population)	  
TABLE	  14.2.15	  
Analysis	  Results	  for	  Supplemental	  SL	  BPN	  (CAM2038	  q1w	  8	  mg)	  Use	  (ITT	  
Population)	  
TABLE	  14.2.16	  
Analysis	  Results	  for	  Additional	  Supplemental	  Counseling	  (ITT	  Population)	  
TABLE	  14.2.17.1	  
Analysis	  Results	  for	  Change	  from	  Baseline	  in	  Measures	  of	  Morning	  Need	  to	  Use	  
(ITT	  Population)	  
TABLE	  14.2.17.2	  
Analysis	  Results	  for	  Change	  from	  Baseline	  in	  Measures	  of	  Morning	  Desire	  to	  Use	  
(ITT	  Population)	  
TABLE	  14.3.1	  
Summary	  of	  Treatment	  Exposure	  (Safety	  Population)	  
TABLE	  14.3.2	  
Summary	  of	  Treatment-­‐Emergent	  Adverse	  Events	  (Safety	  Population)	  
TABLE	  14.3.3	  
Summary	  of	  Columbia	  Suicide	  Severity	  Rating	  Scale	  (C-­‐SSRS)	  (Safety	  Population)	  
TABLE	  14.3.4.1	  
Summary	  of	  Percent	  of	  Subjects	  Who	  Reported	  Injection	  Site	  Related	  Pain,	  
Itching,	  Discharge,	  Tenderness,	  Erythema/Redness,	  and	  Swelling	  by	  Time	  Point	  
(Safety	  Population)	  
TABLE	  14.3.4.2	  
Summary	  of	  Injection	  Site	  Related	  Pain	  Score	  by	  Time	  Point	  (Safety	  Population)	  
TABLE	  14.3.4.3	  
Summary	  of	  Frequency	  of	  Injection	  Site	  Related	  Erythema/Redness	  and	  Swelling	  
Severity	  by	  Time	  Point	  (Safety	  Population)	  
TABLE	  14.3.5.1	  
Summary	  of	  All	  Treatment-­‐emergent	  Adverse	  Events	  by	  System	  Organ	  Class	  and	  
Preferred	  Term	  (Safety	  Population)	  
TABLE	  14.3.5.2	  
Summary	  of	  All	  Injection	  Site	  Treatment-­‐emergent	  Adverse	  Events	  by	  System	  
Organ	  Class	  and	  Preferred	  Term	  (Safety	  Population)	  
TABLE	  14.3.5.3	  
Summary	  of	  All	  Other	  (Non	  Injection	  Site	  Related)	  Treatment-­‐emergent	  Adverse	  
Events	  by	  System	  Organ	  Class	  and	  Preferred	  Term	  (Safety	  Population)	  
TABLE	  14.3.6.1	  
Summary	  of	  All	  Treatment-­‐emergent	  Adverse	  Events	  by	  System	  Organ	  Class,	  
Preferred	  Term,	  and	  Intensity	  (Safety	  Population)	  
TABLE	  14.3.6.2	  
Summary	  of	  All	  Injection	  Site	  Treatment-­‐emergent	  Adverse	  Events	  by	  System	  
Organ	  Class,	  Preferred	  Term,	  and	  Intensity	  (Safety	  Population)	  
TABLE	  14.3.6.3	  
Summary	  of	  All	  Other	  (Non	  Injection	  Site	  Related)	  Treatment-­‐emergent	  Adverse	  
Events	  by	  System	  Organ	  Class,	  Preferred	  Term,	  and	  Intensity	  (Safety	  Population)	  


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HS-­‐‑11-­‐‑421	  Final	  SAP	  
Page	  25	  of	  27	  
	  
TABLE	  14.3.7.1	  
Summary	  of	  All	  Treatment-­‐emergent	  Adverse	  Events	  by	  System	  Organ	  Class,	  
Preferred	  Term,	  and	  Relationship	  to	  Study	  Drug	  (Safety	  Population)	  
TABLE	  14.3.7.2	  
Summary	  of	  All	  Injection	  Site	  Treatment-­‐emergent	  Adverse	  Events	  by	  System	  
Organ	  Class,	  Preferred	  Term,	  and	  Relationship	  to	  Study	  Drug	  (Safety	  Population)	  
TABLE	  14.3.7.3	  
Summary	  of	  All	  Other	  (Non	  Injection	  Site	  Related)	  Treatment-­‐emergent	  Adverse	  
Events	  by	  System	  Organ	  Class,	  Preferred	  Term,	  and	  Relationship	  to	  Study	  Drug	  
(Safety	  Population)	  
TABLE	  14.3.8.1	  
Summary	  of	  All	  Suspected	  to	  Be	  Drug	  Related	  Treatment-­‐emergent	  Adverse	  
Events	  by	  System	  Organ	  Class	  and	  Preferred	  Term	  (Safety	  Population)	  
TABLE	  14.3.8.2	  
Summary	  of	  All	  Suspected	  to	  Be	  Drug	  Related	  Injection	  Site	  Treatment-­‐
emergent	  Adverse	  Events	  by	  System	  Organ	  Class	  and	  Preferred	  Term	  (Safety	  
Population)	  
TABLE	  14.3.8.3	  
Summary	  of	  All	  Other	  (Non	  Injection	  Site	  Related)	  Suspected	  to	  Be	  Drug	  Related	  
Treatment-­‐emergent	  Adverse	  Events	  by	  System	  Organ	  Class	  and	  Preferred	  Term	  
(Safety	  Population)	  
TABLE	  14.3.9.1	  
Summary	  of	  All	  Serious	  Treatment-­‐emergent	  Adverse	  Events	  by	  System	  Organ	  
Class	  and	  Preferred	  Term	  (Safety	  Population)	  
TABLE	  14.3.9.2	  
Summary	  of	  All	  Serious	  Injection	  Site	  Treatment-­‐emergent	  Adverse	  Events	  by	  
System	  Organ	  Class	  and	  Preferred	  Term	  (Safety	  Population)	  
TABLE	  14.3.9.3	  
Summary	  of	  All	  Other	  (Non	  Injection	  Site	  Related)	  Serious	  Treatment-­‐emergent	  
Adverse	  Events	  by	  System	  Organ	  Class	  and	  Preferred	  Term	  (Safety	  Population)	  
TABLE	  14.3.10.1	  
Summary	  of	  All	  Treatment-­‐emergent	  Adverse	  Events	  That	  Lead	  to	  Study	  
Discontinuation	  by	  System	  Organ	  Class	  and	  Preferred	  Term	  (Safety	  Population)	  
TABLE	  14.3.10.2	  
Summary	  of	  All	  Injection	  Site	  Treatment-­‐emergent	  Adverse	  Events	  That	  Lead	  to	  
Study	  Discontinuation	  by	  System	  Organ	  Class	  and	  Preferred	  Term	  (Safety	  
Population)	  
TABLE	  14.3.10.3	  
Summary	  of	  All	  Other	  (Non	  Injection	  Site	  Related)	  Treatment-­‐emergent	  Adverse	  
Events	  That	  Lead	  to	  Study	  Discontinuation	  by	  System	  Organ	  Class	  and	  Preferred	  
Term	  (Safety	  Population)	  
TABLE	  14.3.11.1	  
Summary	  of	  All	  Serious	  Treatment-­‐emergent	  Adverse	  Events	  That	  Lead	  to	  Study	  
Discontinuation	  by	  System	  Organ	  Class	  and	  Preferred	  Term	  (Safety	  Population)	  
TABLE	  14.3.11.2	  
Summary	  of	  All	  Injection	  Site	  Serious	  Treatment-­‐emergent	  Adverse	  Events	  That	  
Lead	  to	  Study	  Discontinuation	  by	  System	  Organ	  Class	  and	  Preferred	  Term	  
(Safety	  Population)	  
TABLE	  14.3.11.3	  
Summary	  of	  All	  Other	  (Non	  Injection	  Site	  Related)	  Serious	  Treatment-­‐emergent	  
Adverse	  Events	  That	  Lead	  to	  Study	  Discontinuation	  by	  System	  Organ	  Class	  and	  
Preferred	  Term	  (Safety	  Population)	  
TABLE	  14.3.12	  
Summary	  of	  All	  Deaths	  and	  Hospitalizations	  (Safety	  Population)	  
TABLE	  14.4.1.1	  
Summary	  of	  Clinical	  Hematology	  Data	  (Safety	  Population)	  
TABLE	  14.4.1.2	  
Shift	  from	  Baseline	  in	  Laboratory	  Tests:	  Hematology	  (Safety	  Population)	  
TABLE	  14.4.1.3	  
Shift	  from	  Baseline	  in	  Laboratory	  Tests:	  >	  3x	  the	  Upper	  Limit	  of	  Normal	  (ULN)	  
for	  ALT,	  AST,	  and	  Doubling	  of	  Baseline	  Total	  Bilirubin	  (Safety	  Population)	  
TABLE	  14.4.2.1	  
Summary	  of	  Clinical	  Chemistry	  Data	  (Safety	  Population)	  
TABLE	  14.4.2.2	  
Shift	  from	  Baseline	  in	  Laboratory	  Tests:	  Chemistry	  (Safety	  Population)	  
TABLE	  14.4.3.1.	  
Summary	  of	  Clinical	  Coagulation	  Profile	  Data	  (Safety	  Population)	  


BRAEBURN	  PHARMACEUTICALS	   CONFIDENTIAL	  
Version	  1.01—4	  November,	  2016	  
HS-­‐‑11-­‐‑421	  Final	  SAP	  
Page	  26	  of	  27	  
	  
TABLE	  14.4.3.2	  
Shift	  from	  Baseline	  in	  Laboratory	  Tests:	  Coagulation	  Profile	  (Safety	  Population)	  
TABLE	  14.4.4	  
Number	  (%)	  of	  Patients	  with	  Abnormal	  Physical	  Examination	  Findings	  (Safety	  
Population)	  
TABLE	  14.4.5	  
Summary	  of	  Vital	  Signs	  at	  Each	  Visit	  (Safety	  Population)	  
TABLE	  14.4.6.1	  
Summary	  of	  12-­‐Lead	  ECG	  Conclusions	  (Safety	  Population)	  
TABLE	  14.4.6.2	  
Summary	  of	  12-­‐Lead	  ECG	  Individual	  Parameters	  (Safety	  Population)	  
TABLE	  14.4.6.3	  
Summary	  of	  12-­‐Lead	  Categories	  (Safety	  Population)	  
TABLE	  14.4.7	  
Pregnancy	  Test	  (In	  clinic	  urine	  pregnancy	  test)	  (Safety	  Population)	  
TABLE	  14.4.8	  
Pregnancy	  Test	  (Serum	  pregnancy	  test)	  (Safety	  Population)	  
	  
List	  of	  Listings	  
	  
Number	  
Title	  
LISTING	  16.2.1.1	  
Patient	  Meets	  Inclusion	  Criteria	  (All	  Subjects)	  
LISTING	  16.2.1.2	  
Patient	  Meets	  Exclusion	  Criteria	  (All	  Subjects)	  
LISTING	  16.2.2	  
Eligibility	  for	  Randomization	  (All	  Subjects)	  
LISTING	  16.2.3	  
Patient	  Randomization	  (All	  Subjects)	  
LISTING	  16.2.4.1	  
Demographics	  (All	  Subjects)	  
LISTING	  16.2.4.2	  
Medical	  History	  (All	  Subjects)	  
LISTING	  16.2.4.3	  
Psychiatric	  History	  (All	  Subjects)	  
LISTING	  16.2.4.4	  
Opioid	  and	  Substances	  Abused	  (All	  Subjects)	  
LISTING	  16.2.5.1	  
Treatment	  (All	  Randomized	  Subjects)	  
LISTING	  16.2.5.2	  
Injection	  Site	  Examination/	  Treatment	  Compliance	  (All	  Subjects)	  
LISTING	  16.2.5.3	  
Dosing	  Record	  (All	  Subjects)	  
LISTING16.2.6.1	  
Clinical	  Opiate	  Withdrawal	  Scale	  (COWS)	  (All	  Subjects)	  
LISTING16.2.6.2	  
Subjective	  Opiate	  Withdrawal	  Scale	  (SOWS)	  (All	  Subjects)	  
LISTING16.2.6.3	  
Opioid	  Craving	  VAS	  (All	  Subjects)	  
LISTING16.2.6.4	  
Illicit	  Drug	  Use	  Self	  Report	  (All	  Subjects)	  
LISTING16.2.6.5	  
Psychosocial	  Counseling	  (All	  Subjects)	  
LISTING16.2.7.1	  
Adverse	  Events	  (All	  Subjects)	  
LISTING16.2.7.2	  
Serious	  Adverse	  Events	  (All	  Subjects)	  (All	  Subjects)	  
LISTING16.2.7.3	  
Adverse	  Events	  That	  Lead	  to	  Study	  Drug	  Discontinuation	  (All	  Subjects)	  
LISTING16.2.7.4	  
Adverse	  Events	  That	  Have	  Death	  as	  the	  Outcome	  (All	  Subjects)	  
LISTING16.2.7.5	  
Death	  Report	  (All	  Subjects)	  
LISTING16.2.7.6	  
Prior	  and	  Concomitant	  Medications/Procedures	  (All	  Subjects)	  
LISTING16.2.8.1	  
Lab	  Test	  Samples	  (All	  Subjects)	  
LISTING16.2.8.2	  
Clinical	  Hematology	  (All	  Subjects)	  
LISTING16.2.8.3	  
Clinical	  Chemistry	  (All	  Subjects)	  
LISTING16.2.8.4	  
Clinical	  Coagulation	  Profile	  (All	  Subjects)	  
LISTING16.2.8.5	  
Urine	  Collection/Toxicology	  (General)	  (All	  Subjects)	  
LISTING16.2.8.6	  
Urine	  Toxicology	  (Illicit	  Opioids)	  (All	  Subjects)	  
LISTING16.2.8.7	  
Pregnancy	  Test	  (All	  Subjects)	  
LISTING16.2.8.8	  
Physical	  Examination	  (All	  Subjects)	  
LISTING16.2.8.9	  
Vital	  Signs	  (All	  Subjects)	  


BRAEBURN	  PHARMACEUTICALS	   CONFIDENTIAL	  
Version	  1.01—4	  November,	  2016	  
HS-­‐‑11-­‐‑421	  Final	  SAP	  
Page	  27	  of	  27	  
	  
LISTING16.2.8.10	  
12-­‐Lead	  ECG	  (All	  Subjects)	  
LISTING16.2.8.11	  
C-­‐SSRS	  (All	  Subjects)	  
LISTING16.2.8.12	  
Patient	  Disposition	  (All	  Subjects)	  
LISTING16.2.8.13	  
Protocol	  Deviations	  (All	  Subjects)	  
List	  of	  Figures	  
	  
Number	  
Title	  
Figure	  14.1.1	  
Responder	  Rate	  Per	  Primary	  Efficacy	  Definition	  (ITT	  Population)	  
Figure	  14.1.2	  
CDF	  of	  Percent	  of	  Urine	  Samples	  Negative	  for	  Illicit	  Opioids	  Weeks	  5-­‐25	  (ITT	  
Population)	  
Figure	  14.1.3	  
Time	  to	  sustained	  abstinence	  of	  opioid	  use	  (ITT	  Population)	  
Figure	  14.1.4.1	  
Change	  from	  Baseline	  in	  Desire	  to	  Use	  VAS	  Over	  Time	  (ITT	  Population)	  
Figure	  14.1.4.2	  
Change	  from	  Baseline	  in	  Need	  to	  Use	  VAS	  Over	  Time	  (ITT	  Population)	  
Figure	  14.1.5.3	  
Change	  from	  Baseline	  in	  Morning	  Desire	  to	  Use	  VAS	  Over	  Time	  (ITT	  Population)	  
Figure	  14.1.5.4	  
Change	  from	  Baseline	  in	  Morning	  Need	  to	  Use	  VAS	  Over	  Time	  (ITT	  Population)	  
Figure	  14.1.6	  
Change	  from	  Baseline	  in	  Clinical	  Opiate	  Withdrawal	  Scale	  (COWS)	  Over	  Time	  
(ITT	  Population)	  
Figure	  14.1.7	  
Change	  from	  Baseline	  in	  Subjective	  Opiate	  Withdrawal	  Scale	  (SOWS)	  Over	  Time	  
(ITT	  Population)