Conditions: Opioid Use Disorder Chronic Pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 66
Healthy volunteers: no

Brief summary:
Phase II, open label, partially randomized, three treatment group study designed to evaluate the steady state pharmacokinetics of buprenorphine and norbuprenorphine following repeated subcutaneous administrations of CAM2038.

Detailed description:
This is a phase II, open label, partially randomized, three treatment group study designed to evaluate the steady state pharmacokinetics of buprenorphine and norbuprenorphine following repeated subcutaneous administrations of CAM2038 weekly and monthly at different injection sites and to evaluate the steady state pharmacokinetics of buprenorphine and norbuprenorphine after repeated subcutaneous administration of CAM2038 monthly in opioid dependent subjects with a history of chronic non cancer pain. The study will involve three phases: Screening, Treatment, and Follow up.

Arms:
arm 1: Group 1, 32 mg of CAM2038 subcutaneous weekly injection at multiple injection sites arm 2: Group 2: 128 mg of CAM2038 subcutaneous monthly injection in the buttocks arm 3: Group 3: 24mg sublingual BPN for the first 7 days, and then 160 mg of CAM2038 subcutaneous monthly injection in the buttocks starting on Day 8.

Interventions: intervention 1: CAM2038
Intervention descriptions: intervention 1: Long-Acting Subcutaneous Injectable Depot of Buprenorphine

Protocol document:
Prot_001.pdf: 
  
 
 
 
Clinical Study Protocol 
HS-15-549 
 
 
 
 
A Phase II, Open-label, Partially Randomized, Three 
Treatment Groups, Multi-site Study Assessing 
Pharmacokinetics after Administration of the Once-Weekly 
and Once-Monthly, Long-Acting Subcutaneous Injectable 
Depot of Buprenorphine (CAM2038) at Different Injection 
Sites in Opioid-Dependent Subjects with Chronic Pain 
 
 
CAM2038 q1w (50 mg/mL buprenorphine FluidCrystal® once-weekly 
subcutaneous injection depot) 
 
CAM2038 q4w (356 mg/mL buprenorphine FluidCrystal® once-monthly 
subcutaneous injection depot) 
 
Original Protocol: 1.0, 15 NOV 2015 
Amendment 1:  2.0, 08 DEC 2015 
Amendment 2:  3.0, 11 MAY 2016 
Amendment 3:  4.0, 31 MAY 2016 
Amendment 4:  5.0, 05 OCT 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.


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Summary of Changes and Justification 
For HS-15-549 
Amendment 4 
 
Change and Location Within the Protocol
Rationale
Changed version and protocol date throughout.
Version was changed from 4.0 to 5.0 and 
protocol date from 31 MAY 2016 to 05 OCT 
2016. 
Updated Project Manager information.
Section 1, Sponsor and Key Personnel 
Updated to reflect change in personnel. 
Protocol updated to include Group 3, including Group-specific 
inclusion criterion, treatment, assessments, and planned 
analysis.  
Updated throughout entire document, including study title. 
 
Addition of Group 3 (n=16 subjects) and 
associated treatment and assessments. Subjects 
in Group 3 will receive 24 mg SL BPN for 7 
days, followed by repeated administration of 160 
mg CAM2038 q4w injections. To be eligible, 
subjects must be taking SL BPN ≥24 mg daily 
for at least 30 days prior to Screening, as BPN 
exposure following administration of CAM2038 
q4w 160 mg is similar to SL BPN 26 mg to 32 
mg. 
Duration of participation for subjects in Group 1.
Section 2, Synopsis 
Updated to be consistent with body of protocol. 
Subjects who discontinue from the study early will undergo 
End of Treatment visit assessments, including PK sampling 
and urine toxicology. 
Section 7, Investigational Plan 
Section 8.3, Removal of Subjects from Therapy or Assessment
Section 10, Table 2 and Table 3: Schedule of Assessments  
Clarification of assessments to be conducted for 
subjects who discontinue early. 
Subjects in Group 1 and Group 2 who choose not to enter the 
open-label extension phase will undergo EOT procedures and 
transition back to standard therapy on Day 50 and Day 113, 
respectively. 
Section 2, Synopsis 
Section 7, Investigational Plan 
Section 10, Table 1 and Table 2: Schedule of Assessments 
Clarification of transition to standard therapy and 
differentiation of EOT for subjects not entering 
the open-label extension phase and those 
entering the open-label extension phase (OLE-
EOT). 
Addition made to specify that a third party could be hired to 
locate subjects who are lost to follow-up. 
Section 8.3, Removal of Subjects from Therapy or Assessment 
In the event a subject is lost to follow-up, a third 
party could be hired to locate the subject to 
ensure safety and collect relevant safety 
information. 


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Change and Location Within the Protocol
Rationale
Day 91 (now Day 92; Group 1) and Day 155 (Group 2) 
designated as in-clinic visits only, with no dosing to occur. 
Section 10, Table 1 and Table 2: Schedule of Assessments 
The schedule of assessments was updated to 
reflect that dosing of CAM2038 on Day 91 
(Group 1) and Day 155 (Group 2) will not occur; 
these study days are in-clinic visits where no 
dosing will occur. 
In-clinic visits for subjects in Group 1 who enter the extension 
phase were updated to Days 85 and 92, instead of Days 84 and 
91. 
Section 10, Table 1: Schedule of Assessments 
The schedule of assessments was updated to 
reflect the correct in-clinic visit days for 
subjects in Group 1 who enter the extension 
phase. 
Follow up visit was updated to be a phone call, and scheduled 
to occur on Day 99 for Group 1. 
Section 10, Table 1 and Table 2: Schedule of Assessments 
The follow-up visit in the schedule of 
assessments was updated to be a follow up 
phone call to be consistent with the body of the 
protocol, and to occur on Day 99 (Group 1) to 
reflect the 7 day interval between the EOT visit 
and call. 
Addition of Table 3 for Group 3 (160 mg CAM2038 q4w)
Section 10, Table 3: Schedule of Assessments 
Addition of visits and procedures for Group 3. 
Addition of Group 3 PK blood volume.
Section 10.3.1.1, Sample Collection, Preparation and Handling
To describe blood volumes required for PK 
sampling in Group 3. 
Update to total blood volume to be drawn for each subject, by 
Group. 
Section 10.5.3, Clinical Laboratory Assessments 
Addition of open-label extension clinical 
laboratory assessment blood volumes for 
Groups 1 and 2, and addition of blood volumes 
for Group 3. 
Addition of non-identifying photographs of injection site 
reactions. 
Section 10.5.7, Injection Site Examinations 
To augment documentation of injection site 
reactions. 
Minor typographical and formatting errors and hyperlinking 
revisions. 
Updated throughout entire document. 
Clarity and consistency. 
 
 
 


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1 
SPONSOR AND KEY PERSONNEL CONTACT 
INFORMATION 
 
 
ROLE IN STUDY                                   NAME                                            CONTACT INFORMATION 
 
Study Sponsor 
Braeburn Pharmaceuticals, 
Inc. 
47 Hulfish Street, Suite 441 
Princeton, NJ  08542 
Medical Monitor 
Charles Laudadio, MD 
pharmmd@gmail.com 
610.812.3477 
Sponsor Project Manager 
Jamie Jarecki-Smith 
jjarecki@braeburnpharma.com 
719.494.6500 - mobile 
Principal Investigator 
Greg Sullivan, MD 
dgregs@gmail.com 
205.815.5000 - office 


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2 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company: Braeburn Pharmaceuticals Inc. 
 
Name of Investigational Products: 
CAM2038 q1w (50 mg/mL buprenorphine FluidCrystal® once-weekly subcutaneous injection depot); CAM2038 
q4w (356 mg/mL buprenorphine FluidCrystal® once-monthly subcutaneous injection depot) 
 
Name of Active Ingredient: Buprenorphine 
Study Title: 
A Phase II, Open-label, Partially Randomized, Three Treatment Groups, Multi-site Study Assessing 
Pharmacokinetics after Administration of the Once-Weekly and Once-Monthly, Long-Acting Subcutaneous 
Injectable Depot of Buprenorphine (CAM2038) at Different Injection Sites in Opioid-Dependent Subjects with 
Chronic Pain 
 
Objectives: 
Primary objectives of the study are: 
 
To evaluate the steady state pharmacokinetics (PK) of buprenorphine (BPN) and norbuprenorphine 
(norBPN) following repeated subcutaneous (SC) administration of CAM2038 q1w (50 mg/mL) at 4 
different injection sites in adult opioid-dependent subjects with chronic pain. 
 
To evaluate steady state PK of BPN and norBPN following repeated SC administration of CAM2038 
q4w (356 mg/mL) with the buttock as the injection site in adult opioid-dependent subjects with 
chronic pain. 
The secondary objectives of the study are: 
 
 
To evaluate the safety and tolerability of CAM2038 q1w and CAM2038 q4w in adult opioid-
dependent subjects with chronic pain. 
 
To assess relative bioavailability of BPN at steady state following repeated SC administration 
of 160 mg CAM2038 q4w compared with repeated sublingual (SL) administration of 24 mg 
BPN in adult opioid-dependent subjects with chronic pain. 
The exploratory objectives of the study are: 
 
To evaluate maintenance of treatment efficacy when transferring adult opioid-dependent subjects 
from SL BPN to CAM2038 q1w and q4w, as determined by urine toxicology. 
 
To evaluate subject-rated worst daily pain and average daily pain, using an 11-point numerical rating 
scale (NRS), following repeated SC administration of CAM2038 q1w and CAM2038 q4w in adult 
opioid-dependent subjects. 
 
Methodology: 
 
This is a Phase II, open-label, partially randomized, 3-treatment group, multi-site study designed to evaluate the 
steady state PK of BPN and norBPN following repeated SC administration of CAM2038 q1w (Group 1) at 
different injection sites, to evaluate the steady state PK of BPN and norBPN after repeated SC administration of 
CAM2038 q4w (Group 2 and Group 3), and to evaluate relative bioavailability of BPN following SC 
administration of 160 mg CAM2038 q4w as compared with 24 mg SL BPN (Group 3) in opioid-dependent 


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subjects with a history of chronic non-cancer pain. The study will involve 4 phases: Screening, Treatment, open 
label safety extension and Follow-up. 
 
Within 21 days of a medical Screening visit and confirmation of eligibility, subjects will be randomized to 1 
of 2 treatment groups (Group 1 or Group 2; refer to Section 10.2, Eligibility Review and Randomization, for 
more detail): 
 
    Group 1: 3 single weekly SC injections of 32 mg CAM2038 q1w (50 mg/mL) administered in 
the buttock to reach steady state, rotating between right and left buttock and injection site, 
followed by 4 single weekly SC injections of 32 mg CAM2038 q1w administered in the buttock 
(reference), abdomen, thigh, and back of upper arm in a randomized, crossover manner, with 
injection site sequence allocated using a randomized crossover design. 
 
Group 2: 4 monthly SC injections of 128 mg CAM2038 q4w (356 mg/mL) administered in the buttock, 
rotating between right and left buttock and injection site. 
An additional group, to which subjects will not be randomized, was added following completion of 
randomization to Groups 1 and 2, in order to evaluate a higher dose of CAM2038 q4w (i.e., 160 mg) and 
compare resultant BPN exposure with SL BPN treatment: 
 
Group 3: 7 consecutive single daily doses of 24 mg SL BPN, followed by 4 monthly SC injections of 
160 mg CAM2038 q4w (356 mg/mL) administered in the buttock, rotating between right and left 
buttock. 
For subjects in Group 1, the first 3 SC injections of CAM2038 q1w will be administered in the buttock, rotating 
between right and left buttock on Day 1, Day 8 and Day 15 in order to achieve steady state PK of BPN and 
norBPN. Subjects will be administered each CAM2038 q1w injection at the clinical research unit (CRU) on an 
outpatient basis. Following the first administration, subjects will attend an interim visit on Day 2 to evaluate 
safety and tolerability of the transition from 24 mg SL BPN (Suboxone or equivalent) to CAM2038 q1w. To 
evaluate steady state PK of BPN and norBPN following CAM2038 q1w administration at various sites, 
CAM2038 q1w will be administered at 4 different injection sites, i.e., buttock (reference), abdomen, thigh and 
back of upper arm, on Day 22, Day 29, Day 36 and Day 43, using a randomized crossover design. Subjects will 
be confined to the CRU for 24 hours while serial PK samples will be collected. Subsequent PK samples will be 
collected for up to 168 hours post-dose.  At the Day 50 (End of Treatment [EOT]) visit, subjects may continue 
on with the open-label extension phase for up to 6 weeks or transition back to standard care. For those enrolling 
into the open-label extension, subjects will receive additional CAM2038 q1w injections and will then transition 
back to standard care on Day 92 (EOT - OLE). At each study visit, including the open-label extension phase, 
safety and efficacy assessments will be conducted at pre-specified times. Subjects will also be required to record 
their worst daily pain and average daily pain using an 11-point NRS on an electronic device. 
 
For subjects in Group 2, SC injections of 128 mg CAM2038 q4w will be administered in the buttock, rotating 
between right and left buttock, on Day 1, Day 29, Day 57 and Day 85, for a total of 4 doses. Following the first 
administration, subjects will attend an interim visit on Day 2 to evaluate safety and tolerability of the transition 
from SL BPN 24 mg to CAM2038 q4w. Following administration of the first 3 doses, PK samples will be 
collected pre-dose and at scheduled times post-dose on an outpatient basis to determine achievement of steady 
state. To characterize steady state PK of BPN and norBPN, subjects will be confined to the CRU and serial PK 
samples will be collected for up to 24 hours following the fourth dose, administered on Day 85; subsequent PK 
samples will be collected up to 28 days’ post-dose on an outpatient basis. At each study visit, safety and efficacy 
assessments will be conducted at pre-specified times. At the Day 113 (EOT) visit, subjects in Group 2 (128 mg 
CAM2038 q4w) may continue on with the open-label extension phase for up to 6 weeks or transition back to 


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standard care. For those enrolling into the open-label extension, subjects will be switched to CAM2038 q1w 
32 mg on Day 113 and will then transition back to standard care on Day 155 (EOT - OLE).  At each study visit, 
including the open-label extension phase, safety and efficacy assessments will be conducted at pre-specified 
times. Subjects will also be required to record their worst daily pain and average daily pain using an 11-point 
NRS on an electronic device. 
 
For subjects in Group 3, single daily doses of 24 mg SL BPN will be administered in the morning on Day 1 
through Day 7 for a total of 7 doses. This will be followed by SC injections of 160 mg CAM2038 q4w in the 
buttock, rotating between right and left buttock, on Day 8, Day 36, Day 64 and Day 92, for a total of 4 doses. 
Following the first 160 mg CAM2038 q4w administration, subjects will attend an interim visit on Day 9 to 
evaluate safety and tolerability of the transition from SL BPN 24 mg to CAM2038 q4w. Following 
administration of the first 3 doses of CAM2038 q4w, PK samples will be collected pre-dose and at scheduled 
times post-dose on an outpatient basis to determine achievement of steady state. To characterize steady state PK 
of BPN and norBPN and evaluate relative bioavailability of CAM2038 q4w as compared with SL BPN, subjects 
will be confined to the CRU and serial PK samples will be collected for up to 24 hours following the seventh 
dose of SL BPN administered on Day 7, and following the fourth dose of CAM2038 q4w administered on Day 
92. Subsequent PK samples will be collected up to 28 days post-dose on an outpatient basis. At the Day 127 
(EOT) visit, subjects will be transitioned back to standard care. At each study visit, safety and efficacy 
assessments will be conducted at pre-specified times. Subjects will also be required to record their worst daily 
pain and average daily pain using an 11-point NRS on an electronic device. 
 
For all Groups, a follow-up call will be conducted approximately 7 days after the last study visit of the 
Treatment Phase or open label safety extension phase. 
 
Number of Subjects (Planned): 
 
Up to a total of approximately 40 subjects will be randomized at a 3:2 ratio to Group 1 (32 mg CAM2038 
q1w) or Group 2 (128 mg CAM2038 q4w). An additional group (Group 3) of approximately 16 subjects will 
be assigned to receive 24 mg SL BPN for 7 days followed by 160 mg CAM2038 q4w. 
At least 20 subjects, and up to 24 subjects, will be randomized to Group 1 and assigned to 1 of the following 
4 injection site sequences: ABDC, BCAD, CDBA, and DACB, where A=buttock (reference), B=abdomen, 
C=thigh, and D=back of upper arm.  For Group 2 (128 mg CAM2038 q4w) and Group 3 (24 mg SL BPN 
followed by 160 mg CAM2038 q4w), approximately 16 subjects will be enrolled into each Group. 
 
Diagnosis and Main Criteria for Inclusion: 
 
This study will enroll opioid-dependent adult subjects (19 to 65 years of age) with a history of moderate to 
severe chronic non-cancer pain. Subjects must have been taking a daily dose of 24 mg SL BPN (Subutex® 
equivalent) for at least 30 days prior to Screening. Subjects must meet each of the following inclusion criteria 
in order to be eligible for participation in the study: 
1.   Subject must provide written informed consent prior to the conduct of any study-related 
procedures. 
2.   Male or non-pregnant, non-lactating female subject, aged 19 to 65 years, inclusive. 
3.   Body mass index between 19 and 35 kg/m2, inclusive. 
4.   Current diagnosis of moderate to severe opioid use disorder (according to the DSM-V) or past medical 
history of opioid use disorder currently being treated with SL BPN. 


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5.   Subject must be taking SL BPN (Subutex® equivalent) 24 mg daily (Group 1 and Group 2) or ≥24 mg 
(Group 3) for at least 30 days prior to Screening. 
6.   Subject has a history of moderate to severe chronic non-cancer pain. 
7.   Male and female subjects of childbearing potential must be willing to use a reliable method of 
contraception during the entire study (Screening visit to Follow-up phone call). 
8.   Subject must be willing and able to comply with all study procedures and requirements. 
 
Subjects will not be eligible to participate in this study if any of the following exclusion criteria are met: 
1.   Individuals meeting DSM-V substance use disorder criteria for alcohol, benzodiazepines, central nervous 
system (CNS) stimulants, or other drugs of abuse (excluding caffeine, tobacco or THC/marijuana). 
2.   Any clinically significant abnormality on the basis of medical history, vital signs, physical examination, 
12-lead electrocardiogram (ECG; Fridericia's corrected QT interval [QTcF] ≥450 msec. for males or 
≥470 msec. for females), and laboratory evaluations (including hematology, clinical chemistry, 
urinalysis at Screening), in the opinion of the Investigator. 
3.   Significant symptoms, medical conditions, or other circumstances which, in the opinion of the 
Investigator, would preclude compliance with the protocol, adequate cooperation in the study or 
obtaining informed consent, or may prevent the subject from safely participating in study, including 
subjects who are at a risk for gastrointestinal obstruction or paralytic ileus or who have severe 
respiratory insufficiency, respiratory depression, airway obstruction, gastrointestinal motility disorders, 
biliary tract disease, severe hepatic insufficiency, planned surgery and prior treatment with monoamine 
oxidase inhibitors. 
4.   Use (therapeutic or non-therapeutic) of opioids other than SL BPN. 
5.   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 study. 
6.   Pregnant or lactating or planning to become pregnant during the study. 
7.   Diagnosis of, or currently under investigation for, fibromyalgia, complex regional pain syndrome, 
neurogenic claudication due to spinal stenosis, spinal cord compression, acute nerve root compression, 
severe or progressive lower extremity weakness or numbness. 
8.   History of chemotherapy or confirmed malignancy (except basal cell or squamous carcinoma of the 
skin) within the past 2 years. 
9.   Clinically significant history of, or current evidence for, suicidal ideation or those who are actively 
suicidal, as based on the Columbia-Suicide Severity Rating Scale (C-SSRS; grade 4 or 
5). 
10. Clinically significant history of major depressive disorder that is poorly controlled with 
medication. 
11. Hypersensitivity or allergy to BPN or other opioids, or excipients of CAM2038. 
12. Exposure to any investigational drug within the 4 weeks prior to Screening. 
13. Participants with a clinically significant history of risk factors of Torsades de Pointes and any existing 
ventricular tachyarrhythmias such as bigeminy, trigeminy, heart failure, hypokalemia, family history of 
Long QT Syndrome. 


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14. On medications that have the potential for prolonging the QT interval or who may require such 
medications during the course of the study along with clinically significant abnormalities on screening 
electrocardiogram (ECG) readings as deemed by the investigator (Appendix 17.1). 
15. 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). 
16. Intolerance to venipuncture and/or difficulty with venous access, as per the judgment of the 
Investigator/research staff. 
17. Is an employee of the Investigator or the study site, with direct involvement in the proposed study or 
other studies under the direction of the Investigator or study site, or is a family member of an employee 
or of the Investigator. 
18.  Any pending legal action that could prohibit participation or compliance in the study. 
 
Investigational Product, Dosage, and Mode of Administration 
CAM2038 q1w (Group 1): BPN FluidCrystal® SC injection depot for once weekly administration (50 mg/mL) 
at a dose of 32 mg (BPN base), 0.64 mL SC injection. 
CAM2038 q4w (Group 2): BPN FluidCrystal® SC injection depot for once monthly administration (356 mg/mL) 
at a dose of 128 mg (BPN base), 0.36 mL SC injection. 
CAM2038 q4w (Group 3): BPN FluidCrystal® SC injection depot for once monthly administration (356 mg/mL) 
at a dose of 160 mg (BPN base), 0.45 mL SC injection. 
 
Reference Product, Dosage, and Mode of Administration 
Group 3: SL BPN (Subutex® equivalent) 24 mg (3 tablets of 8 mg BPN) for once daily administration 
 
Duration of Study: 
 
Group 1: Each subject will participate in the study for up to approximately 17 weeks.  
Group 2: Each subject will participate in the study for up to approximately 26 weeks. 
Group 3: Each subject will participate in the study for up to approximately 21 weeks. 
 
Criteria for Evaluation: 
 
Pharmacokinetic Endpoints: 
The following PK parameters will be derived based on the plasma concentrations of BPN and norBPN, 
if applicable: 
    Group 1: 
o AUCss (area under the plasma concentration-time curve during a 7-day dosing interval at 
steady state) for each injection site, i.e., buttock (reference), abdomen, thigh and back of upper 
arm. 
 
o Css,av (average plasma concentration during a dosing interval at steady state) for each 
injection site. 
o Css,max (maximum observed plasma concentration during a dosing interval at steady state) 
for each injection site. 
o tss,max (time to Css,max) for each injection site. 


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o norBPN/BPN ratios for AUCss and Css,max for each injection site. 
    Group 2 and Group 3: 
o AUCss (AUC during a 24-hour dosing interval at steady state for SL BPN [Group 3 only] and a 
28-day dosing interval at steady state for CAM2038 q4w) 
o Css,av 
o Css,max 
o tss,max 
o Css,28days (observed plasma concentration 28 days after administration of CAM2038 q4w at steady 
state) 
o Css,24h (observed plasma concentration 24 hours after administration of SL BPN at steady state) 
(Group 3 only) 
In Group 3, relative bioavailability of BPN will be assessed at steady state following repeated SC administration 
of 160 mg CAM2038 q4w as compared with repeated SL administration of 24 mg BPN. 
 
Efficacy Variables: 
The following exploratory efficacy variables will be assessed during the study: 
 
Urine toxicology: Frequency and incidence of positive results for opioids (excluding BPN) and other non-
opioid drugs. 
 
NRS scale for pain: change from baseline in weekly average of daily Worst Pain score. 
 
Safety Variables: 
The following safety variables will be assessed during the study: 
 
Adverse events  
 
Concomitant medications/procedures 
 
Clinical laboratory assessments (hematology, biochemistry and urinalysis) 
 
Vital signs (body temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate) 
 
12-lead ECG 
 
Physical examination 
 
Injection site examination 
 
C-SSRS 
 
Subjective Opioid Withdrawal Scale 
 
Clinical Opioid Withdrawal Scale 
 
Statistical Methods (Data Analysis): 
Three study populations are defined: 
 
Safety population: All subjects who receive at least part of an injection of the study medications.  All 
safety analysis will be based on the Safety population. 
 
Pharmacokinetic population: The PK population will consist of all subjects in the Safety population 
who have provided sufficient PK data for all 4 randomized injection sites to derive PK parameters of 
interested (Group 1), or have provided PK data after the last injections of CAM2038 q4w (Group 2 and 
Group 3).  All PK summaries will be based on the PK population. 
 
Efficacy population: The efficacy population will be the intent-to-treat population consisting of all 
subjects that have received at least 1 injection of CAM2038 and provided some efficacy measures.  


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PK parameters of BPN and norBPN will be summarized by descriptive statistics, if appropriate.  For Group 1 
(CAM2038 q1w), the following considerations will apply in the PK analysis.  The primary PK parameters will be 
AUCss and Css, max after steady state injections of CAM2038 q1w at different injection sites.  The injection site 
buttock will be the reference.  The analyses will be based on log-transformed data.  The natural log-transformed 
AUCss and Css, max data will be analyzed using an ANOVA model, sequence, subject within sequence (1, 2, 3, 4 
corresponding to A/B/D/C, B/C/A/C, C/D/B/A, D/A/C/B, where A=buttock, B=abdomen, C=thigh, or D=back of 
upper arm), period, and treatment (treatment sites: A=buttock, B=abdomen, C=thigh, or D=back of upper arm).  
The estimated treatment effects, treatment differences versus the reference (B-A, C-A, and D-A), and the 90% 
confidence intervals of the estimated difference will be presented.  The above estimates will be expressed on the 
raw scale (expressed after performing the anti-log).  All other PK parameters will be summarized by descriptive 
statistics. 
 
For Group 2 (128 mg CAM2038 q4w) and Group 3 (24 mg SL BPN and 160 mg CAM2038 q4w), the PK 
parameters will be summarized by descriptive statistics.  The primary PK parameters will be AUCss and Css, max. 
Relative bioavailability of BPN will be assessed at steady state for 160 mg CAM2038 q4w for comparison with 
24 mg SL BPN (Group 3). 
 
 
 


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3 
TABLE OF CONTENTS 
1 
SPONSOR AND KEY PERSONNEL CONTACT INFORMATION ...............................................4 
2 
PROTOCOL SYNOPSIS ....................................................................................................................5 
3 
TABLE OF CONTENTS ..................................................................................................................12 
4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................................15 
5 
INTRODUCTION .............................................................................................................................17 
5.1 
Background ................................................................................................................................17 
5.1.1 CAM2038 q1w (Once Weekly) ............................................................................................ 17 
5.1.2 CAM2038 q4w (Once Monthly) .......................................................................................... 19 
5.1.3 Study Rationale..................................................................................................................... 20 
5.2 
Overall Risk-Benefit ..................................................................................................................20 
6 
STUDY OBJECTIVES .....................................................................................................................22 
6.1 
Primary Objectives ....................................................................................................................22 
6.2 
Secondary Objectives ................................................................................................................22 
6.3 
Exploratory Objectives ..............................................................................................................22 
7 
INVESTIGATIONAL PLAN ............................................................................................................23 
7.1 
Overall Study Design and Plan ..................................................................................................23 
7.2 
Discussion of Study Design .......................................................................................................26 
8 
SELECTION OF STUDY POPULATION .......................................................................................27 
8.1 
Inclusion Criteria .......................................................................................................................27 
8.2 
Exclusion Criteria ......................................................................................................................27 
8.3 
Removal of Subjects from Therapy or Assessment ...................................................................29 
8.4 
Study restrictions .......................................................................................................................30 
8.4.1 Contraception Requirements ................................................................................................ 30 
8.4.2 Dietary and Fluid Restrictions .............................................................................................. 31 
8.4.3 Alcohol, Caffeine and Other Drug Use ................................................................................ 31 
8.4.4 Activity and Exercise ............................................................................................................ 31 
8.4.5 Other Restrictions ................................................................................................................. 32 
9 
TREATMENTS .................................................................................................................................33 
9.1 
Treatment Administration ..........................................................................................................33 
9.2 
Identity of Investigational Products ...........................................................................................33 
9.2.1 Description of CAM2038 q1w and CAM2038 q4w SC Injection Products ........................ 34 
9.2.2 Description of Sublingual Buprenorphine Products .............. Error! Bookmark not defined. 
9.2.3 Handling, Storage, and Accountability ................................................................................ 34 
9.2.4 Dispensing and Administration ............................................................................................ 34 
9.3 
Method of Assigning Subjects to Treatment Groups .................................................................35 
9.4 
Selection of Doses .....................................................................................................................35 
9.5 
Prior and Concomitant Therapy .................................................................................................35 
9.6 
Treatment Compliance ...............................................................................................................36 
10 STUDY PROCEDURES AND ASSESSMENTS .............................................................................36 
10.1 
Demographics and Other Baseline Characteristics ....................................................................48 
10.1.1 
Informed Consent ............................................................................................................. 48 
10.1.2 
Demographics ................................................................................................................... 48 


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10.1.3 
Medical and Psychosocial History ................................................................................... 48 
10.1.4 
Medication History ........................................................................................................... 48 
10.1.5 
Substance Use and Treatment History .............................................................................. 48 
10.2 
Eligibility Review and Randomization ......................................................................................48 
10.3 
Pharmacokinetic Assessments ...................................................................................................49 
10.3.1 
Drug concentration measurements ................................................................................... 49 
10.3.2 
Pharmacokinetic parameters ............................................................................................. 49 
10.4 
Efficacy Assessments ................................................................................................................50 
10.4.1 
Urine Toxicology .............................................................................................................. 50 
10.4.2 
Numerical Rating Scale (NRS) for Pain ........................................................................... 51 
10.5 
Safety Assessments ....................................................................................................................51 
10.5.1 
Adverse Events and Serious Adverse Events ................................................................... 51 
10.5.2 
Pregnancy ......................................................................................................................... 54 
10.5.3 
Clinical Laboratory Assessments ..................................................................................... 54 
10.5.4 
Vital Signs ........................................................................................................................ 55 
10.5.5 
12-Lead Electrocardiogram .............................................................................................. 56 
10.5.6 
Physical Examination ....................................................................................................... 56 
10.5.7 
Injection Site Examination ............................................................................................... 56 
10.5.8 
Columbia-Suicide Severity Rating Scale ......................................................................... 56 
10.5.9 
Subjective Opioid Withdrawal (SOWS) Scale ................................................................. 57 
10.5.10 Clinical Opioid Withdrawal (COWS) Scale ..................................................................... 57 
10.5.11 Treatment Identification Card .......................................................................................... 57 
10.5.12 Other Safety Considerations ............................................................................................. 57 
10.6 
Efficacy Variables .....................................................................................................................57 
10.6.1 
Urine Toxicology .............................................................................................................. 57 
10.6.2 
Numerical Rating Scale for Pain ...................................................................................... 57 
10.7 
Appropriateness of Measures.....................................................................................................57 
11 DATA QUALITY ASSURANCE .....................................................................................................59 
11.1 
Data Collection ..........................................................................................................................59 
11.2 
Study Auditing and Monitoring .................................................................................................59 
12 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................................61 
12.1 
Statistical and Analytical Plans .................................................................................................61 
12.2 
Analysis Populations .................................................................................................................61 
12.3 
Planned Analyses .......................................................................................................................61 
12.3.1 
Demographics and Other Baseline Characteristics .......................................................... 61 
12.3.2 
Analysis of Pharmacokinetics .......................................................................................... 61 
12.3.3 
Analysis of Safety ............................................................................................................. 62 
12.3.4 
Analysis of Efficacy ......................................................................................................... 62 
12.3.5 
Missing data ...................................................................................................................... 63 
12.4 
Determination of Sample Size ...................................................................................................63 
13 STUDY ADMINISTRATION AND INVESTIGATOR RESPONSIBILITIES ..............................64 
13.1 
Regulatory and Ethical Considerations......................................................................................64 
13.1.1 
Ethical Conduct of the Study ............................................................................................ 64 
13.1.2 
Ethics Approval ................................................................................................................ 64 
13.1.3 
Subject Informed Consent ................................................................................................ 64 
13.2 
Privacy and Confidentiality .......................................................................................................65 


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13.3 
Study and Site Closure ..............................................................................................................65 
13.4 
Regulatory Documents and Records Retention .........................................................................66 
13.5 
Delegation of Responsibilities and Adequate Resources ..........................................................66 
13.6 
Protocol Amendments ...............................................................................................................67 
13.7 
Financial Disclosure ..................................................................................................................67 
14 SPONSOR APPROVAL PAGE ........................................................................................................68 
15 INVESTIGATOR PROTOCOL AGREEMENT PAGE ...................................................................69 
16 REFERENCES ..................................................................................................................................70 
17 APPENDICES ...................................................................................................................................71 
17.1 
Agents Associated with Potential QTc Interval Prolongation ...................................................71 
17.2 
CAM2038 Administration Sites ................................................................................................77 
17.3 
Local Injection Site Tolerability Scale ......................................................................................78 
17.4 
Columbia-Suicide Severity Rating Scale – Baseline/Screening ................................................79 
17.5 
Columbia-Suicide Severity Rating Scale (Since Last Visit) .....................................................82 
17.6 
The Subjective Opioid Withdrawal Scale (SOWS) ...................................................................86 
17.7 
The Clinical Opioid Withdrawal Scale (COWS) .......................................................................87 
 
 
 
LIST OF TABLES 
 
 
Table 1: Schedule of Assessments – Group 1 (CAM2038 q1w) .............................................................. 38 
Table 2: Schedule of Assessments – Group 2 (128 mg CAM2038 q4w) ................................................. 41 
Table 3: Schedule of Assessments – Group 3 (160 mg CAM2038 q4w) ................................................. 45 
Table 4: Clinical Laboratory Assessments ............................................................................................... 55 
 
 
 


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4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
AUCss 
AUC during a dosing interval at steady state
BMI
Body mass index
BPN
Buprenorphine
CFR
Code of Federal Regulations
CNS
Central nervous system
COWS
Clinical Opioid Withdrawal Scale
CRF
Case Report Form (may include electronic data capture systems or paper forms)
CRU
Clinical research unit
CSA
Clinical Study Agreement
C-SSRS
Columbia-Suicide Severity Rating Scale
Css,24h 
Observed plasma concentration 24 hours after administration at steady state
Css,28days
Observed plasma concentration 28 days after administration at steady state
Css,av 
Average plasma concentration during a dosing interval at steady state
Css,max 
Maximum observed 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 percentage
CYP
Cytochrome P450
DSM-V
Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition
ECG
Electrocardiogram
EDC
Electronic data capture
EOT
End of Treatment
FC
FluidCrystal® 
FDA
Food and Drug Administration
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
HIV
Human Immunodeficiency Virus
ICF
Informed consent form
ICH
International Conference on Harmonisation
IRB
Institutional Review Board


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IV
Intravenous
LLOQ
Lower limit of quantification
msec
Millisecond
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary of Regulatory Activities
norBPN
Norbuprenorphine
NRS
Numerical rating scale
PCP
Phencyclidine
PI
Pain Intensity
PID
Pain Intensity Difference
PK
Pharmacokinetics
QTcF
Fridericia’s corrected QT interval
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Subcutaneous
SL
Sublingual
SOC
System Organ Class
SOWS
Subjective Opioid Withdrawal Scale
SUSAR
Suspected unexpected serious adverse reaction
THC
Tetrahydrocannabinol
tss,max 
Time to Css,max 
US
United States
UDS
Urine drug screen


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5 
INTRODUCTION 
5.1 
Background 
Buprenorphine (BPN) is an opioid with mixed agonist-antagonist properties that, together with 
appropriate counseling 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 subjects in 
outpatient treatment programs (Johnson et al., 1992; Strain et al., 1994; Schottenfeld et al.,1997; 
Ling et al., 1998). Buprenorphine is available in several sublingual (SL) formulations for the 
treatment of opioid use disorders, alone (e.g., Subutex®) or as a combination product with 
naloxone (e.g., Suboxone®), as well as in buccal combination formulations (e.g., Bunavail®). 
 
In addition to treatment of opioid use disorders, BPN is currently available in injectable 
formulations to treat moderate to severe (acute) pain (e.g., Buprenex®), transdermal formulations to 
treat chronic pain (e.g., BuTrans®), and buccal formulations to treat chronic severe pain (e.g., 
Belbuca®). 
 
CAM2038 (50 mg/mL BPN FluidCrystal® [FC] subcutaneous [SC] injection depot) once-weekly 
(hereafter referred to as CAM2038 q1w) and once-monthly (356 mg/mL; hereafter referred to as 
CAM2038 q4w) are ready-to-use, extended-release BPN products 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 of 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 at ambient temperature. 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). Overall, CAM2038 depots have been designed 
with a focus on enabling easy administration, dosing flexibility, and importantly, minimizing risks 
of misuse, diversion and poor subject adherence. 
5.1.1 CAM2038 q1w (Once Weekly) 
CAM2038 q1w has so far been investigated after single and repeated doses in 3 clinical trials, 
where a total of 176 human subjects (subjects and healthy volunteers) have been exposed to the 
CAM2038 drug products. An initial study assessed pharmacokinetics (PK), pharmacodynamics and 
safety in opioid-dependent subjects (Study HS-07-307). Study HS-07-307 results showed that 


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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 subjects (9.5%), 3 subjects experienced mild injection site pain and 1 
subject exhibited transient injection site inflammation (mild) and injection site pruritus (moderate). 
 
Two clinical studies were subsequently performed in healthy volunteers (under naltrexone 
blockade) to assess the PK and bioavailability of single and repeat doses of CAM2038 q1w versus 
repeated doses of SL BPN (i.e., at steady state) and single dose of intravenous (IV) BPN (Studies 
HS-11-426 and HS-13-487). These 2 studies 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., approved 8 mg, 16 mg or 24 mg doses) with less 
fluctuation between maximum and minimum plasma concentrations compared to SL BPN. The 
BPN levels after administration of CAM2038 q1w were furthermore similar in healthy volunteers 
and subjects with opioid dependence. The systemic tolerability of CAM2038 q1w was good in both 
studies and similar to the reference IV and SL BPN products. Local tolerability was very good with 
no adverse events (AEs) related to injection site tolerability reported in HS-11-426 (N safety=60). 
Similarly, local tolerability of CAM2038 q1w was also very good in HS-13-487 (1 subject reported 
1 AE of injection site pain), during which 4 repeat SC injections of CAM2038 q1w were 
administered into the buttock site. 
 
Based on these studies, the following main conclusions were drawn regarding clinical properties 
of CAM2038 q1w: 
 
    Extended BPN release over 1 week at target plasma concentrations 
    Dose proportionality and flexible/multiple dosing options 
    6- to 8-fold higher bioavailability as compared to SL BPN 
 BPN plasma concentrations over 7 days within the ranges of those produced by 
corresponding SL BPN doses at steady state (i.e., approved 8 mg, 16 mg, or 24 mg 
doses) 
 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 subjects 
    Safety in healthy volunteers comparable to reference IV and SL BPN treatments 
    Good local tolerability in subjects and healthy volunteers 
 
The clinical PK profile and good systemic and local tolerability of CAM2038 q1w evidenced 
in subjects in these 3 studies is also supported by a large body of data generated in non-clinical 
PK 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. 
Subcutaneous administration of CAM2038 q1w has been shown to be well tolerated both 
systemically and locally in single and repeat dose non-clinical studies in the rat and in the dog. 
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 


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appeared to be reversible and self-limiting, and only apparent at the immediate vicinity of test 
article deposition. In summary, nonclinical studies have not identified systemic toxicity 
associated with CAM2038 q1w or the FC injection depot vehicle. 
5.1.2 CAM2038 q4w (Once Monthly) 
The PK and safety of CAM2038 q4w has been investigated after single administration in a 
bridging clinical PK study 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 (Study 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 
 Dose proportionality was shown within the dosage interval 64 to 192 mg CAM2038 
q4w 
    6- to 8-fold higher bioavailability than SL BPN, comparable to CAM2038 q1w 
 Observed BPN plasma concentrations over 4 weeks comparable to CAM2038 q1w 
over 1 week, and to SL BPN over 24 hours at steady state (i.e., for approved 8 mg, 
16 mg, or 24 mg doses) 
    Predicted Css,av and Css,trough values for 64, 96 and 128 mg CAM2038 q4w similar to 
CAM2038 q1w and SL BPN (i.e., for approved 8 mg, 16 mg, or 24 mg doses); and 
predicted exposure for 160 mg CAM2038 q4w similar to SL BPN 26 mg to 32 mg  
    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, dizziness and vomiting. The local tolerability was good with 
6 subjects experiencing 7 AEs that were assessed as related to CAM2038 q4w (injections 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 and clinical studies 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. 
 


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5.1.3 Study Rationale 
 
This is a Phase II, open-label, partially randomized, 3 treatment groups study assessing the steady 
state PK of BPN and norbuprenorphine (norBPN) after SC injections of CAM2038 q1w at 
different injection sites (Group 1), SC injections of 128 mg CAM2038 q4w (Group 2), and 
160 mg CAM2038 q4w (Group 3).  After the PK portion of the study, subjects in Group 1 and 
Group 2 have the option of continuing into an extension portion of the study where subjects will 
receive 6 injections of CAM2038 q1w. 
 
In clinical practice, CAM2038 may be administered at different injection sites depending on local 
preferences or other reasons. While repeat dose PK has previously been evaluated with multiple 
injections of CAM2038 q1w in healthy volunteers (Study HS-13-487), the injections have only 
been administered in the buttock. The current study will evaluate the impact of using different 
injection sites (arm, abdomen, buttock and thigh) on the exposure of BPN and norBPN (as 
assessed by area under the plasma concentration-time curve during a dosing interval at steady 
state [AUCss] and the maximum observed plasma concentration during a dosing interval at steady 
[Css,max]) after administration of CAM2038 q1w at steady state. The injection sites to be 
evaluated in this study are the buttock (reference), abdomen, thigh and back of upper arm. 
 
This study will also evaluate the PK of BPN and norBPN at steady state following repeated dose 
administration of 128 mg CAM2038 q4w (Group 2) and 160 mg CAM2038 q4w (Group 3) by SC 
injection in the buttock. Additionally, relative bioavailability of BPN will be assessed at steady 
state for 160 mg CAM2038 q4w as compared with 24 mg SL BPN (Group 3). 
 
5.2 Overall Risk-Benefit 
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 human immunodeficiency virus (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.  There is only one approved long-acting (6 months) BPN formulation, 
Probuphine™.  Probuphine™ is indicated for the maintenance treatment of opioid dependence in 
patients who have achieved and sustained prolonged clinical stability on low-to-moderate doses of 
a transmucosal BPN containing product (i.e., doses of no more than 8 mg per day of Subutex® or 
Suboxone® SL tablet or generic equivalent).  Additional long-acting injection depot formulations of 
BPN such as CAM 2038 would likely complement Probuphine™ and offer dosage forms with 
different indications to treat opioid-dependent subjects and improve retention in treatment. For 
example, subjects with chronic cancer and non-cancer pain, long-acting formulations (e.g., 
transdermal) of BPN have proven effective, with a reduction in the need for additional oral 
analgesics and improved quality of life (Liker et al, 2003; Sittl et al., 2005). 
 


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While the rate of BPN delivery can be controlled and stable plasma concentrations achieved by 
using a transdermal BPN formulation (BuTrans US Prescribing Information, 2014). However, 
transdermal BPN formulations may still be subject to abuse and diversion, as the patches may be 
swallowed or the BPN may be extracted from the patches and injected or ingested, including 
improperly disposed patches. Transdermal systems may also be accidently ingested, particularly 
by children. Traditional oral opioid therapies are even more subject to diversion and abuse, 
resulting in significant public health concerns (Salinas et al., 2012; Joint Commission and Food 
and Drug Administration [FDA], 2012). Therefore, CAM2038 SC injection depots have been 
designed with a focus on enabling easy administration, dosing flexibility, and importantly, 
minimizing risks of misuse, diversion and poor subject compliance. CAM2038 q1w and 
CAM2038 q4w are intended for convenient and safe SC injection of BPN depot with a prefilled 
syringe including a needle safety device and with no need for mixing or temperature adjustment 
prior to administration. The route of administration (i.e. SC injection) of CAM2038 by health care 
providers is expected to reduce the risks of diversion and abuse even when compared to 
transdermal and oral opioid formulations, indicating that CAM2038 SC injection depot may be 
particularly well suited for opioid-dependent subjects. In addition, like transdermal formulations, 
CAM2038 SC injection depot may also be suitable for subjects who have difficulty swallowing.  
The sustained and stable plasma concentrations demonstrated for CAM2038 q1w and CAM2038 
q4w are likely to provide an optimal treatment modality for many opioid-dependent subjects. 
The PK profile of CAM2038 q1w indicates that a rapid and long-acting release of BPN will lead 
to rapid onset of action, in combination with a prolonged and stable treatment effect for at least 7 
days following a single dose of CAM2038 q1w, or up to 4 weeks following a single dose of 
CAM2038 q4w. 
 
In summary, CAM2038 SC injection depot is anticipated to provide a convenient and 
advantageous alternative to existing opioid medications, with the potential added benefits of 
obtaining consistent and stable plasma levels of BPN. CAM2038 SC injection depot, which is 
stable at room temperature and introduced through a small gauge needle (e.g. 23G), should thus 
eliminate the need to take daily medications. Moreover, it should help to markedly reduce 
diversion and accidental pediatric exposures, which continue to be important public health goals 
of the FDA and other regulators.


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6 
STUDY OBJECTIVES 
6.1 
Primary Objectives 
The primary objectives of the study are: 
 
 To evaluate the steady state PK of BPN and norBPN following repeated SC 
administration of CAM2038 q1w (50 mg/mL) at 4 different injection sites in adult 
opioid-dependent subjects with chronic pain. 
 To evaluate steady state PK of BPN and norBPN following repeated SC 
administration of CAM2038 q4w (356 mg/mL) with the buttock as the injection site 
in adult opioid-dependent subjects with chronic pain. 
6.2 
Secondary Objectives 
The secondary objectives of the study are: 
 
 To evaluate the safety and tolerability of CAM2038 q1w and CAM2038 q4w in adult 
opioid-dependent subjects with chronic pain. 
 To assess relative bioavailability of BPN at steady state following repeated SC 
administration of 160 mg CAM2038 q4w compared with repeated SL administration 
of 24 mg BPN in adult opioid-dependent subjects with chronic pain. 
6.3 
Exploratory Objectives 
The exploratory objectives of the study are: 
 
    To evaluate maintenance of treatment efficacy when transferring adult 
opioid-dependent subjects from SL BPN to CAM2038 q1w and q4w, as determined 
by urine toxicology. 
 To evaluate subject-rated worst daily pain and average daily pain, using an 11-point 
numerical rating scale (NRS), following repeated SC administration of 
CAM2038 q1w and CAM2038 q4w in adult opioid-dependent subjects. 
 


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7 
INVESTIGATIONAL PLAN 
7.1 
Overall Study Design and Plan 
This is a Phase II, open-label, partially randomized, 3-treatment group study designed to evaluate 
the steady state PK of BPN and norBPN following multiple weekly SC administrations of 
CAM2038 q1w at different injection sites (Group 1), and following multiple monthly SC 
administrations of CAM2038 q4w (Group 2 and Group 3), and to evaluate relative bioavailability 
of BPN following SC administration of 160 mg CAM2038 q4w as compared with 24 mg SL 
BPN (Group 3) in opioid-dependent subjects with a history of chronic non-cancer pain. The study 
will involve 4 phases: Screening, Treatment, open label safety extension and Follow-up. 
 
Medical and eligibility screening will occur within approximately 21 days of the Treatment 
Phase. At Screening, subjects will provide written informed consent to participate in the study 
before any protocol-specified procedures or assessments are completed. The Screening visit will 
include standard medical screening procedures, complete medical/psychosocial history, brief 
substance abuse history and treatment history, clinical laboratory assessments, urine toxicology, 
as outlined in Table 1 (Group 1), Table 2 (Group 2), and Table 3 (Group 3). Subjects will be 
eligible for further participation if they meet all of the inclusion criteria and do not meet any of 
the exclusion criteria (as outlined in Section 8.1 and Section 8.2). 
 
Subjects will remain on their daily SL BPN dose (24 mg/day) throughout the Screening phase. 
The last SL BPN dose will be taken on Day -1 (i.e., the day before the first CAM2038 dose). On 
Day 1, eligibility will be confirmed and up to approximately 40 eligible subjects will be 
randomized to either CAM2038 q1w (Group 1) or 128 mg CAM2038 q4w (Group 2). An 
additional group of 16 subjects was added following completion of randomization to Groups 1 
and 2, in order to evaluate a higher dose of CAM2038 q4w (160 mg) after initial daily treatment 
with SL BPN (Group 3); therefore, these subjects will be enrolled, but not randomized. After 
enrollment/randomization, subjects will be administered CAM2038 SC injection depot 
formulation (all Groups) and SL BPN (Group 3) and monitored for at least 3 hours to ensure that 
the CAM2038 and SL BPN products are tolerated. 
 
Subjects will be treated as follows: 
 
 Group 1: 3 single weekly SC injections of 32 mg CAM2038 q1w (50 mg/mL) 
administered in the buttock to reach steady state, rotating between right and left 
buttock and injection site per Appendix 17.2, followed by 4 single weekly SC 
injections of 32 mg CAM2038 q1w administered in the buttock (reference), 
abdomen, thigh, and back of upper arm in a randomized, crossover manner, with 
injection site sequence allocated using a randomized crossover design. At the Day 
50 (end-of-treatment [EOT]) visit, subjects may continue on with open-label 
extension phase for up to 6 weeks.    
 Group 2: 4 monthly SC injections of 128 mg CAM2038 q4w (356 mg/mL) 
administered in the buttock, rotating between right and left buttock and injection site 
per Appendix 17.2.  At the Day 113 (EOT) visit, CAM2038 q4w 128 mg subjects 


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may be transferred to 32 mg of CAM2038 q1w and continue in an open-label 
extension phase for up to 6 weeks.  
 Group 3: 7 consecutive single daily doses of 24 mg SL BPN, followed by 4 monthly 
SC injections of 160 mg CAM2038 q4w (356 mg/mL) administered in the buttock, 
rotating between right and left buttock per Appendix 17.2. Note: 160 mg CAM2038 
q4w (356 mg/mL) is estimated to be equivalent to 26 mg to 32 mg SL BPN.  
 
GROUP 1: 
 
Each subject in Group 1 will participate in the study for up to approximately 17 weeks, 
including up to 3 weeks for screening, 13 weeks for treatment, and approximately 1 week 
for follow-up. In order to achieve steady state PK of BPN and norBPN, the first 3 SC 
injections of 32 mg CAM2038 q1w will be administered in the buttock, rotating between 
right and left buttock and injection site per Appendix 17.2 on Day 1, Day 8 and Day 15. 
Subjects will be administered each CAM2038 q1w injection at the clinical research unit 
(CRU) on an outpatient basis. Following the first administration, subjects will attend an 
interim visit on Day 2 to evaluate safety and tolerability of the transition from SL BPN 
24 mg to CAM2038 q1w. 
 
To evaluate steady state PK of BPN and norBPN following CAM2038 q1w administration at 
various sites, CAM2038 q1w will be administered at 4 different injection sites, i.e., buttock 
(reference), abdomen, thigh and back of upper arm, on Day 22, Day 29, Day 36 and Day 43. The 
sequence of injection site administration will be randomized using a crossover design. Subjects 
will be confined to the CRU for 24 hours while serial PK samples will be collected. Subsequent 
PK samples will be collected for up to 168 hours post-dose.   
 
On Day 50 (EOT), all subjects will be allowed to continue their CAM2038 q1w dose for up to 6 
weeks for an open-label safety extension phase or transition back to standard care.  The 
CAM2038 q1w injections may be rotated in previously not used SC sites in the abdomen, arm, 
buttock and the thigh. For those subjects enrolling into the open-label extension, transition back 
to standard care will begin on Day 92 (EOT - OLE). 
 
At each study visit, safety and efficacy assessments will be conducted at pre-specified times. 
Subjects will also be required to record their worst daily pain and average daily pain using an 
11-point NRS on an electronic device. 
 
GROUP 2: 
 
Each subject in Group 2 will participate in the study for up to 26 weeks, including up to 
approximately 3 weeks for screening, 22 weeks for treatment, and approximately 1 week for 
follow-up. SC injections of 128 mg CAM2038 q4w will be administered in the buttock, rotating 
between right and left buttock and injection site per Appendix 17.2, on Day 1, Day 29, Day 57 
and Day 85, for a total of 4 doses. Following the first administration, subjects will attend an 
interim visit on Day 2 to evaluate safety and tolerability of the transition from SL BPN 24 mg to 
CAM2038 q4w. 
 
Following administration of the first 3 doses, PK samples will be collected pre-dose and at 
scheduled times post-dose on an outpatient basis to determine achievement of steady state. To 


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characterize steady state PK of BPN and norBPN, subjects will be confined to the CRU and 
serial PK samples will be collected for up to 24 hours following the fourth dose, administered 
on Day 85; subsequent PK samples will be collected up to 28 days post-dose on an outpatient 
basis.  At the Day 113 (EOT) visit, CAM2038 q4w 128 mg subjects may continue on with 
open-label extension phase for up to 6 weeks and will be switched to CAM2038 q1w 32 mg, 
or transition back to standard care. For those subjects enrolling into the open-label extension, 
transition back to standard care will begin on Day 155 (EOT - OLE).    
 
At each study visit, safety and efficacy assessments will be conducted at pre-specified times. 
Subjects will also be required to record their worst daily pain and average daily pain using an 
11-point NRS on an electronic device. 
 
GROUP 3: 
 
Each subject in Group 3 will participate in the study for up to 21 weeks, including up to 
approximately 3 weeks for screening, 17 weeks for treatment, and approximately 1 week for 
follow-up. Single daily doses of 24 mg SL BPN will be administered in the mornings on Day 1 
through Day 7 for a total of 7 doses. This will be followed by SC injections of 160 mg 
CAM2038 q4w in the buttock, rotating between right and left buttock and injection site per 
Appendix 17.2, on Day 8, Day 36, Day 64 and Day 92, for a total of 4 doses. Following the first 
CAM2038 q4w administration, subjects will attend an interim visit on Day 9 to evaluate safety 
and tolerability of the transition from SL BPN to CAM2038 q4w. 
 
Following administration of the first 3 doses of CAM2038 q4w, PK samples will be collected 
pre-dose and at scheduled times post-dose on an outpatient basis to determine achievement of 
steady state. To characterize steady state PK of BPN and norBPN and evaluate relative 
bioavailability CAM2038 q4w as compared with SL BPN, subjects will be confined to the CRU 
and serial PK samples will be collected for up to 24 hours following the seventh dose of SL 
BPN administered on Day 7, and following the fourth dose of CAM2038 q4w administered on 
Day 92. Subsequent PK samples will be collected up to 28 days post-dose on an outpatient 
basis.  
 
At each study visit, safety and efficacy assessments will be conducted at pre-specified times. 
Subjects will also be required to record their worst daily pain and average daily pain using an 
11-point NRS on an electronic device. 
 
For all Groups, subjects will be transitioned to standard care as needed at the EOT or EOT-OLE 
visit, as applicable, and a follow-up call will be conducted approximately 7 days after the last study 
visit. Subjects who discontinue early will undergo EOT visit assessments, including PK sampling 
and urine toxicology. 
 
GENERAL CONSIDERATIONS: 
 
To ensure adequate enrollment and address potential inconvenience to subjects, all subjects will 
receive appropriate compensation for time and travel expenses related to attendance at study 
visits. All costs of medications will also be covered. 
 
Section 10 provides additional information on the PK, efficacy and safety assessments included 
in the study. Statistical analyses are described in Section 12. 


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7.2 Discussion of Study Design 
Subjects with current diagnosis of opioid use disorder (based on criteria defined in the Diagnostic 
and Statistical Manual of Mental Disorders – Fifth Edition [DSM-V]) or past medical history of 
opioid use disorder and currently being treated with SL BPN with concomitant chronic non-cancer 
pain will be enrolled in this study. Because this is the intended patient population, results from this 
study will be directly applicable to the therapeutic use of CAM2038 q1w and CAM2038 q4w in 
clinical practice. In addition to the requirement of opioid dependence, eligible subjects will be 
required to be on maintenance treatment of 24 mg SL BPN to ensure that the subjects will be able 
to safely tolerate the treatment dose levels planned for evaluation (32 mg CAM2038 q1w, 128 mg 
CAM2038 q4w, and 160 mg CAM2038 q4w). 
 
As 1 of the 2 primary objectives, the study will evaluate the comparability of steady state 
exposure to BPN and norBPN after SC administration of CAM2038 q1w at different injection 
sites (Group 1) planned for treatment in a clinical setting, which will require rotation. Subjects 
allocated to Group 1 will first be administered CAM2038 q1w in the buttock, rotating between 
right and left buttock and injection site per Appendix 17.2, once weekly for the first 3 weeks to 
reach steady state. Once at steady state, CAM2038 q1w will be injected in the buttock 
(reference), abdomen, thigh and back of upper arm, using a randomized crossover design. A 
randomized crossover design will be used to minimize the variability in the study and avoid bias 
in the assignment of injection site sequence, as well as to increase the likelihood that known and 
unknown subject attributes (e.g., demographics and baseline characteristics) are evenly balanced 
across injection site sequence. Exposure to BPN and norBPN after administration of CAM2038 
q1w will be evaluated by means of AUCss, Css,max, Css,av, time to Css,max (tss,max), norBPN/BPN 
ratios for Css,max and AUCss, and other derived PK parameters, as applicable. 
 
The present study will also evaluate steady state PK of BPN and norBPN after 4 monthly 
injections of 2 dose levels of CAM2038 q4w in the buttock (128 mg [Group 2] and 160 mg 
[Group 3]). Steady state conditions will be confirmed by collecting pre-dose plasma samples 
prior to each SC administration for analysis of BPN and norBPN concentrations. Steady state 
exposure to BPN and norBPN will be characterized following administration of the last dose of 
CAM2038 q4w, with AUCss, Css,max, Css,av, tss,max, norBPN/BPN ratios for Css,max and AUCss and 
other PK parameters, as appropriate. Relative bioavailability of BPN will be assessed at steady 
state conditions after the fourth dose of 160 mg CAM2038 q4w and the seventh dose of 24 mg 
SL BPN (Group 3). Once the PK of 32 mg CAM2038 q1w and 128 mg CAM2038 q4w PK 
evaluation phases are over, subjects in Group 1 and Group 2 will have the option of receiving 6 
more CAM2038 q1w 32 mg injections in an extension phase of the study. 
 
In addition to evaluating the PK and safety of multiple doses of CAM2038 q1w and q4w, urine 
toxicology will be included as an exploratory efficacy measure of CAM2038 in maintaining 
opioid abstinence. Individuals who are in treatment for opioid dependence also commonly have a 
history of chronic pain (Rosenblum et al., 2003; Brands et al., 2004; Wiest et al., 2014). 
Long-acting transdermal BPN has proven effective in individuals with chronic cancer and non-
cancer pain, with a reduction in the need for additional oral analgesics and improved quality of 
life (Likar et al. 2003; Sittl et al., 2005). Therefore, an additional exploratory objective of the 
current study is to assess daily pain intensity, as measured using an 11-point NRS, following SC 
administration of CAM2038 q1w and q4w.


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8 
SELECTION OF STUDY POPULATION 
At least 20 subjects, but no more than 24 subjects, will be enrolled to Group 1 (CAM2038 q1w). 
Approximately 16 subjects will be enrolled into each of Group 2 (128 mg CAM2038 q4w) and 
Group 3 (160 mg CAM2038 q4w), for a total of approximately 32 subjects administered 
CAM2038 q4w. These sample sizes are consistent with typical PK studies. Replacement subjects 
may be added at the discretion of the Sponsor with the agreement of the Principal Investigator. 
8.1 
Inclusion Criteria 
Subjects must meet each of the following inclusion criteria in order to be eligible for participation 
in the study: 
 
1.   Subject must provide written informed consent prior to the conduct of any study-related 
procedures. 
2.   Male or non-pregnant, non-lactating female subject, aged 19 to 65 years, inclusive. 
3.   Body mass index between 19 and 35 kg/m2, inclusive. 
4.   Current diagnosis of moderate to severe opioid use disorder (according to the DSM-V) or 
past medical history of opioid use disorder currently being treated with SL BPN. 
5.   Subject must be taking SL BPN (Subutex® equivalent) 24 mg (Group 1 and Group 2) 
or ≥24 mg (Group 3) daily for at least 30 days prior to Screening. 
6.   Subject has a history of moderate to severe chronic non-cancer pain. 
7.   Male and female subjects of childbearing potential must be willing to use a reliable 
method of contraception during the entire study (Screening visit to Follow-up phone call) 
(Section 8.4.1). 
8.   Subject must be willing and able to comply with all study procedures and requirements. 
8.2 
Exclusion Criteria 
Subjects will not be eligible to participate in this study if any of the following exclusion criteria 
are met: 
 
1.   Individuals meeting DSM-V substance use disorder criteria for alcohol, benzodiazepines, 
central nervous system (CNS) stimulants, or other drugs of abuse (excluding caffeine, 
tobacco or tetrahydrocannabinol [THC]/marijuana). 
2.   Any clinically significant abnormality on the basis of medical history, vital signs, 
physical examination, 12-lead electrocardiogram (ECG; Fridericia's corrected QT interval 
[QTcF] ≥450 msec. for males or ≥470 msec. for females), and laboratory evaluations 
(including hematology, clinical chemistry, urinalysis at Screening), in the opinion of the 
Investigator. 
3.  Significant symptoms, medical conditions, or other circumstances which, in the opinion of 
the Investigator, would preclude compliance with the protocol, adequate cooperation in the 
study or obtaining informed consent, or may prevent the subject from safely participating in 
study, including subjects who are at a risk for gastrointestinal obstruction or paralytic ileus 
or who have severe respiratory insufficiency, respiratory depression, airway obstruction, 


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gastrointestinal motility disorders, biliary tract disease, severe hepatic insufficiency, 
planned surgery and prior treatment with monoamine oxidase inhibitors. 
4.   Use (therapeutic or non-therapeutic) of opioids other than SL BPN. 
5.   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 study. 
6.   Pregnant or lactating or planning to become pregnant during the study. 
7.   Diagnosis of, or currently under investigation for, fibromyalgia, complex regional pain 
syndrome, neurogenic claudication due to spinal stenosis, spinal cord compression, acute 
nerve root compression, severe or progressive lower extremity weakness or numbness. 
8.   History of chemotherapy or confirmed malignancy (except basal cell or squamous 
carcinoma of the skin) within the past 2 years. 
9.   Clinically significant history of, or current evidence for, suicidal ideation or those who 
are actively suicidal, as based on the Columbia-Suicide Severity Rating Scale (C-SSRS; 
grade 4 or 5). 
10. Clinically significant history of major depressive disorder that is poorly controlled with 
medication. 
11. Hypersensitivity or allergy to BPN or other opioids, or excipients of CAM2038. 
12. Exposure to any investigational drug within the 4 weeks prior to Screening. 
13. Participants with a clinically significant history of risk factors of Torsades de Pointes and 
any existing ventricular tachyarrhythmias such as bigeminy, trigeminy, heart failure, 
hypokalemia, family history of Long QT Syndrome. 
14. On medications that have the potential for prolonging the QT interval or who may 
require such medications during the course of the study along with clinically significant 
abnormalities on screening electrocardiogram (ECG) readings as deemed by the 
investigator (Appendix 17.1). 
15. 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). 
16. Intolerance to venipuncture and/or difficulty with venous access, as per the judgment of 
the Investigator/research staff. 
17. Is an employee of the Investigator or the study site, with direct involvement in the 
proposed study or other studies under the direction of the Investigator or study site, or is a 
family member of an employee or of the Investigator. 
18. Any pending legal action that could prohibit participation or compliance in the study.


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8.3 
Removal of Subjects from Therapy or Assessment 
A subject is free to withdraw his/her consent and discontinue participation in the study 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 study 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 study 
drug, or both 
    Clinically significant QTc interval prolongation following administration of 
CAM2038 q1w or q4w, as judged by the Investigator and agreed upon by the Medical 
Monitor 
    At the request of the Sponsor, regulatory agency, or Institutional Review Board (IRB) 
    Subject is lost to follow-up 
    Death of subject 
 
A subject may also be discontinued from the study, at the discretion of the Investigator and/or 
Sponsor, for any of the following reasons: 
 
    Lack of efficacy 
    Subject refuses or is unable to adhere to the study protocol 
    Major protocol violation 
    Pregnancy 
    Use of unacceptable concomitant medication(s) (Section 9.5) 
 
The Investigator must maintain a record of all subjects who discontinue from the study prior to 
completion; the reason(s) for study discontinuation will be documented. In the event that a 
subject chooses to withdraw from the study, 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. In the event a subject is lost to follow-up, a third party could be hired to 
locate the subject. 
 
All efforts should be made by the Investigator to continue collection of concomitant medications, 
and AEs in subjects that discontinue study drugs, unless the subject withdraws his/her consent at 
the time of early discontinuation. Subjects discontinued due to clinically significant QTc interval 
prolongation should be monitored closely by undergoing daily ECGs, until ECG readings return to 
baseline, or QTc interval values are no longer judged to be clinically significant. The Investigator 
should also ask the subject to complete the Follow-up phone-call, provided that the subject has not 
withdrawn consent. If a subject refuses to complete EOT procedures and/or Follow-up, this 
information will be recorded. 


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8.4 
Study restrictions 
In addition to the criteria described in Sections 8.1 and 8.2, the subject must agree to abide by the 
following study restrictions. 
8.4.1 Contraception Requirements 
Male and female subjects of childbearing potential must be using and willing to continue using 
medically acceptable contraception during the study. Examples of medically acceptable forms of 
contraception include: 
 
 True abstinence, defined as sexual inactivity consistent with the preferred and usual 
lifestyle of the subject. Note: Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods 
of contraception. 
 Hormonal contraceptives (combined oral pill, patch or vaginal ring, intrauterine 
device or system, progestin implant or injection) 
    Surgical sterilization (e.g. vasectomy or bilateral tubal ligation) 
 Condom plus spermicidal agent (foam/gel/film/cream/suppository) during sexual 
intercourse with a female partner. In addition, the female partner should also be on 
another form of contraception (e.g., occlusive cap/diaphragm/intrauterine 
device/hormonal contraception, etc.) if she is of childbearing potential. 
 To prevent exposure of any partner to the semen from a male subject who has been 
exposed to the investigational product, male subjects must use a condom during 
non-vaginal intercourse with any partner - male or female. 
 
The chosen contraception method(s) must be followed from the first administration of CAM2038 
until at least 3 months after receiving the last dose of the investigational product. 
 
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 (FSH) level ≥50 mIU/mL. If females are not 
amenorrheic for 2 years or amenorrheic for 1 year with a documented FSH level ≥50 mIU/mL or 
surgically sterile, then females will have to undergo the pregnancy procedures as stated in Table 1 
(Group 1), Table 2 (Group 2), and Table 3 (Group 3). 
 
Female subjects must not donate ova starting at Screening and throughout the clinical study period 
and for 3 months after final investigational product administration. 
 
Male subjects must not have unprotected sexual intercourse with a female who is pregnant or 
breastfeeding during the study and for 3 months after final investigational product administration.  
 
Subjects must not donate sperm throughout the study and for at least 3 months after receiving the 
last dose of the investigational product. 


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8.4.2 Dietary and Fluid Restrictions 
 
Subjects will be required to fast from all food or drink (except water) for at least 4 hours before 
the Screening visit and the EOT visit. During the in-house stay in the CRU, standardized meals 
and fluids will be provided. 
 
No food and drink containing grapefruit, Chinese grapefruit (pomelo), or Seville orange 
(including marmalade) will be allowed from 48 hours before each visit to the CRU and while 
subjects are confined to the CRU. 
 
Quinine-containing products (e.g., tonic water) will not be allowed from 7 days before each 
confinement to the CRU and while subjects are confined to the CRU. 
 
To avoid falsifying urine drug screen (UDS) results, no food or drink containing poppy seeds 
(e.g., specialty breads and muffins) will be allowed from 72 hours before Screening and 7 days 
before the first administration of CAM2038 through the end of the study. 
8.4.3 Alcohol, Caffeine and Other Drug Use 
Alcohol consumption must be avoided from 48 hours before any study visit and while subjects 
are confined to the CRU. Alcohol abstinence will be confirmed with a breath alcohol test. 
 
Subjects should not regularly consume > 21 units per week for males and > 14 units of alcohol per 
week for females during the off-site days during the study (1 unit is equal to approximately ½ pint 
[200 mL] of beer, 1 small glass [100 mL] of wine, or 1 measure [25 mL] of spirits). 
 
No food or drink containing caffeine (e.g., chocolate, coffee, tea, cola, Red Bull, etc.) will be 
allowed from 24 hours before each study visit and while subjects are confined to the CRU. At 
other times during the study, caffeine intake will be restricted to no more than 6 cups/day (1 
cup = 120 mg caffeine). 
 
Subjects will be asked to abstain from illicit drug use or non-medical use of therapeutic drugs 
throughout the study. 
8.4.4 Activity and Exercise 
Subjects should refrain from carrying out heavy physical training (e.g., long distance running, 
weight lifting, or any physical activity to which the subject is not accustomed) from 7 days 
before the first administration of CAM2038, while subjects are confined to the CRU, and 
through the EOT visit. Subjects should neither start any new physical training nor increase the 
intensity of their usual training during study participation. Subjects may participate in light 
recreational activities during confinement to the CRU (e.g., watch television, play computer 
games, read). 
 
Subjects should refrain from driving a car or other vehicles, operating machines or engaging in 
potentially dangerous activities that require focused attention and intact physical balance until 
the subjects understand how CAM2038 affects their focus. 
 
 
 


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8.4.5 Other Restrictions 
Subjects will be required to avoid using any prohibited medications, as described in Section 9.5.  
Subjects must not donate blood or plasma from 3 months before the first administration of 
CAM2038 and for at least 3 months after completion of the study. 
 
Subjects will be required to follow the informed consent form (ICF) and any clinic rules and 
requirements.


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9 
TREATMENTS 
9.1 
Treatment Administration 
Subjects will remain on their daily SL BPN treatment from Screening until Day -1 (the day 
before the first CAM2038 dose). 
 
On Day 1, subjects will be randomized to Group 1 (32 mg CAM2038 q1w) or Group 2 (128 mg 
CAM2038 q4w), or be enrolled into the additional Group 3 (24 mg SL BPN and 160 mg CAM2038 
q4w). All study drugs will be administered in an open-label manner throughout the study. Subjects 
will receive the following treatments in the study: 
 
 Group 1: 3 single weekly SC injections of 32 mg CAM2038 q1w (0.64 mL) 
administered in the buttock to reach steady state, rotating between right and left 
buttock and injection site per Appendix 17.2, followed by 4 single weekly SC 
injections of 32 mg CAM2038 q1w administered in the buttock (reference), 
abdomen, thigh, and back of upper arm in a randomized, crossover manner, with 
injection site sequence allocated using a randomized crossover design. After the four 
weeks of rotating injections, subjects may continue to receive up to 6 open-label 
injections rotated in the abdomen, arm, buttocks and thigh.  A pictorial of potential 
injection sites is provided in Appendix 17.2. The Investigator will keep a record of 
the specific injection site location at each treatment visit based on the pictorial of 
injection site location provided. Each injection should be rotated such that no 
injections are administered into the same site. 
 Group 2: 4 monthly SC injections of 128 mg CAM2038 q4w (0.36 mL) administered 
in the buttock, to reach steady state. The sites of all of the CAM2038 q4w injections 
will be rotated between right and left buttock such that no injections are administered 
into the same site (Appendix 17.2).  At the Day 113 (EOT) visit, CAM2038 q4w 
128 mg subjects may continue on with open-label extension phase for up to 6 weeks 
and will be switched to CAM2038 q1w 32 mg for up to 6 injections of CAM2038 
q1w 32 mg. Buttock injection sites will be rotated in accordance to Appendix 17.2. 
 Group 3: 7 consecutive daily doses of 24 mg of SL BPN to reach steady state 
followed by 4 monthly SC injections of 160 mg CAM2038 q4w (0.45 mL) 
administered in the buttock, to reach steady state. The sites of all of the CAM2038 
q4w injections will be rotated between right and left buttock such that no injections 
are administered into the same site (Appendix 17.2).   
 
Subjects in Group 1 will receive treatment for up to 13 weeks, subjects in Group 2 will 
receive treatment for up to 22 weeks, and subjects in Group 3 will receive treatment for up 
to 17 weeks during the study. 
9.2 
Identity of Investigational Products 
The following treatments will be used during the treatment phase: 
 
 Group 1: CAM2038 q1w (BPN FluidCrystal® Injection depot for once weekly 
administration), 50 mg/mL: 32 mg (BPN base), 0.64 mL SC injection. 


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 Group 2: CAM2038 q4w (BPN FluidCrystal® Injection depot for once monthly 
administration), 356 mg/mL: 128 mg (BPN base), 0.36 mL SC injection. 
 Group 3: SL BPN (Subutex® equivalent) 24 mg (3 tablets of 8 mg BPN) for once daily 
administration, followed by CAM2038 q4w (BPN FluidCrystal® Injection depot for 
once monthly administration), 356 mg/mL: 160 mg (BPN base), 0.45 mL SC injection. 
 
The following treatment will be used during the open-label extension phase: 
 
 Group 1 and Group 2: CAM2038 q1w (BPN FluidCrystal® Injection depot for 
once weekly administration), 50 mg/mL: 32 mg (BPN base), 0.64 mL SC 
injection. 
9.2.1 Description of CAM2038 q1w and CAM2038 q4w 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.  All containers/packages/boxes of study drug will be clearly labeled 
with study-specific information meeting all the applicable regulatory/institutional 
requirements. 
9.2.2 Handling, Storage, and Accountability 
All study 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. A description of storage conditions for CAM2038 and SL BPN will 
be provided to the CRU. 
 
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 study. All unused supplies will be checked against the drug accountability records 
during the study and/or at the end of the study. 
 
Buprenorphine is a Schedule III controlled substance and study drugs must be handled and 
stored strictly in accordance with restrictions related to controlled substances. Study drugs 
must be kept securely locked with access limited to appropriate study personnel, according 
to applicable regulations. 
9.2.3 Dispensing and Administration 
Only eligible subjects participating in the study will receive the study drug. Only 
authorized research site staff may administer the study drugs. Once dispensed, study drug 
may not be relabeled or reassigned for use by other subjects. 
 


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CAM2038 q1w and CAM2038 q4w SC injections will be administered by designated 
healthcare professional(s) at the CRU. Detailed instructions for use will be provided to the 
study staff. 
 
Subjects in Group 3 will be instructed to place SL BPN tablets (3 x 8 mg tablets) under the 
tongue until dissolved. Tablets should be placed in different areas under the tongue at the 
same time. Administration of SL BPN will be conducted at the CRU. 
 
Study drug administration, including SL BPN administration in Group 3, will be clearly 
documented. 
9.3 
Method of Assigning Subjects to 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. Once any subject number or randomization number is assigned, it cannot be 
reassigned to any other subject. 
 
On Day 1, before the first dose of CAM2038, subjects will be randomized into Group 1 
(CAM2038 q1w) or Group 2 (128 mg CAM2038 q4w) in a 3:2 ratio, or enrolled into the 
additional Group 3 (160 mg CAM2038 q4w). 
 
For subjects in Group 1, injection site rotation will be randomized (on Day 1) to avoid bias 
in the assignment of injection site sequence. The sequences will be as follows, ABDC, 
BCAD, CDBA, and DACB, where A=buttock, B=abdomen, C=thigh, and D=back of upper 
arm. The injection site sequence assignment will be made at the time of Group 
randomization. 
9.4 
Selection of Doses 
The study will include 3 dose levels of CAM2038, a once weekly CAM2038 q1w 32 mg 
SC injection, a once monthly CAM2038 q4w 128 mg SC injection, and a once monthly 
CAM2038 q4w 160 mg SC injection.  For CAM2038 q1w, this study is expected to 
provide data on the plasma BPN and norBPN levels across 4 injections sites (buttock 
[reference], abdomen, thigh and back of upper arm). The 32 mg dose is the highest single 
dose strength available for CAM2038 q1w and predicted steady state plasma 
concentrations of BPN are expected to be within known therapeutic plasma levels based on 
previous studies (HS-11-426 and HS-13-487). 
 
A previous study (HS-13-487) has demonstrated PK parameters for CAM2038 q4w after 
single dose administration; this study is expected to provide PK of CAM2038 q4w at 
steady state. The 128 mg CAM2038 q4w dose is 33% lower and the 160 mg CAM2038 
q4w dose is 17% lower than the maximum dose given as a single dose (192 mg) to healthy 
subjects under naltrexone blockade, and which was shown to be safe and well tolerated. 
9.5 
Prior and Concomitant Therapy 
All non-study 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 


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the study. The Investigator will determine if the prior/concomitant medication(s) affect the 
subject’s eligibility to participate or continue to participate in the study. The following 
restrictions on concomitant medications will be in place during the study: 
 
 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 (Group 1) or 
up to a month (Group 2 [for subjects not entering the open-label extension] and 
Group 3) 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 be carefully evaluated and fully 
documented for subjects who have a requirement for any opioid analgesic for >7 days 
continually or general anesthesia for surgery. Particular care should be taken in 
subjects with chronic respiratory disease, bowel disease and liver disease during 
anesthesia and the post-operative period. 
 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 CYP3A4 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 study treatment. The 
Medical Monitor must be consulted prior to starting subjects on any of these agents. 
 Concomitant use of other narcotic anesthetics, benzodiazepines, phenothiazines, other 
tranquilizers, or other CNS depressants (including alcohol and sedative/hypnotics) 
may cause respiratory and CNS depression. Use of these substances should be 
minimized during treatment with CAM2038 (see also Section 8.4.3). If these 
sedatives are required during the study, the Medical Monitor must be consulted prior 
to providing narcotic anesthetics, benzodiazepines, phenothiazines, other 
tranquilizers, or other CNS depressants (including alcohol and sedative/hypnotics). 
Subjects should be advised of the danger of concomitant use of sedatives while 
participating in in the study. Subjects should be explicitly advised of the danger of IV 
abuse of benzodiazepines and abuse of alcohol while under treatment with 
CAM2038. 
9.6 
Treatment Compliance 
Study drugs will be administered by study personnel; thus no subject compliance procedures are 
necessary.   
10 
STUDY PROCEDURES AND ASSESSMENTS 
All study assessments will be performed at the visits and the time points outlined in the Schedule 
of Assessments for Group 1 (Table 1), Group 2 (Table 2), and Group 3 (Table 3). The following 
sections outline the details and procedures associated with the assessments. 


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HS-15-549 
Braeburn Pharmaceuticals
CONFIDENTIAL
 
Version: 5.0, 05 OCT 2016 
Page 38 of 87 
 
 
Table 1: Schedule of Assessments – Group 1 (CAM2038 q1w)  
Study 
Screening
Treatment Phase 
Open-label Safety Extension Phase 
 
Treatment:  
CAM2038 q1w 
CAM2038 q1w 
FU 
CAM2038 q1w Dose: 
Doses 1 to 3 
Doses 4 to 7 
Doses 8 to 13 
 
 
Day:
 
-21 to -1 
D1 
D2 
D8 D15 
D22, D29
D36, D43
D23-27, D30-
34, D37-41, 
D44-48 
D50/
EOT D57 D64 D71 D78 D85
 
D92/ 
EOT
D99/FU
Informed Consenta 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria Reviewb 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, Psychosocial and Medication History
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Substance Use and Treatment History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Weight, BMI 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECGd 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Biochemistry, Hematology, Urinalysis, and 
Coagulation Profile 
X 
X 
 
Xe
Xe
Xe 
 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy Testf
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
Adverse Eventsg
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications/Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
a Subjects must voluntarily provide written informed consent prior to any study-related procedures being performed. 
b Prior to treatment on Day 1, all Inclusion and none of the Exclusion criteria must be met. 
c Vital signs (temperature, blood pressure, pulse rate, respiratory rate) will be measured pre-dose and 15 minutes’ post-dose after each CAM2038 q1w administration 
and will be measured once at each non-dosing visit. 
d ECG will be measured at the Screening and EOT visits, and pre-dose and 23 (±2) hours after the first CAM2038 q1w administration. ECGs will be measured at 1, 4, 6, 10, 24, 48, 
72, 96 and 168 hours post-dose on doses 4 through 7. 
e Assessment of serum sodium, bicarbonate, potassium, magnesium, calcium levels only. 
f A serum pregnancy test will be performed at Screening and EOT visits. An “in-office” urine pregnancy test will be required prior to all doses of CAM2038 q1w (for women of 
childbearing potential) during days 1 through 50. An “in-office” urine pregnancy test will be required prior to all doses of CAM2038 q1w (for women of childbearing potential) for 
those women who continue in the extension phase will also be required. 
g Any spontaneously reported AEs will be recorded after the subject signs the ICF. In addition, AEs will be elicited using a non-leading question each time the subject visits the 
clinic and once daily during inpatient stays. 


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CONFIDENTIAL
 
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Study Period/Phase:
Screening
Treatment Phase 
Open-label Safety Extension Phase 
 
Treatment:  
CAM2038 q1w 
CAM2038 q1w 
FU 
CAM2038 q1w Dose: 
Doses 1 to 3 
Doses 4 to 7 
Doses 8 - 13 
 
 
Day:
-21 to -1
D1 
D2
D8
D15
D22, 
D29 
D36, 
D23-27, D30-
34, D37-41, 
D44-48
D50/
EOT
D57 D64 D71 
D78 D85 D92/ 
EOT 
D99/ 
FU 
C-SSRSh
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
Injection Site Examinationi
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK samples 
 
Xj 
 
Xj 
Xj 
X
k
Xk 
Xk 
 
 
 
 
 
X 
 
COWSl 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
X 
 
SOWSl 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
X 
 
UDS and Breath Alcohol Test 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
NRS for Painm
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomizationn
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CAM2038 q1w SC injectiono
 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Admission to CRU 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Discharge from CRU 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Outpatient visits 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Telephone call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Transfer to previous BPN therapy 
 
 
 
 
 
 
 
Xp 
 
 
 
 
 
X 
 
h C-SSRS-Screening will be performed at Screening and then C-SSRS-since last visit will be performed at other subsequent visits. 
i Injection site examinations will occur at each visit and once daily during inpatient stays. 
j Pharmacokinetic samples will be collected at pre-dose CAM2038 q1w doses 1, 2 and 3. 
k Pharmacokinetic samples will be collected at pre-dose and at 0.5, 1, 2, 4, 6, 10, 24, 30, 48, 72, 96, 120 and 168 hours post CAM2038 q1w doses 4, 5, 6 and 7. When a pre-dose 
and 168 hour post-dose time point coincide, only 1 PK sample will be collected.  If a subject terminates early from the study, then a PK blood sample is to be drawn. 
l COWS and SOWS will be performed pre-dose on all dosing days and at each other visit. 
m Average daily NRS pain score will be recorded each day using an electronic device. 
n Randomization to Group 1 or Group 2. Randomization to Group 1 will also include injection site sequence. 
o The first 3 SC injections (Day 1, Day 8, Day 15) will be administered in the buttock (rotating between right and left buttock and injection site per Appendix 17.2) then the injection 
site sequence (buttock [reference], abdomen, thigh, back of upper arm) for the last 4 SC injections (Day 22, Day 29, Day 36, Day 43) will be randomly allocated to each subject 
utilizing 1 of 4 pre-determined sequences.  On Days 50, 57, 64, 71,78 and 85 injections will be rotated in abdomen, arm, buttocks, thigh in the opposite arm of doses 4-7. 
p If not participating in the open-label safety extension or terminated early from the study, subjects will transition back to standard care at the Day 50/EOT study visit. 
  
 


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HS-15-549 
Braeburn Pharmaceuticals
CONFIDENTIAL
 
Version: 5.0, 05 OCT 2016 
Page 40 of 87 
 
BMI=body mass index; BPN=buprenorphine; COWS=Clinical Opioid Withdrawal Scale; CRU= clinical research unit; C-SSRS=Columbia-Suicide Severity Rating Scale; 
D=day; ECG=electrocardiogram; EOT=End of Treatment; NRS=numerical rating scale; PK=pharmacokinetic; SC=subcutaneous; SOWS=Subjective Opioid Withdrawal Scale; 
UDS=urine drug screen.


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Braeburn Pharmaceuticals
CONFIDENTIAL
 
Version: 5.0, 05 OCT 2016 
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Table 2: Schedule of Assessments – Group 2 (128 mg CAM2038 q4w) 
 
a Subjects must voluntarily provide written informed consent prior to any study-related procedures being performed. 
b Prior to treatment on Day 1, all Inclusion and none of the Exclusion criteria must be met. 
c Vital signs (temperature, blood pressure, pulse rate, respiratory rate) will be measured pre-dose and 15 minutes post-dose after each CAM2038 q4w administration. 
Vital signs will also be measured at the Screening, Day 2 and EOT visits, and at each admission. 
d ECG will be measured at the Screening and EOT visits, and pre-dose and 6 (±1) hours after each CAM2038 q4w administration. After dose 4, ECGs will be measured at 1, 4, 
6, 10, 24, 72, 120, 168 (7 days), 336 (14 days) and 672 (28 days) hours post-dose. 
e Assessment of serum sodium, bicarbonate, potassium, magnesium, calcium levels only. 
f A serum pregnancy test will be performed at Screening and EOT visits. An “in-office” urine pregnancy test will be required prior to all doses of CAM2038 q4w (for women of childbearing 
potential) during days 1 through 113.  An “in-office” urine pregnancy test will be required prior to all doses of CAM2038 q1w (for women of childbearing potential) for those women that 
continue to the extension phase. 
Study Period/Phase:
Screening
Treatment Phase 
Open-label Safety Extension Phase 
CAM2038 q1w 
 
Treatment:  
128 mg CAM2038 q4w 
FU 
CAM2038 q4w Dose:  
Dose 1 
Dose 2 
Dose 3 
Dose 4 
 
 
Day:
-21 to -1
D1
D2
D8  
D15 
D22 
D29
D31 
D36 
D43 
D50
D57
D59 
D64 
D71 
D78
D85 D86
D87, D88 
D89, D90 
D92, D95 
D99, D106 
 
D113/ 
EOT 
 D120  D127 D134 D141 D148 D155/
EOT D162 
Informed Consenta
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria Reviewb
X 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, Psychosocial and Medication History
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Substance Use and Treatment History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Weight, BMI 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsc
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECGd
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Biochemistry, Hematology, Urinalysis, and 
Coagulation Profile 
X 
X 
 
 
Xe 
 
Xe 
 
Xe 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy Testf
X 
X  
 
X  
X  
X  
 
X 
 
 
X 
 
 
X 
 
Adverse Eventsg
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications/Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Braeburn Pharmaceuticals
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Version: 5.0, 05 OCT 2016 
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g Any spontaneously reported AEs will be recorded after the subject signs the ICF. In addition, AEs will be elicited using a non-leading question each time the subject visits the 
clinic and once daily during inpatient stays.


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HS-15-549 
Braeburn Pharmaceuticals
CONFIDENTIAL
 
Version: 5.0, 05 OCT 2016 
Page 43 of 87 
 
 
Study Period/Phase:
Screening
Treatment Phase 
Open-label Safety Extension Phase  
CAM2038 q1w 
 
Treatment:  
128 mg CAM2038 q4w 
FU 
CAM2038 q4w Dose:  
Dose 1 
Dose 2 
Dose 3 
Dose 4 
 
 
Day: -21 to -1 
D1 D2
D8  
D15
D22
D29
D31
D36
D43
D50
D57
D59  
D64  
D71 
D78
D85 D86
D87, D88 
D89, D90 
D92, D95 
D99, D106 
D113/
EOT D120 
D127 D134 D141 D148 
D155/
EOT 
D162
C-SSRSh
X 
X X 
 
X  
X  
X  
 
X 
 
 
X 
 
 
X 
 
Injection Site Examinationi
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK samples 
 
Xj  
Xj
Xk
Xk
Xk
Xk
Xl
X
m
X
m 
X
 
 
 
 
 
X 
 
COWSn 
 
X X 
 
X  
X  
X  
 
X 
 
 
 
 
 
X 
 
SOWSn 
 
X X 
 
X  
X  
X  
 
X 
 
 
 
 
 
X 
 
UDS and breath alcohol test 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
NRS for Paino
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomizationp
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CAM2038 q4w SC injectionq 
 
X  
 
X  
X  
X  
 
 
 
 
 
 
 
 
 
CAM2038 q1w SC injectionq 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
Admission to CRU 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
Discharge from CRU 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
Outpatient visits 
 
X X 
X 
X 
X 
X 
X  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Telephone call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Transfer to previous BPN therapy 
 
 
 
 
 
 
 
 
 
 
 
Xr
 
 
 
 
 
X 
 
h C-SSRS-Screening will be performed at Screening and then C-SSRS-since last visit will be performed at other subsequent visits. 
i Injection site examinations will occur at each visit and once daily during inpatient stays. 
j Pharmacokinetic samples will be collected at pre-dose, 168 hrs (7 days), 336 hrs (14 days) and 504 hrs (21 days) after CAM2038 q4w dose 1. If a subject terminates early from the study, then a 
PK blood sample is to be drawn. 
k Pharmacokinetic samples will be collected at pre-dose, one sample any time between 4 and 8 hrs post-dose, approximately 48 hrs, 168 hrs (7 days), 336 hrs (14 days) and 504 hrs 
(21 days) after CAM2038 q4w doses 2 and 3. 
l Pharmacokinetic samples will be collected at pre-dose, 0.5, 1, 2, 4, 6, and 10 hours after CAM2038 q4w dose 4. 
m Pharmacokinetic samples will be collected at approximately 24, 48, 72, 96, 120, 168 (7 days), 240 (10 days), 336 (14 days), 504 (21 days) and 672 (28 days) hours after CAM2038 q4w dose 
4. 
n COWS and SOWS will be performed pre-dose on all dosing days and at each other visit. 
o Average daily NRS pain score will be recorded using an electronic device each day. 


Clinical Study Protocol
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Braeburn Pharmaceuticals
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Version: 5.0, 05 OCT 2016 
Page 44 of 87 
 
p Randomization to Group 1 or Group 2. 
q The SC injections will be administered in the buttock, rotating between right and left buttock and injection site per Appendix 17.2.  On Day 113, subjects will have the option of switching from 
128 mg CAM2038 q4w to 32 mg CAM2038 q1w.  
r If not participating in the open-label safety extension or terminated early from the study, subjects will transition back to standard care at the Day 50/EOT study visit. 
 
BMI=body mass index; BPN=buprenorphine; COWS=Clinical Opioid Withdrawal Scale; CRU=clinical research unit; C-SSRS=Columbia-Suicide Severity Rating Scale; D=day; 
ECG=electrocardiogram; EOT=End of Treatment; NRS=numerical rating scale; PK=pharmacokinetic; SC=subcutaneous; SOWS=Subjective Opioid Withdrawal Scale; UDS=urine drug screen. 
 


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HS-15-549 
Braeburn Pharmaceuticals
CONFIDENTIAL
 
Version: 5.0, 05 OCT 2016 
Page 45 of 87 
 
Table 3: Schedule of Assessments – Group 3 (160 mg CAM2038 q4w) 
 
a Subjects must voluntarily provide written informed consent prior to any study-related procedures being performed. 
b Prior to treatment on Day 1, all Inclusion and none of the Exclusion criteria must be met. 
c Vital signs (temperature, blood pressure, pulse rate, respiratory rate) will be measured pre-dose and 15 minutes post-dose after the SL BPN dose on Day 1 and after 
each CAM2038 q4w administration. Vital signs will also be measured at the Screening, Day 8 discharge, Day 9 and EOT visits, and at each admission. 
d ECG will be measured at the Screening and EOT visits, at pre-dose and 1 hour after SL BPN administration on Day 1, and pre-dose and 6 (±1) hours after each CAM2038 q4w 
administration. After CAM2038 dose 4, ECGs will be measured at 1, 4, 6, 10, 24, 72, 120, 168 (7 days), 336 (14 days) and 672 (28 days) hours post-dose. 
e Day 1 only. 
f Assessment of serum sodium, bicarbonate, potassium, magnesium, calcium levels only. 
g A serum pregnancy test will be performed at Screening and EOT visits. An “in-office” urine pregnancy test will be required prior to SL BPN dosing on Day 1 and all doses of CAM2038 q4w 
(for women of childbearing potential). 
hAny spontaneously reported AEs will be recorded after the subject signs the ICF. In addition, AEs will be elicited using a non-leading question each time the subject visits the 
clinic and once daily during inpatient stays.
Study Period/Phase: Screening
Treatment Phase 
 
Treatment:   
SL BPN 
160 mg CAM2038 q4w 
FU
 
 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
 
 
Day:
-21 to -1
D1
-
D6
D7
D8
D9
D15 
D22 
D29 
D36 D38, D43, 
D50, D57
D64 D66, D71, 
D78, D85
D92 
D93 
D94, D95, D96, 
D97, D99, D102, 
D106, D113 
D120/
EOT D127
Informed Consenta
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria Reviewb
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, Psychosocial and Medication 
History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Substance Use and Treatment History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight, BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsc
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECGd
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
Biochemistry, Hematology, Urinalysis, and 
Coagulation Profile 
X 
Xe 
 
X 
 
 
Xf 
 
Xf 
 
Xf 
 
 
X 
 
Pregnancy Testg
X 
X 
 
X  
 
X 
 
X 
 
X 
 
 
X 
 
Adverse Eventsh
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Braeburn Pharmaceuticals
CONFIDENTIAL
 
Version: 5.0, 05 OCT 2016 
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Study Period/Phase: Screening 
Treatment Phase 
 
Treatment:  
SL BPN 
160 mg CAM2038 q4w 
FU 
 
 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
 
 
Day:
-21 to -1 
D1-
D6
D7 
D8 D9
D15 
D22 
D29 
D36 D38, D43, 
D50, D57 
D64 D66, D71, 
D78, D85 
D92 
D93 
D94, D95, D96, 
D97, D99, D102, 
D106, D113 
D120/
EOT 
D127
Concomitant Medications/Procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
X
C-SSRSi
X 
X 
X 
X 
X
 
X 
 
X 
 
X 
 
 
X 
 
Injection Site Examinationj
 
 
 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK samples 
 
 
Xk
Xk
 
Xk
Xl
Xl 
Xl
Xl 
Xm
Xm 
Xm 
Xm 
 
COWSn 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
SOWSn 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
UDS and breath alcohol test 
X 
X 
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
NRS for Paino
X 
X 
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
SL BPN administration 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CAM2038 q4w SC injectionp 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
Admission to CRU 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Discharge from CRU 
 
 
 
Xq
 
 
 
 
 
 
 
X 
 
 
 
Outpatient visits 
 
X 
 
 
X
X 
X 
X 
X 
X 
 
 
X 
X 
 
Telephone call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Transfer to previous BPN therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
i C-SSRS-Screening will be performed at Screening and then C-SSRS-since last visit will be performed at other subsequent visits. 
j Injection site examinations will occur at each visit after CAM2038 q4w administration and once daily during inpatient stays. 
k Pharmacokinetic samples will be collected at pre-dose (within 45 minutes), 10, 20, 30 and 40 minutes, and 1, 1.5, 2, 3, 4, 6, 10 and 24 hours after SL BPN dose 7, and pre-dose, 168 
hrs (7 days), 336 hrs (14 days) and 504 hrs (21 days) after CAM2038 q4w dose 1. If a subject terminates early from the study, then a PK blood sample is to be drawn. 
l Pharmacokinetic samples will be collected at pre-dose, one sample any time between 4 and 8 hrs post-dose, approximately 48 hrs, 168 hrs (7 days), 336 hrs (14 days) 
and 504 hrs (21 days) after CAM2038 q4w doses 2 and 3. 
m Pharmacokinetic samples will be collected at pre-dose, 0.5, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120, 168 (7 days), 240 (10 days), 336 (14 days), 504 (21 days) and 672 (28 days) hours 
after CAM2038 q4w dose 4. 
n COWS and SOWS will be performed pre-dose on all dosing days and at each other visit. 
o Average daily NRS pain score will be recorded using an electronic device each day. 
p The 4 SC injections will be administered in the buttock, rotating between right and left buttock and injection site per Appendix 17.2.  
q Subjects will be discharged at least 6 hours after CAM2038 q4w dose 1, once the ECG and other safety assessments are completed, and the Investigator deems it safe for 
the subject to leave the CRU.  


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BMI=body mass index; BPN=buprenorphine; COWS=Clinical Opioid Withdrawal Scale; CRU=clinical research unit; C-SSRS=Columbia-Suicide Severity Rating Scale; D=day; 
ECG=electrocardiogram; EOT=End of Treatment; NRS=numerical rating scale; PK=pharmacokinetic; SC=subcutaneous; SL=sublingual; SOWS=Subjective Opioid Withdrawal 
Scale; UDS=urine drug screen. 


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10.1 Demographics and Other Baseline Characteristics 
10.1.1 Informed Consent 
The nature of the study and its risks and benefits will be explained to the subject by the 
Investigator or designated study personnel. The subject must voluntarily provide written informed 
consent on an ethics-approved ICF, prior to performing any study-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 study-
specific procedures. Documentation that the subject was given adequate time to ask the 
Investigator (or designee) questions about their participation in the study 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. 
10.1.2 Demographics 
The following demographics will be recorded: age (birthdate), sex, weight, height, body mass 
index (BMI), race, and ethnicity. 
10.1.3 Medical and Psychosocial History 
 
The complete medical history will include histories of acute, chronic, or infectious disease; 
surgical or oncologic histories; and any reported conditions affecting major body systems in the 
past five years or deemed to be clinically significant in the opinion of the Investigator. All 
findings on medical history will be evaluated by the Investigator for clinical significance. 
 
A complete psychosocial history will be obtained including education, employment status, 
marital/significant other status, residential status and legal status/arrest history. 
10.1.4 Medication History 
All medications (prescription and non-prescription or herbal medications/natural health products) 
taken by the subjects during the 30 days prior to Screening will be recorded in the source 
documentation as medication history. Substance Use and Treatment History (Section 10.1.5) will 
be collected separately and stored in the subject’s file. 
10.1.5 Substance Use and Treatment History 
DSM-V modules will be included to evaluate alcohol and substance use disorders. 
 
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 using a timeline follow-back type of interview (Fals-Stewart et al., 2000). 
10.2 Eligibility Review and Randomization 
The Investigator or designee must document that the subjects meet each individual criterion (as 
outlined in Section 8.1 and Section 8.2) via a signed note or eligibility and clinical stability 
checklist during Screening. Signatures on these documents must be dated on or before the date of 


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study start (Day 1). Prior to the first dose with CAM2038 q1w or CAM2038 q4w on Day 1, a re-
check of the eligibility criteria will be performed. 
 
Up to a total of 40 subjects will be randomized at a 3:2 ratio to Group 1 (CAM2038 q1w group 
with 24 subjects) Group 2 (128 mg CAM2038 q4w group with 16 subjects). Approximately 16 
subjects will be enrolled into the additional Group 3 (24 mg SL BPN followed by 160 mg 
CAM2038 q4w). 
 
Subjects randomized to Group 1 (CAM2038 q1w) will be randomized at a 1:1:1:1 ratio to 1 of 
the following 4 injection sequences: ABDC, BCAD, CDBA, and DACB, where A=buttock 
(reference), B=abdomen, C=thigh, and D=back of upper arm. 
10.3 Pharmacokinetic Assessments 
10.3.1 Drug concentration measurements 
10.3.1.1 
Sample Collection, Preparation and Handling 
PK samples for analysis will be collected at the time points specified in Table 1 (Group 1), Table 2 
(Group 2), and Table 3 (Group 3). 
 
The actual date and time of each PK sample collection will be recorded. The approximate total 
PK blood volume (6 mL per sample) to be taken per subject during the study is: 
 
    Group 1 total PK blood volume = 342 mL 
    Group 2 total PK blood volume = 204 mL 
    Group 3 total PK blood volume = 276 mL 
10.3.1.2 
Determination of Drug Concentration 
Plasma concentrations of BPN and norBPN will be determined using a validated LC-MS-MS 
method. The method is validated for a range of 0.0250 to 10.0 ng/mL for BPN and 0.0200 to 8.00 
ng/mL for norBPN, based on the analysis of 0.500 mL of K2 EDTA plasma. 
10.3.2 Pharmacokinetic parameters 
Pharmacokinetic parameters of BPN and its active metabolite norBPN will be estimated using 
Phoenix® WinNonlin® (Certara, L.P., 100 Overlook Center, Princeton, NJ 08540 USA), version 6.4 
or higher. Standard non-compartmental methods and actual dates and times of dosing and blood 
sampling will be used in the calculations. The following PK parameters will be determined for 
BPN and norBPN (if applicable):  
    Group 1: 
o AUCss (area under the plasma concentration-time curve during a 7-day dosing 
interval at steady state) for each injection site, i.e., buttock (reference), 
abdomen, thigh and back of upper arm. 
 
o Css,av for each injection site, i.e., buttock (reference), abdomen, thigh and back 
of upper arm. 
 


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o Css, max for each injection site, i.e., buttock (reference), abdomen, thigh and 
back of upper arm. 
 
o tss,max for each injection site, i.e., buttock (reference), abdomen, thigh and back 
of upper arm. 
o norBPN/BPN ratios for AUCss and Css max for each injection site, i.e., buttock 
(reference), abdomen, thigh and back of upper arm. 
    Group 2 and Group 3: 
o AUCss (AUC during a 24-hour dosing interval at steady state for SL BPN 
[Group 3 only] and  a 28-day dosing interval at steady state for CAM2038 q4w) 
o Css,av 
o Css,max 
o tss,max 
o Css,28days (for CAM2038 q4w treatment) and Css,24h (for SL BPN treatment) 
o norBPN/BPN ratios for AUCss and Css,max 
In Group 3, relative bioavailability of BPN will be assessed at steady state following repeated 
SC administration of 160 mg CAM2038 q4w as compared with repeated SL administration of 
24 mg BPN. 
Details of the PK evaluation will be presented in the statistical analysis plan (SAP). Values that 
are below the lower limit of quantification will be handled as described in the SAP. 
10.4 Efficacy Assessments 
The following sections provide an overview of the exploratory efficacy assessments included in 
the study. 
10.4.1 Urine Toxicology 
A 12-panel UDS will test for the following drugs of abuse: THC/marijuana, cocaine, 
phencyclidine (PCP), morphine and its related metabolites derived from opium (opiates), 
methamphetamines, methadone, amphetamines, barbiturates, benzodiazepines, 
methylenedioxymethamphetamine (MDMA), oxycodone and propoxyphene. 
 
Urine drug screen samples will be collected at the time points specified in Table 1 (Group 1), Table 
2 (Group 2), and Table 3 (Group 3) 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 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). Direct observation approach to obtaining urine samples may be used if the 
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10.4.2 Numerical Rating Scale (NRS) for Pain 
The NRS is an 11-point scale with anchors 0 (no pain) and 10 (worst pain imaginable). Subjects 
will record their Worst and Average Pain Score over the past 24 hours in an electronic diary on a 
daily basis. Study personnel and subjects will undergo training on how to complete the NRS 
assessment. 
10.5 Safety Assessments 
Safety monitoring will be performed throughout the study for all subjects. All AEs, regardless of 
causality or severity, will be recorded on the AE case report form (CRF). CAM2038 injections 
may be discontinued as clinically indicated. 
10.5.1 Adverse Events and Serious Adverse Events 
10.5.1.1 
Adverse Event Reporting 
Throughout the study, AEs will be documented on the appropriate page of the CRF whether or 
not considered treatment-related. This includes any new signs, symptoms, injury or illness, 
including increased severity of previously existing signs, symptoms, injury, or illness.  
CAM2038 injections sites will be examined during each scheduled visits for any signs of 
adverse site reactions, including erythema, pruritus, edema, pain, etc.  The new injection site 
will also be examined shortly minutes after each injection to determine if any site related AEs 
have occurred.  Subjects will also be queried specifically about local tolerability AEs in 
connection to the examinations. 
 
Conditions existing prior to dosing will be recorded as part of the subject’s medical history. The 
Investigator is responsible for assessing the relationship of AEs to the study drug; relationship 
will be classified as not related, unlikely related, possibly related, or probably related (see 
Section 10.5.1.2 for definitions). 
 
All AEs and SAEs will be collected by the Investigator from the time informed consent is signed 
until 7 days after the EOT visit. This includes any AEs that are ongoing at the 
completion/termination of the study, and any AEs that start after the last dose of study drug. SAEs 
and AEs that have been designated as possibly related to study drug will be followed until 
resolution or stabilization. Any SAEs considered related to study drug should be reported to the 
Sponsor without regards to these timelines. 
 
Any SAE, including death resulting from any cause, which occurs to any subject participating in 
this study or within 14 days of the EOT visit or premature discontinuation from the study whether 
or not related to the study drug, must be reported via email, facsimile or telephone within 24 
hours of first being advised of the SAE. Follow-up information collected for any initial report of 
an SAE must be reported to the Sponsor or designee within 24 hours of receipt by the 
Investigator. In the event discussion is necessary call the Medical Monitor. 
 
The Sponsor or designee will determine whether the SAE must be reported within 7 or 15 days to 
the FDA. If so, the Sponsor (or the Sponsor’s representative) will report the event to the FDA. The 
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as he or she is made aware of the circumstances. The Investigator will report SAEs to the IRB per 
IRB policy. 
  
10.5.1.2 
Adverse Event Definitions 
An AE is any unfavorable or unintended change in body structure (signs), body function 
(symptoms), laboratory result (e.g., biochemistry, ECG, etc.), or worsening of a pre-existing 
condition associated temporally with the use of the study drug whether or not considered related 
to the study drug. 
 
A treatment-emergent AE is any condition that was not present prior to treatment with study drug 
but appeared following treatment, was present at treatment initiation but worsened  during 
treatment, or was present at treatment initiation but resolved and then reappeared while  the 
individual was on treatment (regardless of the intensity of the AE when the treatment was 
initiated). 
 
All AEs, including either observed or volunteered problems, complaints, signs, or symptoms 
must  be recorded on the AE page of the CRF, regardless of whether associated with the use of 
study drug. This would include AEs resulting from concurrent illness, reactions to concurrent 
medication use, or progression of disease states (excluding the disease under study). AEs should 
be recorded in standard medical terminology. 
 
The Investigator will evaluate each AE for duration, intensity, and relationship to study drug, 
record the action taken, and any treatment given. Recurrent symptoms of  a chronic pre-existing 
condition are not considered AEs unless they occur in a worse or  unexpected pattern during 
study drug administration. 
10.5.1.3 
Intensity of AEs 
The intensity (or severity) of AEs is characterized as mild, moderate, or severe: 
 
Mild AEs are usually transient, requiring no special treatment, and do not interfere with the 
subject’s daily activities. 
 
Moderate AEs introduce a low level of inconvenience or concern to the subject and may 
interfere with daily activities, but are usually ameliorated by simple therapeutic measures. 
 
Severe AEs interrupt a subject’s usual daily activity and typically require systemic drug therapy 
or other treatment. 
 
When the intensity category of the AE changes more frequently than once daily, the maximum 
intensity for the event is recorded. If the intensity category changes after a number of days, then 
these sub-events or changes are recorded separately (i.e., having distinct onset and stop dates). 
10.5.1.4 
Relationship to Study Drug 
The degree of “relatedness” of the AE to the study drug may be described using the following 
scale: 
 
Not related indicates that the AE is definitely not related to the study drug. 


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Unlikely related indicates that there are other, more likely causes and study drug is not suspected 
as a cause.  
Possibly related indicates that a direct cause and effect relationship between study drug and the 
AE has not been demonstrated but there is a reasonable possibility that the event was caused by the 
study drug. 
 
Probably related indicates that there probably is a direct cause and effect relationship between the 
AE and the study drug. 
 
It is the Sponsor’s policy to consider “Probable” and “Possible” causality assessments as positive 
causality. It is the Sponsor’s policy to consider “Not” and “Unlikely” causality assessments as 
negative causality. 
 
Assessments are to be recorded on the CRF and must indicate clearly the relationship being 
assessed. 
10.5.1.5 
Serious Adverse Event 
An SAE is defined as an AE that: 
 
    Results in death 
 Is immediately life-threatening (there is an immediate risk of death from the AE as it 
occurred; this does not include an AE that had it occurred in a more serious form may 
have caused death) 
 Results in or prolongs an inpatient hospitalization (Note: a hospitalization for elective 
or  pre-planned surgery, procedure, or drug therapy does not constitute an SAE unless 
there  is a complication resulting in hospitalization prolongation). An AE that results 
in a visit to an Emergency Room that does not require an inpatient stay is not always 
classified as an SAE. 
 Results in permanent or substantial disability (permanent or substantial disruption of 
one’s ability to conduct normal life functions) 
 Is a congenital anomaly/birth defect (in offspring of a patient using the study drug 
regardless of time to diagnosis) 
    Is considered an important medical event 
 
Life-threatening events are defined as events that place the subject, in the view of the Investigator, 
at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that, 
had it occurred in a more severe form, might have caused death. 
 
Disability is defined as a substantial disruption of a person’s ability to conduct normal life 
functions. 
 
Important medical events are defined as events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes. Examples of important medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 


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10.5.2 Pregnancy 
Pregnancies among study 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 will not 
receive any more CAM2038 doses, will be discontinued from the study and referred back to the 
care of their usual provider or continue in the study after discussion with and documentation by 
the 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. 
10.5.3 Clinical Laboratory Assessments 
All protocol-specified laboratory tests on blood and urine samples will be performed at a selected 
laboratory. The lab will generate laboratory reports and forward them to the CRU in a timely 
manner. It is the responsibility of the Investigator to review and sign all laboratory reports 
expeditiously, in order to document appropriate safety monitoring of study subjects. The 
Investigator should sign and date each laboratory report concurrent with her or his review, and 
should indicate the clinical significance of each abnormal/flagged value by noting “NCS” (not 
clinically significant) or “CS” (clinically significant), for example. 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 4. Of note, a targeted assessment of electrolytes will be conducted 
throughout the study at pre-specified time points, and at additional time points at the discretion of 
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Table 4: Clinical Laboratory Assessments 
Hematology 
Biochemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
Red blood cell count 
Red blood cell 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) 
12 panel illicit drug screen 
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, International 
normalized ratio 
 
In addition to the clinical laboratory tests, a serum pregnancy test will be performed at the 
Screening and EOT visits. A urine pregnancy test will be required prior to all doses of CAM2038 
q1w and q4w for all women of childbearing potential. Results must be reviewed and confirmed to 
be negative prior to start of CAM2038 treatment (Day 1). 
 
The approximate total blood volume, including PK sample collections (Section 10.3.1.1) to be 
taken per subject during the study is the following: 
 
    Group 1 total blood volume: approximately 546 mL 
    Group 2 total blood volume: approximately 382.5 mL 
    Group 3 total blood volume: approximately 352.5 mL 
10.5.4 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. Vital signs will be measured at the time points 


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specified in Table 1 (Group 1), Table 2 (Group 2), and Table 3 (Group 3). Clinically significant 
values will be recorded as AEs. 
 
10.5.5 12-Lead Electrocardiogram 
12-Lead ECGs will be performed after the subject has been resting in a recumbent/supine 
position for at least 3 minutes at the times specified in Table 1 (Group 1), Table 2 (Group 2), 
and Table 3 (Group 3). The ECG variables will include ventricular heart rate and the PR, QRS, 
QT, 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. Subjects who have QTc > 500 msec or post-baseline 
increase > 60 msec will be discontinued from the study and will not receive any more injections 
of CAM2038. Subjects will then have daily ECGs until QTc values return to baseline. The 
Investigator can refer the subject to a Cardiologist, if necessary. 
10.5.6 Physical Examination 
A complete physical examination including all major body systems will be performed at Screening 
and EOT visits. 
 
Height, weight and BMI will be determined at the Screening visit. Weight and BMI will also be 
determined at the EOT visit. 
10.5.7 Injection Site Examination 
All CAM2038 injection sites (new and old) will be examined during each scheduled visit after the 
first dose of CAM2038 for any signs of adverse site reactions, including erythema, pruritus, 
edema, pain, etc. Injection site examination form is included in Appendix 17.3. Subjects will also 
be queried specifically about local tolerability AEs in connection to the examinations. Non-
identifying photographs will be taken to document any injection site reactions.  
10.5.8 Columbia-Suicide Severity Rating Scale 
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 study: the Baseline/Screening version (6 months 
and lifetime history; Appendix 17.4) and the Since Last Visit version (Appendix 17.5). The 
Screening version of the C-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 1 
(Group 1), Table 2 (Group 2), and Table 3 (Group 3). 
 
The C-SSRS is to be administered by the Investigator or his/her qualified designee. Qualified 
designee is defined has completed the C-SSRS training within the last 2 years. The survey should 
be administered by the same assessor, where possible, throughout the study.  


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10.5.9 Subjective Opioid Withdrawal (SOWS) Scale 
In the SOWS, subjects rate the intensity of each of 16 common motoric, autonomic, 
gastrointestinal, musculoskeletal, and psychic symptoms of opioid withdrawal on a 5-point 
Likert scale, i.e., from 0 (“not at all”) to 4 (“extremely”), based on how they were feeling at the 
time of testing (Appendix 17.6). 
10.5.10 Clinical Opioid Withdrawal (COWS) Scale 
Study personnel will assess clinical observations indicative of withdrawal using the COWS 
(Appendix 17.7). This scale consists of 11 common opioid withdrawal signs or symptoms, rated 
on a numeric scale and based on a timed period of observation of the subject by the rater. 
10.5.11 Treatment Identification Card 
Subjects will receive a wallet card indicating that they are receiving BPN as part of the study. 
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. Sample wallet cards will be 
provided for IRB submission. 
10.5.12 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 during induction 
and to exercise caution in performing activities requiring alertness such as driving a car during the 
first few days until such time that they are reasonably certain that their ability to engage in such 
activities is not adversely affected. 
10.6 Efficacy Variables 
10.6.1 Urine Toxicology 
The frequency and incidence of urine toxicology results positive for opioids other than BPN, and 
positive results for other, non-opioid, drugs of abuse will be measured via qualitative methods. 
10.6.2 Numerical Rating Scale for Pain 
The weekly average of daily Pain Intensity (PI) will be calculated based on non-missing NRS 
scores (i.e., the missing daily scores will not be used in the calculation for the average). This 
weekly average will be called PI for that week. Pain Intensity Difference (PID) for a post-
baseline Week i will then be derived as 
 
PID at week 1i = PI at baseline – PI at week i. 
 
Based on this definition, a positive PID is indicative of an improvement. The efficacy endpoint will 
be the change from Baseline in the weekly average of the daily Worst Pain score. 
10.7  Appropriateness of Measures 
The primary objective of this study is to evaluate steady state PK of CAM2038 q1w following SC 
injection at various administration sites and steady state PK of CAM2038 q4w; therefore, PK 


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blood samples will be collected to assess plasma concentrations of BPN and norBPN and derive 
the necessary PK parameters to evaluate rate and extent of exposure. 
 
Standard safety outcomes, such as AEs, vital signs and clinical laboratory testing will be assessed 
during the study. In addition, frequent ECG assessments will be included to monitor potential 
QTc interval prolongation following repeated administration of CAM2038 q1w and q4w. The 
COWS and SOWS are included to monitor any potential opioid withdrawal symptoms associated 
with transitiong from SL BPN to CAM2038 and throughout the study. 
 
Exploratory measures include urine toxicology and pain NRS scores, which are typical of studies 
evaluating efficacy in managing opioid dependence and chronic pain.


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11 
DATA QUALITY ASSURANCE 
This study 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 study centers; the review of protocol procedures with the 
Investigator and study personnel prior to study 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, laboratory results, 
participant diaries, data recorded in automated instruments, microfilm or magnetic media, and 
pharmacy records, etc. This study 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 study personnel. 
All data entries will be verified for accuracy and correctness by independent monitors. The EDC 
system maintains a full audit trail. 
11.2 Study Auditing and Monitoring 
Monitoring of the study 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 study objectives and/or 
endpoints, the purpose of the study, study 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, study drug 
stocks, drug accountability records, participant charts and source documents, and other  


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records related to study conduct. The purpose of the Sponsor audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether the study-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 International Conference on Harmonisation (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 SAP. The 
SAP may include more detail of analysis populations, summary strategies, and any clarifications 
or changes necessary due to, for example, regulatory requests. The SAP must be finalized before 
database lock. Any changes to the final SAP will be discussed in the final study report. 
12.2 Analysis Populations 
Three study populations are defined. 
 Safety population: All subjects who receive at least part of an injection of the study 
medications. All safety analyses will be based on the Safety population. 
 Pharmacokinetic population: The PK population will consist of all subjects in the 
Safety population who have provided sufficient PK data for all 4 randomized 
injection sites to derive PK parameters of interest (Group 1), or have provided PK 
data after the last injection of CAM2038 q4w (Group 2 and Group 3). All PK 
summaries will be based on the PK population. 
 Efficacy population: The efficacy population will be the intent to treat population 
consisting of all subjects that have received at least 1 injection of CAM2038 and 
provided some efficacy measures. 
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 by 
sequence and overall. The summaries will be performed by group, and sequence if appropriate. 
 
Tabular summaries and/or listings will be provided for baseline clinical characteristics, such as 
illicit drug and treatment use history, medical history, inclusion/exclusion criteria, and 
medication history. 
12.3.2 Analysis of Pharmacokinetics 
Summaries of plasma concentrations of BPN and norBPN will be presented for the PK population 
by Group, treatment, and injection site, if applicable. The following descriptive statistics will be 
presented at each nominal timepoint: n, arithmetic mean, standard deviation, and coefficient of 
variation percentage (CV%), median, geometric mean, geometric CV%, minimum and maximum 
values. Mean plasma concentration-time data will be displayed for the PK population in linear and 
semi-logarithmic scales by Group, treatment and injection site, if applicable. Individual 
plasma concentrations of BPN and norBPN will be listed for the Safety population by Group, 
treatment, and injection site, if applicable.  
 


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For Group 1 (CAM2038 50 mg/mL q1w), the following considerations will apply in the PK 
analyses. The primary PK parameters will be AUCss and Css,max after steady state injections of 
CAM2038 q1w at different injection sites. The injection site buttock will be the reference. The 
analyses will be based on log-transformed data. The natural log-transformed AUCss and Css,max data 
will be analyzed using an ANOVA model, sequence, subject within sequence (1, 2, 3, 4 
corresponding to A/B/D/C, B/C/A/D, C/D/B/A, D/A/C/B, where A=buttock, B=abdomen C=thigh, 
or D=back of upper arm), period, and treatment (treatment sites: A=buttock, B=abdomen C=thigh, 
or D=back of upper arm). The estimated treatment effects, treatment differences versus the 
reference (B-A, C-A, and D-A), and the 90% confidence intervals of the estimated differences will 
be presented. The above estimates will be expressed on the raw scale (expressed after performing 
the anti-log). All other PK parameters will be summarized by descriptive statistics.  
 
For Group 2 (CAM2038 q4w) and Group 3 (CAM2038 q4w and SL BPN), the PK parameters will 
be summarized by descriptive statistics. The primary PK parameters will be AUCss and Css,max. 
 
The PK parameters (Section 10.3.2) will be listed for the Safety population and summarized by 
Group, treatment, and injection site, if applicable, for the PK population. Summary statistics will 
include: n, arithmetic mean, standard deviation, CV%, median, geometric mean, geometric CV%, 
minimum and maximum values. 
12.3.3 Analysis of Safety 
Exposure will be summarized by Group, treatment, and injection site, as applicable. 
 
AEs 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 by Group. Summaries of these AE 
subsets will be presented for relationship to study drug, intensity, seriousness, AEs or SAEs 
leading to discontinuation. Frequencies for deaths and hospitalizations will also be summarized 
by Group and overall. Injection specific AEs will also be summarized. 
 
Data for clinical laboratory tests, ECG, vital signs, and physical and injection site examinations 
will be summarized by Group using standard descriptive and change from baseline statistics. 
Shift tables and tabular summaries of abnormalities will be provided by Group, where 
appropriate. 
 
The average SOWS and COWS scores over the Treatment Phase and average change from 
baseline (Day 1) SOWS and COWS scores will be presented. 
 
Medications will be coded using the World Health Organization Drug dictionary and may be 
summarized by Group using descriptive statistics. 
 
By-subject listings will be provided for all safety data. 
12.3.4 Analysis of Efficacy 
The frequency and incidence of urine toxicology results positive for opioids other than BPN, and 
positive results for other, non-opioid, drugs of abuse will be listed by subject and summarized by 
Group. 


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Change from Baseline in the weekly average of the daily Worst Pain score will be listed by subject 
and summarized by Group. 
 
12.3.5 Missing data 
Missing dates/times in AE and concomitant medication data and other missing safety data will be 
handled as described in the SAP. There will be no imputation schemes applied to missing PK 
data. 
12.4 Determination of Sample Size 
At least 20 subjects but no more than 24 subjects will be enrolled to Group 1 (CAM2038 q1w). 
Approximately 16 subjects will be enrolled into each of Group 2 (128 mg CAM2038 q4w) and 
Group 3 (160 mg CAM2038 q4w), for a total of approximately 32 subjects administered 
CAM2038 q4w. These sample sizes are consistent with typical PK studies.


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13 
STUDY 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 Study 
The Investigator will conduct the study in accordance with GCP and all applicable regulations, 
including, where applicable, the Declaration of Helsinki. The study 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 study protocol 
and ICF will be reviewed by the IRB prior to enrolling participants into the study; 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 study at his or her research site and 
notification of study 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 study 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 study. Each prospective subject will 
receive an IRB-approved ICF that summarizes the pertinent study information and will be given 
ample time to read the form and ask questions about the study. All information will 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 study. If the participant chooses to 
participate, he/she must sign the ICF before any study-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 study 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 study 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 study 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 [US] FDA) may inspect medical records related to the study to check the validity 
and accuracy of the data gathered in this study. 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 study 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. Study 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 study, 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 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 Study and Site Closure 
Upon completion of the study, all study data will be provided to the Sponsor following review of 
site study records for completeness, and data clarifications and resolutions. Accounting, 
reconciliation, and final disposition of used and unused study drugs and treatment codes will be 
performed, as applicable. 
 
In addition, the Sponsor reserves the right to temporarily suspend or prematurely discontinue this 
study 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 study, if the study is  
suspended or terminated for safety reasons and will inform the regulatory authorities of the 
suspension or termination of the study and the reason(s) for the action. If required by applicable 
regulations, the Investigator will inform the IRB promptly and provide the study participants 
with the reason for the suspension or termination. If the study is prematurely discontinued, all 
study data will be returned to the Sponsor. 
13.4 Regulatory Documents and Records Retention 
The Investigator is responsible for creating and/or maintaining all study documentation required 
by 21 Code of Federal Regulations (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 study. 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 study 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 study 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 study drug for the purposes that 
were the subject of the investigation. 
The Sponsor will notify Investigators once 1 of the above 2 time frames 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 or request for marketing approval (New Drug 
Application/Marketing Authorisation Application). 
 
If the Investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the study 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. Study 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 study properly and should have an 
adequate number of qualified staff to assist with the conduct of the study.  
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 


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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 study 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 study. 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 
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, 
an 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 study.


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14 
SPONSOR APPROVAL PAGE 
 
A Phase II, Open-label, Partially Randomized, Three Treatment Groups, 
Multi-site Study Assessing Pharmacokinetics after Administration of the 
Once-Weekly and Once-Monthly, Long-Acting Subcutaneous Injectable 
Depot of Buprenorphine (CAM2038) at Different Injection Sites in Opioid-
Dependent Subjects with Chronic Pain 
 
 
 
Version: 5.0 
 
Date: 05 OCT 2016 
 
 
Braeburn Pharmaceuticals Inc. 
 
 
 
Sponsor Representative 
Full Title 
 
Date 
(DD-MMM-YYYY) 
 
 


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15 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
A Phase II, Open-label, Partially Randomized, Two Treatment Groups, Multi-
site Study Assessing Pharmacokinetics after Administration of the Once-
Weekly and Once-Monthly, Long-Acting Subcutaneous Injectable Depot of 
Buprenorphine (CAM2038) at Different Injection Sites in Opioid-Dependent 
Subjects with Chronic Pain 
 
 
 
Version: 5.0 
 
Date: 05 OCT 2016  
 
I have read this protocol and I agree to conduct the study in accordance with the protocol and 
with all applicable government regulations and the 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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16 
REFERENCES 
Butrans (buprenorphine) US prescribing information. Purdue Pharm L.P. June 2014. 
Brands B, Blake J, Sproule B, Gourlay D, Busto U. Prescription opioid abuse in patients 
presenting for methadone maintenance treatment Drug Alcohol Depend. 2004;73: 199–207. 
 
Fals-Stewart W, O'Farrell TJ, Freitas TT, McFarlin SK, Rutigliano P. The timeline followback 
reports of psychoactive substance use by drug-abusing patients: psychometric properties. J 
Consult Clin Psychol. 2000; 68:134–44. 
 
Johnson RE, Jaffe JH, Fudala PJ. A controlled trial of buprenorphine treatment for opioid 
dependence. JAMA 1992; 267(20):2750-5. 
 
Joint Commission and the FDA take steps to curb adverse events related to the use and misuse of 
opioid drugs. ED Manag. 2012;24(10):112-6. 
 
Likar R, Griessinger N, Sadjak A, Sittl R. [Transdermal buprenorphine for treatment of chronic 
tumor and non-tumor pain]. Wien Med Wochenschr. 2003;153(13-14):317-22. 
 
Ling W, Charuvastra C, Collins JF, Batki S, Brown LS Jr, Kintaudi P, Wesson DR, McNicholas L, 
Tusel DJ, Malkerneker U, Renner JA Jr, Santos E, Casadonte P, Fye C, Stine S, Wang RI, Segal 
D. Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized 
clinical trial. Addiction. 1998; 93(4):475-86. 
 
Rosenblum A, Joseph H, Fong C, Kipnis S, Cleland C, Portenoy RK. Prevalence and 
characteristics of chronic pain among chemically dependent patients in methadone maintenance 
and residential treatment facilities. JAMA 2003; 289:2370–8. 
 
Salinas GD, Robinson CO, Abdolrasulnia M. Primary care physician attitudes and perceptions of 
the impact of FDA-proposed REMS policy on prescription of extended-release and long-acting 
opioids. J Pain Res. 2012;5:363-9. 
 
Schottenfeld RS, Pakes JR, Oliveto A, Ziedonis D, Kosten TR. Buprenorphine vs methadone 
maintenance treatment for concurrent opioid dependence and cocaine abuse. Arch Gen 
Psychiatry 1997; 54(8):713-20. 
 
Sittl R, Likar R, Nautrup BP. Equipotent doses of transdermal fentanyl and transdermal 
buprenorphine in subjects with cancer and noncancer pain: results of a retrospective cohort study. 
Clin Ther. 2005;27(2):225-37. 
 
Strain EC, Stitzer mL, Liebson IA, Bigelow GE. Comparison of Buprenorphine and Methadone 
in the treatment of Opioid dependence. Am J Psychiatry 1994; 151(7):1025-30. 
 
Wiest KL, Colditz JB, Carr K, Asphaug VJ, McCarty D, Pilkonis PA. Pain and emotional distress 
among substance-use patients beginning treatment relative to a representative comparison group 
J Addict Med. 2014; 8:407–14.


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17 
APPENDICES 
17.1 Agents Associated with Potential QTc Interval Prolongation 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Alfuzosin 
Uroxatral® 
Alpha1-blocker 
Amantadine 
Symmetrel®, Symadine® 
Antiviral 
Amiodarone 
Cordarone®, Pacerone®, Nexterone® 
Antiarrhythmic 
Amitriptyline 
Elavil® (Discontinued 6/13), Tryptomer®, 
Tryptizol®, Laroxyl®, Saroten®, Sarotex® 
Lentizol®, Endep® 
Antidepressant, Tricyclic 
Anagrelide 
Agrylin®, Xagrid® 
Phosphodiesterase 3 inhibitor 
Apomorphine 
Apokyn®, Ixense®, Spontane®, Uprima® 
Dopamine agonist 
Aripiprazole 
Abilify®, Aripiprex® 
Antipsychotic, atypical 
Arsenic trioxide 
Trisenox® 
Anticancer 
Artenimol+ 
piperaquine 
Eurartesim® 
Antimalarial 
Atazanavir 
Reyataz® 
Antiviral 
Atomoxetine 
Strattera® 
Norepinephrine reuptake 
inhibitor 
Azithromycin 
Zithromax®, Zmax® 
Antibiotic 
Bedaquiline 
Sirturo® 
Antibiotic 
Bortezomib 
Velcade®, Bortecad® 
Proteasome inhibitor 
Bosutinib 
Bosulif® 
Tyrosine kinase inhibitor 
Ceritinib 
Zykadia® 
Kinase inhibitor 
Chloral hydrate 
Aquachloral®, Novo-Chlorhydrate®, Somnos®, 
Noctec®, Somnote® 
Sedative 
Chloroquine 
Aralen® 
Antimalarial 
Chlorpromazine 
Thorazine®, Largactil®, Megaphen® 
Antipsychotic / Antiemetic 
Cilostazol 
Pletal® 
Phosphodiesterase 3 inhibitor 
Ciprofloxacin 
Cipro®, Cipro-XR®, Neofloxin® 
Antibiotic 
Citalopram 
Celexa®, Cipramil® 
Antidepressant, SSRI 
Clarithromycin 
Biaxin®, Prevpac® 
Antibiotic 
Clomipramine 
Anafranil® 
Antidepressant, Tricyclic 


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Generic Name 
Brand Names (Partial List) 
Drug Class 
Clozapine 
Clozaril®, Fazaclo®, Versacloz® 
Antipsychotic, atypical 
Cocaine 
Cocaine 
Local anesthetic 
Crizotinib 
Xalkori® 
Kinase inhibitor 
Dabrafenib 
Tafinlar® 
Kinase inhibitor 
Dasatinib 
Sprycel® 
Tyrosine kinase inhibitor 
Degarelix 
Firmagon® 
Gonadotropin Releasing 
Hormone Agonist/antagonist 
Desipramine 
Pertofrane®, Norpramine® 
Antidepressant, Tricyclic 
Dexmedetomidine 
Precedex®,  Dexdor®,  Dexdomitor® 
Sedative 
Diphenhydramine 
Benadryl®, Nytol®, Unisom®, Sominex®, 
Dimedrol®, Daedalon® 
Antihistamine 
Disopyramide 
Norpace® 
Antiarrhythmic 
Dofetilide 
Tikosyn® 
Antiarrhythmic 
Dolasetron 
Anzemet® 
Antiemetic 
Donepezil 
Aricept® 
Cholinesterase inhibitor 
Doxepin 
Sinequan®, Silenor®, Aponal®, Adapine®, Doxal®, 
Deptran®, Sinquan® 
Antidepressant, Tricyclic 
Dronedarone 
Multaq® 
Antiarrhythmic 
Droperidol 
Inapsine®, Droleptan®, Dridol®, Xomolix® 
Antipsychotic / Antiemetic 
Eribulin mesylate 
Halaven® 
Microtubule inhibitor 
Erythromycin 
E.E.S.®, Robimycin®, EMycin®, Erymax®, 
Ery-Tab®, Eryc Ranbaxy®, Erypar®, Eryped®, 
Erythrocin Stearate Filmtab®, Erythrocot®, 
E-Base®, Erythroped®, Ilosone®,  MY-E®, 
Pediamycin®, Zineryt®, Abboticin®, 
Abboticin-ES®, Erycin®, PCE Dispertab®, 
Stiemycine®, Acnasol®, Tiloryth® 
Antibiotic 
Escitalopram 
Cipralex®, Lexapro®, Nexito®, Anxiset-E® (India), 
Exodus® (Brazil), Esto® (Israel), Seroplex®, 
Elicea®, Lexamil®, Lexam®, Entact® (Greece), 
Losita® (Bangladesh), Reposil® (Chile), Animaxen® 
(Colombia), Esitalo® (Australia), Lexamil® (South 
Africa) 
Antidepressant, SSRI 
Famotidine 
Pepcid®, Fluxid®, Quamatel® 
H2-receptor antagonist 
Felbamate 
Felbatol® 
Anticonvulsant 


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Generic Name 
Brand Names (Partial List) 
Drug Class 
Fingolimod 
Gilenya® 
Sphingosine phospate receptor 
modulator 
Flecainide 
Tambocor®, Almarytm®, Apocard®, Ecrinal®, 
Flécaine® 
Antiarrhythmic 
Fluconazole 
Diflucan®, Trican® 
Antifungal 
Fluoxetine 
Prozac®, Sarafem®, Fontex® 
Antidepressant, SSRI 
Foscarnet 
Foscavir® 
Antiviral 
Furosemide 
Lasix®, Fusid®, Frumex® 
Diuretic 
Galantamine 
Reminyl®, Nivalin®, Razadyne-ER®, 
Cholinesterase inhibitor 
Gemifloxacin 
Factive® 
Antibiotic 
Granisetron 
Kytril®,  Sancuso®, Granisol® 
Antiemetic 
Halofantrine 
Halfan® 
Antimalarial 
Haloperidol 
Haldol® (US & UK), Aloperidin®, Bioperidolo®, 
Brotopon®, Dozic®, Duraperidol® (Germany), 
Einalon S®, Eukystol®, Halosten®, Keselan®, 
Linton®, Peluces®, Serenace®, Serenase®, 
Sigaperidol® 
Antipsychotic 
Hydrochlorothiazide 
Apo-Hydro®, Aquazide H®, BP Zide®, 
Dichlotride®, Hydrodiuril®, HydroSaluric®, 
Hydrochlorot®, Microzide®, Esidrex®, Oretic® 
Diuretic 
Hydroxychloroquine 
Plaquenil®,  Quineprox® 
Antimalarial, 
Anti-inflammatory 
Hydroxyzine 
Atarax®,  Vistaril®,  Aterax®,  Alamon®,  Durrax®,  
Equipose®,  Masmoran®,  Orgatrax®,  Paxistil® 
Quiess®,  Tran-Q®,  Tranquizine® 
Antihistamine 
Ibutilide 
Corvert® 
Antiarrhythmic 
Iloperidone 
Fanapt®, Fanapta®, Zomaril® 
Antipsychotic, atypical 
Imipramine 
Tofranil® 
Antidepressant, Tricyclic 
Indapamide 
Lozol®, Natrilix®, Insig® 
Diuretic 
Isradipine 
Dynacirc® 
Antihypertensive 
Itraconazole 
Sporanox®, Onmel® 
Antifungal 
Ketoconazole 
Nizoral®, Sebizole®, Ketomed®, Keton® 
Antifungal 
Lapatinib 
Tykerb®, Tyverb® 
Kinase inhibitor 


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Generic Name 
Brand Names (Partial List) 
Drug Class 
Leuprolide 
Lupron®,  Eligard®,  Viadur®,  Carcinil®,  
Enanton®,  Leuplin®,  Lucrin®,  Procren®,  
Prostap® and others 
Gonadotropin receptor 
agonist/antogist 
Levofloxacin 
Levaquin®, Tavanic® 
Antibiotic 
Lithium 
Eskalith®, Lithobid® 
Antimania 
Methadone 
Dolophine®, Symoron®, Amidone®, Methadose®, 
Physeptone®, Heptadon® 
Opioid agonist 
Metoclopramide 
Reglan®,  Afipran®,  Maxolon®,  Cerucal®,  
Clopamon®,  Clopra®,  Maxeran®,  Maxolon®,  
Metozolv®,  Plasil®,  Pramin®,  Primperan®,  
Perinorm® 
Antiemetic 
Metronidazole 
Flagyl® and many others 
Antibiotic 
Mifepristone 
Korlym®, Mifeprex® 
Progesterone antagonist 
Mirabegron 
Myrbetriq® 
Beta3 adrenergic antagonist 
Mirtazapine 
Remeron 
Antidepressant, Tetracyclic 
Moexipril/HCTZ 
Uniretic®, Univasc® 
Antihypertensive 
Moxifloxacin 
Avelox®, Avalox®, Avelon® 
Antibiotic 
Nelfinavir 
Viracept® 
Antiviral 
Nicardipine 
Cardene® 
Antihypertensive 
Nilotinib 
Tasigna® 
Kinase inhibitor 
Norfloxacin 
Noroxin®, Ambigram® 
Antibiotic 
Nortriptyline 
Pamelor®, Sensoval®, Aventyl®, Norpress®, 
Allegron®, Noritren®, Nortrilen® 
Antidepressant, Tricyclic 
Ofloxacin 
Floxin® 
Antibiotic 
Olanzapine 
Zyprexa®, Zydis®, Relprevv® 
Antipsychotic, atypical 
Ondansetron 
Zofran®, Anset®, Ondemet®, Zuplenz®, Emetron®, 
Ondavell®, Emeset®, Ondisolv®, Setronax® 
Antiemetic 
Oxytocin 
Pitocin®, Syntocinon® 
Oxytocic 
Paliperidone 
Invega®, Xepilon® 
Antipsychotic, atypical 
Panobinostat 
Farydak® 
Histone deacetylase inhibitor 
Pantoprazole 
Protonix® and others 
Proton Pump Inhibitor 
Papaverine HCl 
none 
Vasodilator, Coronary 
Paroxetine 
Paxil®, Aropax®, Pexeva®, Seroxat®, Sereupin® 
Antidepressant, SSRI 
Pasireotide 
Signifor® 
Somatostatin analog 


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Generic Name 
Brand Names (Partial List) 
Drug Class 
Pazopanib 
Votrient® 
Tyrosine kinase inhibitor 
Pentamidine 
Pentam® 
Antifungal 
Perflutren lipid 
microspheres 
Definity® 
Imaging contrast agent 
Pimozide 
Orap® 
Antipsychotic 
Posaconazole 
Noxafil®,  Posamol® 
Antifungal 
Procainamide (Oral 
off US mkt) 
Pronestyl®, Procan® 
Antiarrhythmic 
Promethazine 
Phenergan® 
Antipsychotic / Antiemetic 
Propofol 
Diprivan®,  Propoven® 
Anesthetic, general 
Quetiapine 
Seroquel® 
Antipsychotic, atypical 
Quinidine 
Quinaglute®, Duraquin®, Quinact®, Quinidex®, 
Cin-Quin®, Quinora® 
Antiarrhythmic 
Quinine sulfate 
Qualaquin® 
Antimalarial 
Ranolazine 
Ranexa®, Ranozex® 
Antianginal 
Rilpivirine 
Edurant®, Complera®, Eviplera® 
Antiviral 
Risperidone 
Risperdal® 
Antipsychotic, atypical 
Ritonavir 
Norvir® 
Antiviral 
Saquinavir 
Invirase®(combo) 
Antiviral 
Sertraline 
Zoloft®, Lustral®, Daxid®, Altruline®, Besitran®, 
Deprax®, Elrval®, Emergen®, Gladem®, 
Implicane®, Sedoran®, Sealdin®, SerivoLowfin®, 
Stimuloton®, Tresleen®, Sertralin Bluefish® 
Antidepressant, SSRI 
Sevoflurane 
Ulane®, Sojourn® 
Anesthetic, general 
Solifenacin 
VESIcare® 
Muscle relaxant 
Sorafenib 
Nexavar® 
Tyrosine kinase inhibitor 
Sotalol 
Betapace®, Sotalex®, Sotacor® 
Antiarrhythmic 
Sunitinib 
Sutent® 
Kinase inhibitor 
Tacrolimus 
Prograf®, Prograf®, Advagraf®, Protopic® 
Immunosuppressant 
Tamoxifen 
Nolvadex®(discontinued 6/13), Istubal®, Valodex® 
Anticancer 
Telaprevir 
Incivek®, Incivo® 
Antiviral 
Telavancin 
Vibativ® 
Antibiotic 
Telithromycin 
Ketek® 
Antibiotic 


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Generic Name 
Brand Names (Partial List) 
Drug Class 
Tetrabenazine (Orphan 
drug in US) 
Nitoman®, Xenazine® 
Monoamine Transporter 
Inhibitor 
Thioridazine 
Mellaril®, Novoridazine®, Thioril® 
Antipsychotic 
Tizanidine 
Zanaflex®, Sirdalud® 
Muscle relaxant 
Tolterodine 
Detrol®, Detrusitol® 
Muscle relaxant 
Toremifene 
Fareston® 
Estrogen agonist/antagonist 
Torsemide 
Demadex®, Diuver®, Examide® 
Diuretic 
Trazodone 
Desyrel® (discontinued 6/13), Oleptro®, Beneficat®, 
Deprax®, Desirel®, Molipaxin®, Thombran®, 
Trazorel®, Trialodine®, Trittico®, Mesyrel® 
Antidepressant, SARI 
Trimipramine 
Surmontil®, Rhotrimine®, Stangyl® 
Antidepressant, Tricyclic 
Vandetanib 
Caprelsa® 
Anticancer 
Vardenafil 
Levitra® 
Phosphodiesterase 5 inhibitor 
Vemurafenib 
Zelboraf® 
Kinase inhibitor 
Venlafaxine 
Effexor®, Efexor® 
Antidepressant, SNRI 
Voriconazole 
VFend® 
Antifungal 
Vorinostat 
Zolinza® 
Histone deacetylase inhibitor 
Ziprasidone 
Geodon®, Zeldox® 
Antipsychotic, atypical 
Source: http://www.crediblemeds.org/


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17.2 CAM2038 Administration Sites 
Twenty-six administration sites have been identified for injection of CAM2038. 
 
 CAM2038 q1w must not be administered into a previously injected site for at least 8 
weeks. 
 CAM2038 q4w must not be administered in a site previously injected with CAM2038 
q4w. 
 
The pictorial below will help record the injection site location.  The injection site location will be 
recorded in the EDC. 
 


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17.3 Local Injection Site Tolerability Scale 
 
A 4-point verbal rating scale is employed to assess local tolerability on the following parameters: 
 
1.   Erythema 
 
2.   Swelling 
 
The investigator will assess the degree of erythema and swelling at the injection site at scheduled 
time points during the study using the 4-point rating scale: 
 
Erythema 
 
0 = None (no erythema observed) 
 
1 = Mild (erythema barely perceptible) 
 
2 = Moderate (well-defined erythema) 
 
3 = Severe (from beet redness to slight eschar formation) 
 
Swelling (superficial) 
 
0 = None (no swelling observed) 
 
1 = Mild (swelling barely perceptible; longest diameter < 2 cm) 
 
2 = Moderate (well-defined swelling; longest diameter 2-7 cm) 
 
3 = Severe (well-defined swelling; longest diameter >7 cm)


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17.4 Columbia-Suicide Severity Rating Scale – Baseline/Screening 
 


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17.5 Columbia-Suicide Severity Rating Scale (Since Last Visit) 
 


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17.6 The Subjective Opioid Withdrawal Scale (SOWS) 
 
 
 
PLEASE SCORE EACH OF THE 16 ITEMS BELOW ACCORDING TO
HOW YOU FEEL 
NOW 
 
SYMPTOM
NOT AT ALL
A LITTLE
MODERATELY 
QUITE 
A BIT 
EXTREMELY
1 
I feel anxious 
0 
1 
2 
3 
4 
2 
I feel like yawning 
0 
1 
2 
3 
4 
3 
I am perspiring 
0 
1 
2 
3 
4 
4 
My eyes are teary 
0 
1 
2 
3 
4 
5 
My nose is running 
0 
1 
2 
3 
4 
6 
I have goosebumps 
0 
1 
2 
3 
4 
7 
I am shaking 
0 
1 
2 
3 
4 
8 
I have hot flushes 
0 
1 
2 
3 
4 
9 
I have cold flushes 
0 
1 
2 
3 
4 
10 
My bones and 
muscles ache 
0 
1 
2 
3 
4 
11 
I feel restless 
0 
1 
2 
3 
4 
12 
I feel nauseous 
0 
1 
2 
3 
4 
13 
I feel like vomiting 
0 
1 
2 
3 
4 
14 
My muscles twitch 
0 
1 
2 
3 
4 
15 
I have stomach 
cramps 
0 
1 
2 
3 
4 
16 
I feel like using now 
0 
1 
2 
3 
4 
 
Range 0-64. Handelsman, L., Cochrane, K. J., Aronson, M. J. et al. (1987) 
Two New Rating Scales for Opiate Withdrawal, American Journal of Alcohol Abuse, 13, 293-308.


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17.7 The Clinical Opioid Withdrawal Scale (COWS) 
  
 
 
 

SAP_000.pdf: 
HS-15-549 
Phase II 
A Phase II, Open-label, Partially Randomized, Three Treatment 
Groups, Multi-site Study Assessing Pharmacokinetics after 
Administration of the Once-Weekly and Once-Monthly, Long-
Acting Subcutaneous Injectable Depot of Buprenorphine 
(CAM2038) at Different Injection Sites in Opioid-Dependent 
Subjects with Chronic Pain 
Statistical Analysis Plan (SAP) 
Sponsor 
BRAEBURN PHARMACEUTICALS 
47 Hulfish Street, Suite 441 
Princeton, NJ 08542 
Tel:  (609) 751-5375 
Fax:  (609) 921-2156 
Version 1.00 
16 December, 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-15-549 data. 
 
 
BRAEBURN PHARMACEUTICALS  
 
Sonnie Kim, Pharm.D. 
 
 
 
Dec. 29, 2016 
Print Name 
 
Signature 
 
Date 
 
 
 
 
STATISTICIAN 
 
Michael Chen 
 
 
 
Dec 29, 2016 
Print Name 
 
Signature 
 
Date 


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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 ...................................................................................................................... 6 
4.3 
Study Design ............................................................................................................................... 7 
4.4 
Randomization and Blinding ................................................................................................ 8 
5.0 
ANALYSIS POPULATIONS ...................................................................................................................... 8 
5.1 
Safety Population ...................................................................................................................... 8 
5.2 
Pharmacokinetic population ................................................................................................ 9 
5.3 
evaluable Pharmacokinetic population ............................................................................ 9 
5.4 
Intent-to-Treat 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 
Numerical Rating Scale (NRS) for Pain ........................................................................... 11 
9.2 
Urine Toxicology .................................................................................................................... 11 
9.3 
Interim Analyses .................................................................................................................... 11 
9.4 
Adjustments for Multiplicity .............................................................................................. 11 
9.5 
Power and Sample Size Justification ............................................................................... 12 
10.0 
SUMMARIES OF PHARMACOKINETIC ANALYSIS ........................................................................ 12 
10.1 
Pharmacokinetic parameters ............................................................................................ 12 
10.2 
Handling of values below the LLOQ ................................................................................. 13 
10.3 
Analysis of pharmacokinetics ........................................................................................... 13 
11.0 
SUMMARIES OF MEASURES OF SAFETY ........................................................................................ 14 
11.1 
Extent of Exposure ................................................................................................................. 14 
11.2 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................... 14 
11.3 
Cows and sows ........................................................................................................................ 14 


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11.4 
Adverse Events ........................................................................................................................ 14 
11.5 
Laboratory Assessments ..................................................................................................... 15 
11.6 
Vital Signs ................................................................................................................................. 16 
11.7 
Physical Exam .......................................................................................................................... 16 
11.8 
12-Lead Electrocardiogram (ECG) ................................................................................... 16 
11.9 
injection Site Examination .................................................................................................. 16 
12.0 
IDENTIFICATION AND SUMMARY OF PROTOCOL DEVIATIONS ........................................... 16 
13.0 
DATA QUALITY ASSURANCE ............................................................................................................. 16 
14.0 
REFERENCES ........................................................................................................................................... 17 
15.0 
APPENDICES ........................................................................................................................................... 18 
15.1 
Appendix A - Imputation Algorithm for Partial and Missing Dates ..................... 18 
 


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1.0 
DOCUMENT HISTORY 
Version 
Date  
Changes made since previous version 
0.01 
4 August, 2016 
First draft 
1.00 
16 December, 2016 
Incorporate comments 
 
2.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
AUCss 
Adverse Event 
Area under the plasma concentration-time curve (AUC) during a dosing interval 
at steady state 
BMI 
BPN 
Body Mass Index  
Buprenorphine 
COWS 
Clinical Opioid Withdrawal Scale 
CRF 
Case Report Form (may include electronic data capture systems or paper forms) 
CSR 
Css,av 
Css,max 
Ctrough 
Clinical Study Report 
Average plasma concentration during a dosing interval at steady state 
Maximum observed plasma concentration during a dosing interval at steady state 
Observed plasma concentration prior to next actual or scheduled hypothetical 
dose 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IVRS 
Interactive Voice Response System 
IWRS  
LLOQ 
Interactive Web Response System 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
norBPN 
Milligram 
Norbuprenorphine 
PK 
Pharmacokinetics 
PT 
MedDRA Preferred Term 
SAE  
Serious Adverse Event 
SL BPN 
Sublingual Buprenorphine or Buprenorphine/Naloxone 
SOC 
MedDRA System Organ Class 
SOWS 
Subjective Opioid Withdrawal Scale 
TEAE 
tss,max 
Treatment-Emergent Adverse Event 
Time to Css,max 
VAS 
Visual Analog Scale 
%Fluctuation 
Percent fluctuation during a dosage interval at steady state 
 


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3.0 
INTRODUCTION 
This statistical analysis plan (SAP) is based on Protocol HS-15-549, Amendment 4: 5.0, 05 OCT 2016. 
The purpose of this document is to provide details and clarifications 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 pharmacokinetics (PK), 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.  Deviations from the final approved plan will be noted in the clinical study 
report. 
 
4.0 
STUDY DESCRIPTION 
4.1 
STUDY OBJECTIVES 
Primary objectives of the study are: 
• 
To evaluate the steady state PK of buprenorphine (BPN) and norbuprenorphine (norBPN) 
following repeated subcutaneous (SC) administration of CAM2038 q1w (50 mg/mL) at 4 
different injection sites in adult opioid-dependent subjects with chronic pain. 
• 
To evaluate steady state PK of BPN and norBPN following repeated SC administration of 
CAM2038 q4w (356 mg/mL) with the buttock as the injection site in adult opioid-dependent 
subjects with chronic pain. 
The secondary objective of the study is: 
• 
To evaluate the safety and tolerability of CAM2038 q1w and CAM2038 q4w in adult opioid 
dependent subjects with chronic pain. 
• 
To assess relative bioavailability of BPN at steady state following repeated  SC administration of 
160 mg CAM2038 q4w compared with repeated SL administration of 24 mg BPN in adult 
opioid-dependent subjects with chronic pain 
The exploratory objectives of the study are: 
• 
To evaluate maintenance of treatment efficacy when transferring adult opioid-dependent subjects 
from Sublingual (SL) BPN to CAM2038 q1w and q4w, as determined by urine toxicology. 
• 
To evaluate subject-rated worst daily pain and average daily pain, using an 11-point numerical 
rating scale (NRS), following repeated SC administration of CAM2038 q1w and CAM2038 q4w 
in adult opioid-dependent subjects. 
4.2 
STUDY TREATMENTS  
Within 21 days of a medical Screening visit and confirmation of eligibility, subjects will be randomized 
to 1 of 2 treatment groups (refer to Section 10.2 of the clinical study protocol, Eligibility Review and 
Randomization, for more detail.  Please also note that Group 3 was not randomized.): 
 
• 
Group 1: 3 single weekly SC injections of 32 mg CAM2038 q1w (50 mg/mL) administered in the 
buttock to reach steady state, rotating between right and left buttock sites, followed by 4 single 


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weekly SC injections of 32 mg CAM2038 q1w administered in the buttock (reference), abdomen, 
thigh, and back of upper arm in a randomized, crossover manner, with injection site sequence 
allocated using a randomized crossover design. 
• 
Group 2: 4 monthly SC injections of 128 mg CAM2038 q4w (356 mg/mL) administered in the 
buttock, rotating between right and left buttock injection sites.  
• 
Group 3: 7 daily doses of 24 mg of SL BPN followed by 4 monthly SC injections of 160 mg 
CAM2038 q4w (356 mg/mL) administered in the buttock, rotating between right and left buttock 
injection sites. 
4.3 
STUDY DESIGN 
This is a Phase II, open-label, partially randomized, 3-treatment group, multi-site study designed to 
evaluate the steady state PK of BPN and norBPN following repeated SC administration of CAM2038 
q1w (Group 1) at different injection sites and to evaluate the steady state PK of BPN and norBPN after 
repeated SC administration of CAM2038 q4w (Groups 2 and 3) in opioid-dependent subjects with a 
history of chronic non-cancer pain. The study will involve 4 phases: Screening, Treatment, open label 
safety extension and Follow-up.   
 
Within 21 days of a medical Screening visit and confirmation of eligibility, subjects will be randomized 
to 1 of 2 treatment groups (refer to Section 10.2 of the clinical study protocol, Eligibility Review and 
Randomization, for more detail): 
 
• 
Group 1: 3 single weekly SC injections of 32 mg CAM2038 q1w (50 mg/mL) administered in the 
buttock to reach steady state, rotating between right and left buttock sites, followed by 4 single 
weekly SC injections of 32 mg CAM2038 q1w administered in the buttock (reference), abdomen, 
thigh, and back of upper arm in a randomized, crossover manner, with injection site sequence 
allocated using a randomized crossover design. 
• 
Group 2: 4 monthly SC injections of 128 mg CAM2038 q4w (356 mg/mL) administered in the 
buttock, rotating between right and left buttock injection sites.  
• 
Group 3: 7 daily doses of 24 mg of SL BPN followed by 4 monthly SC injections of 160 mg 
CAM2038 q4w (356 mg/mL) administered in the buttock, rotating between right and left buttock 
injection sites. 
For subjects in Group 1, the first 3 SC injections of CAM2038 q1w will be administered in the buttock, 
rotating between right and left buttock on Day 1, Day 8 and Day 15 in order to achieve steady state PK of 
BPN and norBPN. Subjects will be administered each CAM2038 q1w injection at the clinical research 
unit (CRU) on an outpatient basis. Following the first administration, subjects will attend an interim visit 
on Day 2 to evaluate safety and tolerability of the transition from 24 mg SL BPN (Suboxone or 
equivalent) to CAM2038 q1w. To evaluate steady state PK of BPN and norBPN following CAM2038 
q1w administration at various sites, CAM2038 q1w will be administered at 4 different injection sites, i.e., 
buttock (reference), abdomen, thigh and back of upper arm, on Day 22, Day 29, Day 36 and Day 43, 
using a randomized crossover design. Subjects will be confined to the CRU for 24 hours while serial PK 
samples will be collected. Subsequent PK samples will be collected for up to 168 hours post-dose. At the 
Day 50 (EOT) visit, subjects may continue on with open-label extension phase for up to 6 weeks. At each 
study visit, including the open-label extension phase, safety and efficacy assessments will be conducted at 
pre-specified times. Subjects will also be required to record their worst daily pain and average daily pain 
using an 11-point NRS on an electronic device. 
 


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For subjects in Group 2, SC injections of CAM2038 q4w will be administered in the buttock, rotating 
between right and left buttock, on Day 1, Day 29, Day 57 and Day 85, for a total of 4 doses. Following 
the first administration, subjects will attend an interim visit on Day 2 to evaluate safety and tolerability of 
the transition from 24 to CAM2038 q4w. Following administration of the first 3 doses, PK samples will 
be collected pre-dose and at scheduled times post-dose on an outpatient basis to determine achievement of 
steady state. To characterize steady state PK of BPN and norBPN, subjects will be confined to the CRU 
and serial PK samples will be collected for up to 24 hours following the fourth dose, administered on Day 
85; subsequent PK samples will be collected up to 28 days’ post-dose on an outpatient basis. At each 
study visit, safety and efficacy assessments will be conducted at pre-specified times. At the Day 113 
(EOT) visit, CAM2038 q4w 128 mg subjects may continue on with open-label extension phase for up to 
6 weeks and will be switched to CAM2038 q1w 32 mg. Subjects will also be required to record their 
worst daily pain and average daily pain using an11-point NRS on an electronic device. 
 
For subjects in Group 3 (160 mg CAM2038 q4w), repeated daily doses of 24 mg SL BPN will be 
administered in the morning on Day 1 through Day 7 for a total of 7 doses. This will be followed by SC 
injections of 160 mg CAM2038 q4w in the buttock, rotating between right and left buttock, on Day 8, 
Day 36, Day 64 and Day 92, for a total of 4 doses. Following the first 160 mg CAM2038 q4w 
administration, subjects will attend an interim visit on Day 9 to evaluate safety and tolerability of the 
transition from SL BPN 24 mg to CAM2038 q4w. Following administration of the first 3 doses of 
CAM2038 q4w, PK samples will be collected pre-dose and at scheduled times post-dose on an outpatient 
basis to determine achievement of steady state. To characterize steady state PK of BPN and norBPN and 
evaluate relative bioavailability of buprenorphine after administration of CAM2038 q4w as compared 
with SL BPN, subjects will be confined to the CRU and serial PK samples will be collected for up to 24 
hours following the seventh dose of SL BPN administered on Day 7, and following the fourth dose of 
CAM2038 q4w administered on Day 92. Subsequent PK samples will be collected up to 28 days post-
dose on an outpatient basis. At the Day 127 (EOT) visit, subjects will be transitioned back to standard 
care. At each study visit, safety and efficacy assessments will be conducted at pre-specified times. 
Subjects will also be required to record their worst daily pain and average daily pain using an 11-point 
NRS on an electronic device.  
 
For all Groups, follow-up call will be conducted approximately 7 days after the last study visit of the 
Treatment Phase or open label safety extension phase. 
4.4 
RANDOMIZATION AND BLINDING 
Up to a total of 40 subjects will be randomized at a 3:2 ratio to Group 1 (CAM2038 q1w) or Group 2 
(CAM2038 q4w).  Per Protocol Amendment 05, up to additional 16 subjects will be enrolled to Group 3 
to receive 160 mg CAM2038 q4w.  The study is not blinded. 
At least 20 subjects, and up to 24 subjects, will be randomized to Group 1 and assigned to 1 of the 
following 4 injection site sequences at a 1:1:1:1 ratio: ABDC, BCAD, CDBA, and DACB, where 
A=buttock (reference), B=abdomen, C=thigh, and D=back of upper arm. For Group 2 (CAM2038 q4w), 
approximately 16 subjects will be enrolled.  
5.0 
ANALYSIS POPULATIONS 
5.1 
SAFETY POPULATION 


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The safety population will include all subjects who have received study medication.  Analyses based on 
this population will group subjects according to the treatment they actually received regardless of the 
treatment they are randomized to receive.  All safety analyses will use the safety population. 
5.2 
PHARMACOKINETIC POPULATION  
Pharmacokinetic (PK) population will consist of all subjects in the Safety population who have provided 
PK data.  
5.3 
EVALUABLE PHARMACOKINETIC POPULATION 
Evaluable pharmacokinetic (PKEVAL) population will consist of all subjects in the PK population who 
have provided sufficient PK data for all 4 randomized injection sites to derive PK parameters of interested 
(Group 1), or have provided PK data after the last injections of CAM2038 q4w (Groups 2 and 3). All 
primary PK summaries will be based on the PKEVAL population. 
5.4 
INTENT-TO-TREAT POPULATION 
The efficacy population will be the intent-to-treat population consisting of all subjects that have received 
at least 1 injection of CAM2038 and provided some efficacy measures.  All efficacy summaries will be 
based on the ITT population. 
 
6.0 
GENERAL CONVENTIONS 
Unless otherwise stated, all statistical analyses will be performed using SAS Version 9.2 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 exact method. 
 
Data listings will present all data collected on 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 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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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 the data 
base lock. 
 
7.0 
DESCRIPTION OF THE STUDY POPULATIONS 
All tables, figures, and listings must include a population descriptor (e.g., ITT population, Safety 
Population, PKEVAL Population, or PK Population) in the title. 
7.1 
DISPOSITION 
Subject disposition summaries will be presented by treatment arm and treatment sequence and will 
include the number of subjects randomized, the number and percentage of randomized subjects in the 
Safety, ITT, PKEVAL, and PK 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.   
7.2 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
A summary of demographics and baseline characteristics will be presented by treatment arm and 
treatment sequence for the ITT, Safety, Evaluable PK and PK populations.  The demographic 
characteristics will consist of age, sex, ethnicity, and race using descriptive statistics. 
 
Age will be calculated based on the following conditional algorithm:  
 
• 
Has the subject 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 summaries will include BMI, Psychosocial History. Clinical baseline 
characteristics will summarized by treatment group, sequence, and overall. 
7.3 
MEDICAL HISTORY 
Medical history will be coded using MedDRA dictionary. A medical history listing will be presented.   
 
8.0 
PRIOR AND CONCOMITANT MEDICATIONS 
All medications recorded on the CRFs will be coded using the WHO DRUG Dictionary.  Prior and 
concomitant medications will be summarized by treatment arm in the safety population by anatomical 
therapeutic chemical (ATC) 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 and no more 
than 30 days after the last administration of study treatment. Medications 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 study treatment will be included in 
the prior medications table, and medications that clearly started on or after date of first administration of 


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study treatment 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 
The primary objective of the study is to assess PK profile.  The efficacy evaluation is for exploratory 
purpose only.   
9.1 
NUMERICAL RATING SCALE (NRS) FOR PAIN 
Numerical Rating Scale (NRS) for pain will be used to assess the worst daily and average daily pain.  The 
NRS is an 11-point scale with anchors 0 (no pain) and 10 (worst pain imaginable). Subjects will record 
their Worst and Average Pain Score over the past 24 hours in an electronic diary on a daily basis.   
 
The average of the worst daily pain (AWDP) at a visit will be defined as the average of the non-missing 
worst daily pain score since previous visit; the average of the average daily pain (AADP) at a visit will be 
defined as the average of the non-missing average daily pain score since previous visit.   
 
Changes from baseline in AWDP will be defined as Baseline AWDP – Post-baseline AWDP.  A positive 
change is indicative of improvement.  Similarly, changes from baseline in AADP will be defined as 
Baseline AADP – Post-baseline AADP.  A positive change is indicative of improvement. 
 
Changes from baseline in AADP and in AADP will be summarized over post-baseline visits by treatment 
group based on the subjects who have provided baseline assessments. 
 
AADP and in AADP will be summarized over post-baseline visits by treatment group. 
9.2 
URINE TOXICOLOGY 
The urine toxicology for opioids other than BPN, and other non-opioid drugs of abuse will be measured 
via qualitative methods.  Frequency and incidence of positive urine toxicology results will be summarized 
by treatment group.   
9.3 
INTERIM ANALYSES 
No interim analysis will be performed.  Data for all subjects from Groups 1 and 2 who either completed 
or discontinued prematurely from this open label study will be cleaned and locked.  The data will then be 
analyzed according to the SAP and the results may be presented in a preliminary report.  Regardless of 
the analysis results, no additional subjects will be enrolled into Groups 1 and 2.   
 
Data from subjects in Group 3 will continue to be cumulated after data from subjects in Groups 1 and 2 
are locked.  After all subjects in Group 3 are either completed or discontinued prematurely from this open 
label study, these data will be cleaned and locked.   The final analyses from all data from Groups 1, 2, and 
3 will be performed according to the SAP after Group 3 data are locked.  The formal results of the study 
will be presented in the CSR. 
9.4 
ADJUSTMENTS FOR MULTIPLICITY 
As the efficacy evaluation is for exploratory purpose only, no adjustment for multiple testings will 
be made.     


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9.5 
POWER AND SAMPLE SIZE JUSTIFICATION 
At least 20 subjects, but no more than 24 subjects, will be enrolled to Group 1 (CAM2038 q1w). 
Approximately 16 subjects will be enrolled to each of Group 2 (128 mg CAM2038 q4w) and Group 3 
(160 mg CAM2038 q4w), for a total of approximately 32 subjects administered CAM2038 q4w.. These 
sample sizes are consistent with typical PK studies. Replacement subjects may be added at the discretion 
of the Sponsor with the agreement of the Principal Investigator. 
 
10.0 SUMMARIES OF PHARMACOKINETIC ANALYSIS 
10.1 PHARMACOKINETIC PARAMETERS 
PK parameters of BPN and its active metabolite norBPN will be estimated using Phoenix® WinNonlin® 
(Certara, L.P., 100 Overlook Center, Princeton, NJ 08540 USA), version 6.4 or higher. Standard non-
compartmental methods and actual dates and times of dosing and blood sampling will be used in the 
calculations. The following PK parameters will be determined for BPN and norBPN (if applicable): 
Group 1:  
o AUCss (area under the plasma concentration-time curve during a 7-day dosing interval at 
steady state) for each injection site, i.e., buttock (reference), abdomen, thigh and back of 
upper arm 
o Average plasma concentration during a dosing interval at steady state (Css,av) for each 
injection site, i.e., buttock (reference), abdomen, thigh and back of upper arm  
o Maximum observed plasma concentration during a dosing interval at steady state (Css,max) 
for each injection site, i.e., buttock (reference), abdomen, thigh and back of upper arm  
o Time to Css,max (tss,max) for each injection site, i.e., buttock (reference), abdomen, thigh and 
back of upper arm.  
o Trough concentration Css,trough measured prior to the next actual dose or next scheduled 
hypothetical dose at steady state.  
o norBPN/BPN ratios for AUCss and Css,max for each injection site, i.e., buttock  
(reference), abdomen, thigh and back of upper arm. 
Group 2: 
o AUCss (AUC during a 28-day dosing interval at steady state) 
o Css,av  
o Css,max  
o tss,max  
o Css,trough 
o %Fluctuation 
o norBPN/BPN ratios for AUCss and Css,max 
 
Group 3: 
o AUCss (AUC during a 24-hour (SL BPN) and 28-day (CAM2038 q4w) dosing interval at 
steady state) 
o Css,av  
o Css,max  
o tss,max  
o Css,trough 
o %Fluctuation 
o norBPN/BPN ratios for AUCss and Css,max 
 


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AUCss will be calculated using the linear trapezoidal method up to Css, max and the logarithmic trapezoidal 
method for the remainder of the curve up to 168 hours after dose for CAM2038 q1w, 672 hours after dose 
for CAM2038 q4w and 24 hours after dose for SL BPN. 
 
Css,av will be calculated as AUCss/τ, where τ is the dosing interval (168 hours for CAM2038 q1w,  672 
hours for CAM2038 q4w and 24 hours for SL BPN. 
 
%Fluctuation will be calculated as (Css,max – Css,min)*100/Css,av for CAM2038 q4w and SL BPN, where 
Css,min is the minimum plasma concentration during a dosage interval at steady state (4th dose for 
CAM2038 q4w and 7th dose for SL BPN).    
 
The norBPN/BPN ratios for AUCss and Css,max will be adjusted for differences in molecular weight 
between buprenorphine (molecular weight 467.64 g/mol) and norbuprenorphine (molecular weight 413.55 
g/mol). 
 
Plasma concentration levels of BPN and norBPN assessed prior to next actual or hypothetical dose 
(Ctrough) will be assessed after Dose 1 to 7 in Group 1 and after Dose 1 to 4 for CAM2038 q4w in Groups 
2 and 3.  
 
Unless otherwise stated, PK data will be analyzed by a third party Clinical Research Organization (CRO), 
Worldwide Clinical Trials.  PK results will be produced by the CRO in a separated report.  The PK results 
will also be discussed in the Clinical Study Report (CSR) by reference to the PK report. 
10.2 HANDLING OF VALUES BELOW THE LLOQ 
Plasma concentration values below the limit of quantification (LLOQ) will be assigned a value of zero 
when they preceedprecede the first quantifiable sample. Values below LLOQ embedded between two 
quantifiable data points or occuring after the last quantifiable concentration will be treated as missing 
data.  
10.3 ANALYSIS OF PHARMACOKINETICS 
Summaries of plasma concentrations of BPN and norBPN will be presented for the PKEVAL population 
and PK population by group and injection site, if applicable. The following descriptive statistics will be 
presented at each nominal time point: n, arithmetic mean, standard deviation, and coefficient of variation 
percentage (CV%), median, geometric mean, geometric CV%, minimum and maximum values. Mean 
plasma concentration-time data will be displayed for the PKEVAL population and the PK population in 
linear and semi-logarithmic scales by group and injection site, if applicable. Individual plasma 
concentrations of BPN and norBPN will be listed for the PK population by group. 
 
The PK parameters (Section 10.1) will be listed for the PK population and summarized for the PKEVAL 
population and PK population by group and injection site, if applicable. Summary statistics will include n, 
arithmetic mean, standard deviation, CV%, median, geometric mean, geometric CV%, minimum and 
maximum values. 
 
For Group 1 (CAM2038 50 mg/mL q1w), the following considerations will apply in the PK analyses. The 
primary PK parameters will be AUCss and Css,max after steady state injections of CAM2038 q1w at 
different injection sites. The injection site buttock will be the reference. The analyses will be based on 
log-transformed data. The natural log-transformed AUCss and Css,max data will be analyzed using an 
ANOVA model, sequence, subject within sequence (1, 2, 3, 4 corresponding to A/B/D/C, B/C/A/D, 
C/D/B/A, D/A/C/B, where A=buttock, B=abdomen C=thigh, or D=back of upper arm), period, and 


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treatment sites (treatment sites: A=buttock, B=abdomen C=thigh, or D=back of upper arm). The 
estimated injection site effects, injection site differences versus the reference (B-A, C-A, and D-A), and 
the 90% confidence intervals of the estimated differences will be presented. The above estimates will be 
expressed on the raw scale (expressed after performing the anti-log).  
 
No interim analysis will be performed.  However, after all Groups 1 and 2 subjects either completed the 
study or discontinued from the study prematurely, the above analysis may be performed before subjects 
from Group 3 complete the study or discontinued from the study prematurely.  Before the analysis is 
conducted all data records related to the PK parameters will be locked. Any changes to the records after 
the analysis will be discussed in the CSR.  No additional subjects will be permitted to enter Groups 1 or 2 
after the analysis is conducted. 
 
For Groups 2 and 3 (CAM2038 q4w), the PK parameters will be summarized by descriptive statistics. 
The primary PK parameters will be AUCss and Css,max. Relative bioavailability of BPN will be assessed at 
steady state for 160 mg CAM2038 q4w vs 24 mg SL BPN by ANOVA with 90% confidence intervals 
tabulated for treatment differences (back transformed and expressed as a percentage).  
 
11.0 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, 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. 
11.1 EXTENT OF EXPOSURE 
Summary statistics (number and percentage) of weeks of exposure to study drug (i.e. from date of initial 
injection to the end of the study) will be tabulated by treatment group., 
11.2 COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
Columbia-Suicide Severity Rating Scale (C-SSRS) will be summarized for the Safety Population. 
11.3 COWS AND SOWS 
Clinical Opioid Withdrawal (COWS) Scale, and Subjective Opioid Withdrawal (SOWS) Scale will be 
summarized over time by treatment group. 
11.4 ADVERSE EVENTS 
Each AE and SAE term recorded on the case report forms (CRFs) by primary system organ class (SOC) 
and will be mapped to a preferred term using the MedDRA dictionary.  The investigator will assess AE 
severity and relationship to the study treatment. 
 
A treatment emergent adverse event (TEAE) is defined as any AE with an onset date on or after date of 
randomization (Groups 1 and 2) or first SL BPN dose (Group 3), 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 summary tables.  For the purpose calculating treatment emergence 
and inclusion in summary tables, incomplete onset dates will be imputed as detailed in Appendix A.   


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TEAEs will be summarized by the number and percent of subjects in each primary SOC and preferred 
term.  Subjects 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 
TEAE 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 TEAE within a 
primary SOC category, the subject will be counted only once in that SOC category by using the event 
with the highest intensity. TEAEs by primary SOC, preferred term and relationship to study drug will be 
provided as well. If a subject has more than one TEAE 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 TEAE 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, serious adverse events (SAE) by 
primary SOC and preferred term will be provided. Deaths and SAEs will be summarized similarly to 
AEs. All adverse event tables will also include the total number of events, counting multiple events per 
subject. 
 
Injection related TEAEs, Other (non-injection related) TEAEs as well as all TEAEs will be presented by 
treatment group and overall. Summaries of these TEAE subsets will be presented for the following 
categories: 
 
• 
Study drug related 
• 
Intensity 
• 
Relationship to injection 
• 
Serious 
• 
AEs which led to discontinuation 
• 
SAEs which led to discontinuation 
• 
TEAEs 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. 
 
Other safety analyses will be performed as appropriate. 
11.5 LABORATORY ASSESSMENTS 
Chemistry, Hematology, Urinalysis and Coagulation Profile will be assessed over time (see Section 
10.5.3 of the clinical study 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 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).    
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. 


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For the purpose of determining baseline, the last nonmissing observation on or prior to randomization will 
be used.   
11.6 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).  Vital sign values and change from baseline in the vital 
signs will be summarized for each treatment group. 
11.7 PHYSICAL EXAM 
Number and percent of subjects with abnormal physical exam findings at Screening will be summarized 
by body system for each treatment group and overall. Physical Exam data for each subject will also be 
presented in a listing. 
11.8 12-LEAD ELECTROCARDIOGRAM (ECG) 
12-Lead ECGs will be performed over time. 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 actual 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 to 
<60 msec and greater than/equal to 60 msec will be summarized at each visit and overall at the visits 
where ECG is scheduled). 
 
Buprenorphine plasma concentration vs QT, QTcB and/or QTcF interval relationships will be 
graphicsllygraphically explored. 
11.9 INJECTION SITE EXAMINATION  
All CAM2038 injection sites (new and old) will be examined during each scheduled visit after the first 
dose of CAM2038 for any signs of adverse site reactions, including erythema, pruritus, edema, pain, etc. 
Injection site examination form is included in Appendix 17.3 of the protocol. Subjects will also be 
queried specifically about local tolerability AEs in connection to the examinations. 
 
AEs that believed to be associated with injection procedures will be summarized similarly to the 
summaries for other AEs (not associated with injections). 
 
12.0 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. 
 
13.0 DATA QUALITY ASSURANCE 


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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. 
 
14.0 REFERENCES 
None.


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15.0 APPENDICES 
15.1 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.