Clinical trial NCT02946073
Conditions: Chronic Lower Back Pain Chronic Pain
Sponsor: Braeburn Pharmaceuticals
Start date: 2016-09-01; Completion date: 2019-02-01
Enrollment: 1053 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase III, placebo-controlled, multicenter study with an enriched-enrollment withdrawal (EEW) design to evaluate the efficacy and safety of CAM2038 in opioid-experienced subjects with moderate to severe CLBP that requires continuous, around-the-clock (ATC) opioid treatment ≥ 40 mg morphine equivalent dose (MED). The study includes 5 phases: A Screening Phase (up to 2 weeks), a Transition Phase (up to 2 weeks), an Open-Label Titration Phase (up to 10 weeks), a Double-Blind Treatment Phase including a Final Study Visit (12 weeks), and a Follow-up Phase (4 weeks). The overall duration of participation in the core phase of the study (randomized Double-Blind Phase) is up to 30 weeks, from the Screening Phase through the Follow-up Phase. Subjects who complete the Double-Blind Treatment Study Phase will be offered an opportunity to continue treatment in an open label safety extension for up to 60 weeks. Additional subjects may be recruited to open label safety extension to meet the goal of 100 subjects with 60 weeks of treatment.

Detailed description:

Arms: arm 1: CAM2038 placebo injections arm 2: CAM2038 50 mg/mL q1w at doses of 8 mg, 12 mg, 16 mg, 24 mg, or 32 mg. CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg.
Interventions: intervention 1: buprenorphine intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
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Clinical Trial Protocol 
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A Phase III, Randomized, Double-Blind, Placebo-Controlled, 
Enriched-Enrollment Withdrawal, Multicenter Study to Evaluate the 
Efficacy and Safety of a Long-Acting Subcutaneous Injectable Depot 
of Buprenorphine (CAM2038) in Subjects with Moderate to Severe 
Chronic Low Back Pain Currently Treated with Daily Opioids 
 
IND 127,493 
 
Original Protocol: v1.0, 22-Mar-2016 
Protocol Amendment 1, v2.0, 13-May-2016 
Protocol Amendment 2, v3.0, 29-June-2016 
Protocol Amendment 3, v4.0, 08-Aug-2016 
Protocol Amendment 4, v5.0, 01-Sep-2016 
Protocol Amendment 5, v6.0, 09-Nov-2016 
Protocol Amendment 6, v7.0, 22-Feb-2017 
Protocol Amendment 7, v8.0, 01-May-2017 
Protocol Amendment 8, v9.0, 17-Aug-2017 
Protocol Amendment 9, v10.0, 12-Apr-2018 
 
 
 
 
BRAEBURN PHARMACEUTICALS: 
47 Hulfish Street, Suite 441 
Princeton, NJ 08542 
 
 
 
CONFIDENTIAL 
This protocol administrative change is the property of Braeburn Pharmaceuticals and is intended solely for 
the guidance of the clinical investigation. This protocol administrative change 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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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 
Robert Allen, MD 
rallen@braeburnpharma.com  
610-393-1303 
Sponsor Contact 
Sonnie Kim, PharmD 
sonnie@braeburnpharma.com 
609-751-5375 
Principal Investigator 
Martin Hale, MD 
goldcoast@halemd.com 
954-474-3331 


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2. 
PROTOCOL SYNOPSIS 
 
Name of Sponsor/Company: Braeburn Pharmaceuticals 
Name of Investigational Products: 
CAM2038 6.25 mg/mL (buprenorphine FluidCrystal® once-weekly subcutaneous injection depot)* 
CAM2038 50 mg/mL q1w (buprenorphine FluidCrystal once-weekly subcutaneous injection depot) 
CAM2038 356 mg/mL q4w (buprenorphine FluidCrystal once-monthly subcutaneous injection 
depot) 
* CAM2038 6.25 mg/mL has been interchangeably referred to as CAM2048 during its development. 
The active ingredient is the same as for CAM2038 q1w. It also has the same excipients, as the 
CAM2038 q1w. For the purposes of this protocol, all reference to CAM2048 shall be considered to 
refer to and interchangeable with CAM2038 q1w. 
Name of Active Ingredient: Buprenorphine 
Study Title: 
A Phase III, Randomized, Double-Blind, Placebo-Controlled, Enriched-Enrollment Withdrawal, 
Multicenter Study to Evaluate the Efficacy and Safety of a Long-Acting Subcutaneous Injectable 
Depot of Buprenorphine (CAM2038) in Subjects with Moderate to Severe Chronic Low Back 
Pain Currently Treated with Daily Opioids 
Objectives: 
Primary Objective: 
The primary objective of this study is to evaluate the efficacy of long-acting subcutaneous (SC) 
injectable depots of buprenorphine (BPN) (CAM2038 once-weekly [q1w] and CAM2038 once-
monthly [q4w]) compared to placebo on average pain intensity (API) scores, as measured on an 
11-point, numerical rating scale (NRS-11) in subjects currently taking daily opioids for moderate 
to severe chronic low back pain (CLBP). 
Secondary Objectives: 
The secondary objectives of the study are: 
▪ 
Change from baseline in the weekly average of daily worst pain intensity (WAWPI) 
scores at Week 12 of the Double-Blind Phase based on the NRS-11. 
▪ 
To evaluate the safety and tolerability of treatment with CAM2038 q1w and CAM2038 
q4w in subjects currently taking opioids for moderate to severe CLBP. 
Open Label Safety Extension Objectives 
Primary Objectives of Open Label Safety Extension 
The primary objective of the open label extension phase is: 
 
To evaluate the safety and tolerability of treatment with CAM2038 q1w and CAM2038 
q4w up to 52 weeks in subjects with moderate to severe chronic pain requiring daily 
treatment with opioids. 
Secondary Objectives of Open Label Safety Extension 
The secondary objectives of the open label extension phase are: 
• 
Evaluate the steady-state pharmacokinetics of BPN for CAM2038 q1w and CAM2038 
q4w in subjects with moderate to severe chronic pain requiring daily treatment with 


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opioids 
• 
Evaluate the efficacy and safety of CAM2038 q1w and CAM2038 q4w administration for 
up to 52 weeks in the treatment of subjects with moderate to severe chronic pain requiring 
daily treatment with opioids. 
Methodology: 
This is a Phase III, placebo-controlled, multicenter study with an enriched-enrollment withdrawal 
(EEW) design to evaluate the efficacy and safety of CAM2038 in opioid-experienced subjects 
with moderate to severe CLBP that requires continuous, around-the-clock (ATC) opioid treatment 
≥ 40 mg morphine equivalent dose (MED). The study includes 5 phases: A Screening Phase (up 
to 2 weeks), a Transition Phase (up to 2 weeks), an Open-Label Titration Phase (up to 10 weeks), a 
Double-Blind Treatment Phase including a Final Study Visit (12 weeks), and a Follow-up Phase 
(4 weeks). The overall duration of participation in the core phase of the study (randomized 
Double-Blind Phase) is up to 30 weeks, from the Screening Phase through the Follow-up Phase.  
 
Subjects will record their API at Screening and prior to the test dose on a paper diary at the site. 
Throughout the study, after subjects receive their first CAM2038 injection, they will record their 
WPI and API using the NRS-11 in an electronic diary. Subjects will be instructed to record their 
WPI and API once daily between 18:00 and 23:59 (i.e., 6:00 pm and 11:59 pm). Subjects will be 
instructed to make all attempts to record their pain scores at the same time of day throughout the 
study. In addition, subjects will be instructed to record their pain intensity in the electronic diary 
on the NRS-11 “at that moment” prior to taking rescue medication. Rescue medication use will 
also be recorded in the electronic diary. 
 
Following screening and confirmation of eligibility, subjects will enter a Transition Phase of up 
to 2 weeks during which their current opioid dose will be down-titrated by approximately 25% 
per day to: 
• 
≤80 mg/day MED (for subjects whose opioid dose at screening is > 80 mg/day MED) 
• 
or to ≤40mg/day MED (for subjects whose opioid dose at screening is between 40 
mg/day and 79 mg/day MED). 
 
Following the down titration, subjects will be transitioned to an immediate-release (IR) morphine 
for at least 2 days before they enter the Open-Label Titration Phase, as follows: 
• 
15 mg 4 times daily [QID] for subjects whose MED at screening was ≥ 80 mg/day 
• 
15 mg 3 times daily (TID) for subjects whose MED at screening was 40-79 mg/day. 
 
Subjects who were previously on BPN prior to Screening will not need to participate in the 
morphine IR phase. However, subjects who were previously on BPN will be required to refrain 
from taking BPN for 12-24 hours as a washout prior to starting open label titration on CAM2038. 
 
Following the morphine IR treatment, subjects will enter the Titration Phase. On Day 1 of the 
Titration Phase, subjects will return to the clinic after a washout of at least 12 hours from their last 
morphine IR dose, or 12-24 hours from their last BPN dose. Subjects who report a CLBP of ≥5 on 
the API scale and have a Clinical Opiate Withdrawal Scale (COWS) score of ≥5, will receive a 
BPN test dose (Buprenex®0.30 mg intramuscular [IM] injection) at the clinical site. After the 
Buprenex test dose, subjects will be assessed for any changes in QTcF (Fridericia’s corrected 
QTc) and withdrawal. Subjects who tolerate the BPN test dose, do not show an increase >30 ms in 


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QTcF within 1 hour after the test dose, and have a COWS score of <5 within 15 minutes after the 
test dose will receive the first dose of SC CAM2038 q1w within 4 hours (+30 minutes) after the 
test dose (4 mg CAM2038 for subjects whose screening MED was between 40 mg/day and 79 
mg/day; and 8 mg CAM2038 for subjects whose screening MED was ≥80 mg/day). 
 
During the first week of the Titration Phase, subjects who experience significant pain may, at the 
discretion of the investigator, receive an additional dose at their corresponding CAM2038 q1w 
dosing level (4 mg or 8 mg respectively) on Day 3, 4 or 5. Subjects will then attend clinic visits 
every week for dosage adjustment. Dose adjustments will be made by increasing the dose level of 
CAM2038 q1w at the scheduled weekly visits (doses of 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, or 32 
mg per week). Subjects who require doses >32 mg/week will be discontinued from the study.  
 
Rescue medication, consisting of hydrocodone/acetaminophen 5 mg/325 mg every 4 to 6 hours 
(q4-6h), may be taken during the Titration Phase as needed (prn), up to 15 mg/975 mg/day (3 
tablets) for subjects whose MED at screening was 40-79 mg/day or up to 30 mg/1950 mg/day (6 
tablets) for subjects whose MED at screening was ≥80 mg/day). The goal of the Titration Phase is 
to reach a stable dose of CAM2038 q1w that produces analgesia, by the end of the 10–week 
period.  
 
Eligible subjects will receive CAM2038 titrated to a dose that meets the following criteria: 
• 
Provides analgesia (i.e., 7-day mean API ≤4) 
• 
The API is at least 2 points below the value at the start of CAM2038  titration 
• 
The dose of CAM2038 is well-tolerated for 7 days before randomization (no adverse 
effects that require a change in study dosing or interruption) 
• 
Subject does not require, on average, more than one dose of rescue medication per day 
over the 7 days before randomization. 
 
Subjects who are stabilized and responding to their CAM2038 q1w dose (4, 8, 12, 16, 24, or 32 
mg) at the end of the Titration Phase and who fulfill the pre-defined randomization criteria will be 
randomized to one of two treatment groups in the 12-week Double-Blind Phase: 
• 
Group 1: CAM2038 (q1w or q4w) SC injections 
• 
Group 2: Placebo (q1w or q4w) SC injections 
 
During the Double-Blind Phase, all subjects who are receiving 4, 8 or 12 mg CAM2038 q1w at the 
end of the Titration Phase will be randomized to continue their respective CAM2038 q1w dosing (4 
mg, 8 mg or 12 mg) or matching placebo q1w for a total treatment duration of 12 weeks. Subjects 
who are receiving 16 mg, 24 mg or 32 mg CAM2038 q1w at the end of the Titration Phase will be 
randomized to CAM2038 q4w 64 mg, 96 mg or 128 mg, respectively or to matching placebo q4w 
for a total treatment duration of 12 weeks. 


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Rescue medication, hydrocodone/acetaminophen 5 mg/325 mg q4-6h prn, will be allowed during the 
Double-Blind Phase (up to three tablets or 15 mg/975 mg/day for subjects whose MED at screening 
was between 40-79 mg/day and up to six tablets or 30 mg/1950 mg/day for subjects whose MED at 
screening was ≥80 mg/day). Whenever subjects take rescue medication, they must record their pain 
intensity “at that moment” prior to taking rescue medication in the electronic diary. A Final Study Visit 
will take place 1 week after the last CAM2038/placebo q1w dose or 4 weeks after the last 
CAM2038/placebo q4w dose. 
 
At the Final Study Visit (or early termination), subjects will be transitioned back to standard care or to 
their treatment prior to study entry. Subjects will then be contacted at Follow-up, within 4 weeks after 
the Final Study Visit, to assess adverse events (AE) and concomitant medications. 
 
Open Label Safety Extension 
Subjects who complete the Double-Blind Treatment Study Phase will be offered an opportunity to 
continue treatment in an open label safety extension for up to 60 weeks. Enrollment in the open label 
safety extension will continue until a sufficient number of subjects have been recruited to obtain at least 
52 weeks of safety information in approximately 100 subjects. Subjects who sign the informed consent 
for the safety extension will not be required to participate in the post-Double-Blind follow-up period 
and may proceed directly into the safety extension phase.  
 
Once the required number of subjects for the Double-Blind phase of the trial has been recruited, 
enrollment for the Double-Blind phase will be closed, and remaining subjects offered the opportunity 
to proceed directly to the long-term safety extension without having to participate in a double-blind 
treatment phase. However, to be eligible to proceed to the safety extension, subjects must meet the 
following criteria: 
• 
Have CAM2038 titrated to a dose that provides analgesia (i.e., 7-day mean API ≤4) 
• 
The dose of CAM2038 is well-tolerated for 7 days before randomization (no adverse effects 
that require a change in study dosing or interruption) 
• 
Subject does not require, on average, more than one dose of rescue medication per day over 
the previous 7 days 
The opening of recruitment of subjects for the safety extension is to ensure that a sufficient number of 
subjects are enrolled to provide required long-term safety data to support the clinical development of 
CAM2038 for the indication of chronic pain requiring daily treatment with opioids. 
 
These so called “de novo” subjects may have CLBP or other severe chronic pain disorders (such as 
osteoarthritis) and will not be required to participate in the Double-Blind Phase. The de novo subjects 
will undergo the same screening procedures, down titration, morphine IR, and CAM2038 up-titration 
as required for subjects going through the Double-Blind phase of the study. The CAM2038 dosing 
titration and rescue medication requirements for the safety extension for subjects whose opioid doses 
at screening are ≥ 80 mg/day MED, and 40-79 mg/day MED respectively shall be the same as 
described for the subjects participating in the Double-Blind Randomization phase. 
 
Pharmacokinetics: Subjects in the safety extension will return to the study clinic for their regular 
weekly or monthly CAM2038 injections until the end of the study. Starting at the Month-4 safety 
extension visit (Visit Week 23 for De Novo subjects and Visit Weeks 35-36 for subjects transitioned 


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from randomized Double-Blind Phase), PK sampling for CAM2038 steady state pharmacokinetics will 
be performed on all subjects who provide additional consent for the pharmacokinetic sampling. PK 
sample can be done at any visit timepoint after the subject has stabilized but no later than 4 week prior 
to EOT. Blood samples will be collected prior to administration (within 45 minutes); and at 
approximately 2 hours, 6 hours, 24 hours, 72 hours, 168 hours, 336 hours, and 672 hours post 
administration to measure plasma levels of BPN and norbuprenorphine (norBPN) for subjects 
receiving both CAM2038 qlw and CAM2038 q4w treatments. Actual dates and times of dosing of IMP 
during the safety extension phase as well as blood sampling for PK measurement will be recorded. 
Number of Subjects (Planned): 
Approximately 875 subjects will be screened in order to obtain approximately 340 randomized subjects 
(170 subjects per treatment group) in the core study. The core study comprises two treatment arms: a 
group of approximately 170 subjects receiving SC CAM2038 q1w or CAM2038 q4w and a group of 
approximately 170 subjects receiving SC placebo q1w or q4w. Approximately 85 study sites in the 
United States will be utilized. 
 
Subjects who discontinue prematurely may be replaced at the discretion of the Medical Monitor and 
the Principal Investigator, in order to maintain study power.  Enrollment in the open label safety 
extension will continue until a sufficient number of subjects have been recruited to obtain at least 52 
weeks of exposure safety information in approximately 100 subjects. 
Study Population and Main Criteria for Inclusion (Core or Randomized Double-Blind Phase of the 
Study): 
The study population will consist of adult males and females with moderate to severe CLBP 
currently treated with daily opioids ≥ 40 mg MED. 
Inclusion Criteria: 
1. Written informed consent provided prior to the conduct of any study-related procedures. 
2. Male or non-pregnant, non-lactating female subject, greater than or equal to 18 years old. 
3. Body mass index (BMI) between 18 and 38 kg/m2, inclusive. 
4. Treated with daily opioids for moderate to severe CLBP for a minimum of 3 months prior 
to Screening. 
5. On a stable dose of ≥40 mg/day of oral morphine or MED during the 14 days prior to Screening. 
6. Systolic blood pressure ≥100 mmHg and diastolic blood pressure ≥60 mmHg. 
7. Female subject of childbearing potential who is willing to use a reliable method of contraception 
during the entire study (Screening Visit to final Follow-up). To be considered not of childbearing 
potential, female subjects must be surgically sterile (hysterectomy or bilateral oophorectomy, or 
bilateral tubal ligation with surgery at least 6 weeks before Screening). 
8. Male subject who is willing to use reliable contraception 
9. Willing and able to comply with all study procedures and requirements. 


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Exclusion Criteria: 
1. Positive for hepatitis B surface antigen, hepatitis C viral RNA, or antibodies to 
human immunodeficiency virus (HIV). 
2. Clinically 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 the study, 
including the following: 
a) Severe respiratory insufficiency, respiratory depression, airway obstruction, gastrointestinal 
motility disorders, biliary tract disease, severe hepatic insufficiency, or planned surgery. 
b) Bipolar disorder 
3. Current diagnosis of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition–defined 
moderate to severe substance use disorder (including alcohol), other than caffeine or nicotine. 
4. Female subject planning to become pregnant during the study. 
5. Surgical procedure(s) for CLBP within 6 months prior to Screening. 
6. Concomitant disease(s) that could prolong the QTcF interval, such as autonomic neuropathy (caused 
by diabetes or Parkinson’s disease), HIV, cirrhosis, Long QT Syndrome, or family history of Long 
QT Syndrome. 
7. QTcF >450 ms for males and >470 ms for females, or clinically significant electrocardiogram 
(ECG) abnormality at Screening, at the investigator’s discretion. 
8. Currently taking medications that have the potential to prolong the QTcF interval or may require 
such medications during the course of the study (Appendix 1) and has clinically significant 
abnormalities on screening ECG readings, as determined by the investigator. 
9. A nerve or plexus block, including epidural steroid injections or facet blocks, within 1 month prior 
to Screening or botulinum toxin injection in the lower back region within 3 months of Screening. 
10. History of chemotherapy or confirmed malignancy (except basal cell carcinoma) within the past 
2 years. 
11. Any other acute or chronic pain condition that could interfere with the subject’s ability to report 
their CLBP accurately and consistently and/or interfere with the study staff’s ability to assess the 
subjects CLBP. 
12. An active or pending workman’s compensation, insurance claim, or litigation related to back pain 
(i.e., primary claim is back pain). 
13. Clinically significant history, in the opinion of the investigator, of suicidal ideation or current 
evidence that the subject is actively suicidal. 
14. Clinically significant history of major depressive disorder that is poorly controlled with medication, 
per investigator judgment. 
15. Hypersensitivity or allergy to BPN, other opioids, or excipients of CAM2038. 
16. Hypersensitivity or allergy to acetaminophen. 
17. Use of 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) within the 30 days prior to Screening, 
18. Use or planned use of natural supplements that can affect CYP3A4, such as St. John’s Wort, 
throughout the study. 
19. Has a major bleeding disorder, such as hemophilia, or treated with high levels of anticoagulants per 
the investigator’s discretion. 
20. Current or confirmed past diagnosis of Sphincter of Oddi dysfunction. 
 


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21. Has a significant hepatic disease, as indicated by Screening clinical laboratory assessment results 
(aspartate aminotransferase, alanine aminotransferase, or lactate dehydrogenase values ≥3 × the 
upper limit of normal [ULN]) or has a creatinine value ≥1.5 × ULN). 
22. Is an employee of the investigator or the trial site, with direct involvement in the proposed trial or 
other studies under the direction of the investigator or trial site or is a family member of the 
investigator or of an employee of the investigator. 
23. Has any pending legal action that could prohibit participation or compliance in the study. 
 Criteria for Entry into the Titration Phase: 
1. After at least a 12-hour washout from the last IR morphine dose, subject must have a COWS ≥5 and 
an API pain score over the past 24 hours ≥5 in order to receive a test dose of Buprenex. 
2. Passed all baseline criteria, including a normal QTcF, had no change in QTcF >30 ms at 1 hour after 
the test dose with Buprenex, and had a COWS score <5 after the test dose with Buprenex. 
Note: 
• 
Subjects on BPN at Screening are required to participate in the down titration and will 
undergo a washout period prior to the test dose and first on-study treatment.  Subjects 
entering the study on BPN will not transition to IR Morphine, but will refrain from 
taking their BPN for 12 -24 hours prior to the test dose to achieve the desired washout 
period.       
• 
Subjects on BPN at Screening are still required to follow the same Day 1 procedures 
(e.g., confirmation of pain scores, COWS assessment and Buprenex test dose) as non-
BPN subjects. 
 Criteria for Randomization into the Double-Blind Phase: 
1. Been on a stable dose of CAM2038 q1w for at least 2 consecutive weeks. 
2. CAM2038 titrated to a dose that provides analgesia (i.e., 7-day API score of ≤4 and at least 2 points 
below the value at the start of Titration Phase) and is well tolerated for 7 days before randomization. 
3. Requires no more than an average of one hydrocodone/acetaminophen 5 mg/325 mg/day during the 
last 7 days prior to randomization. 
4. Demonstrated study medication (CAM2038) compliance ≥80% during the previous 14 days. 
5. Demonstrated daily compliance with pain intensity scoring for ≥11 of the previous 14 days, 
including the last 3 days prior to randomization. 
Inclusion Criteria for Open Label Extension 
For Subjects Continuing from The Randomized Double-Blind Phase.  
Subjects must have: 
1. Completed Double Blind Phase of the study 
2. Signed Informed Consent for Safety Extension 
 
Subjects completing the double-blind phase will be enrolled directly into the open label extension at their 
respective dose level of CAM2038. They will not be required to participate in a Buprenex treatment test 
dosing or participate in a titration phase. 
 


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For De Novo Subjects (New Subjects Recruited Directly into The Open Label Extension) 
Subjects who are not participating in the Double-Blind Phase of the Study must meet all of 
the following inclusion criteria in order to be eligible for participation in the study: 
1. Written informed consent provided prior to the conduct of any study-related procedures. 
2. Male or non-pregnant and non-lactating female subject, greater than or equal to 18 years old. 
3. BMI between 18 and 38 kg/m2, inclusive. 
4. Treated with daily opioids for moderate to severe chronic pain disorder such as CLBP or 
osteoarthritis for a minimum of 3 months prior to Screening.  
5. On a stable dose of >40 mg/day of oral morphine or MED during the 14 days 
prior to Screening. 
6. Systolic blood pressure ≥100 mmHg and diastolic blood pressure ≥60 mmHg. 
7. Female subject of childbearing potential who is willing to use a reliable method of 
contraception during the entire study (Screening Visit to final Follow-up). To be 
considered not of childbearing potential, female subjects must be surgically sterile 
(hysterectomy or bilateral oophorectomy, or bilateral tubal ligation with surgery at 
least 6 weeks before Screening). 
8. Male subject who is willing to use reliable contraception  
9. Willing and able to comply with all study procedures and requirements. 
 
Exclusion Criteria for Subjects Continuing from The Randomized 
Double-Blind Phase 
1. Clinically 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 the study. 
Exclusion Criteria for De Novo Subjects only: 
Same exclusion criteria as for subjects participating in the Randomized Double-Blind Treatment Phase.  
Criteria for Entry into the Titration Phase (for De novo subjects): 
1. After at least a 12-hour washout from the last IR morphine dose, subject should have a COWS ≥5 
and an API pain score over the past 24 hours ≥5 in order to receive a test dose of Buprenex. 
2. Passed all baseline criteria, including a normal QTcF, had no change in QTcF >30 ms at 1 hour after 
the test dose with Buprenex, and had a COWS score <5 after the test dose with Buprenex. 
Note: 
• 
Subjects on BPN at Screening are required to participate in the down titration and will undergo 
a washout period prior to the test dose and first on-study treatment.  Subjects entering the study 
on BPN will not transition to IR Morphine, but will refrain from taking their BPN for 12 -24 
hours prior to the test dose to achieve the desired washout period.       


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• 
However, subjects on BPN at Screening are still required to follow the same Day 1 procedures 
(e.g., confirmation of pain scores, COWS assessment and Buprenex test dose) as non-BPN 
subjects. 
 
Criteria for Enrolment into the Open Label Treatment Phase (for de Novo subjects): 
1. Been on a stable dose of CAM2038 q1w for at least 2 consecutive weeks. 
2. CAM2038 titrated to a dose that provides analgesia (i.e., 7-day API score of ≤4 and at least 2 points 
below the value at the start of Titration Phase) and is well tolerated for 7 days before randomization. 
3. Requires no more than an average of one hydrocodone/acetaminophen 5 mg/325 mg/day during the 
last 7 days prior to randomization. 
 
Investigational Product, Dosage, and Mode of Administration: 
CAM2038 in the Titration Phase: 
CAM2038 6.25 mg/mL q1w (BPN FluidCrystal (FC) q1w SC injection depot) at a dose of 4 mg (0.64 
mL). CAM2038 50 mg/mL q1w (BPN FC q1w SC injection depot) at doses of 8 mg, 12 mg, 16 mg, 24 
mg, or 32 mg (0.16, 0.24, 0.32, 0.48, and 0.64 mL). 
 
During the first week of the Titration Phase, subjects may receive one titration dose of 4 or 8 mg 
CAM2038 q1w on Day 1. During the first week of the Titration Phase, subjects who experience 
significant pain may, at the discretion of the investigator, receive a second dose of their CAM2038 on 
Day 3, 4, or 5 (4 mg CAM2038 q1w for subjects whose screening MED was 40-79 mg/day; 8 mg 
CAM2038 q1w for subjects whose screening MED was ≥80 mg/day). 
 
CAM2038 in the Double-Blind Phase and Open Label Extension Phase: 
CAM2038 6.25 mg/mL q1w (BPN FC q1w SC injection depot) at a dose of 4 mg (0.64 mL). 
CAM2038 50 mg/mL q1w (BPN FCq1w SC injection depot) at doses of 8 mg, 12 mg, 16 mg, 24 mg, 
or 32 mg (0.16, 0.24, 0.32, 0.48, and 0.64 mL). 
CAM2038 356 mg/mL q4w (BPN FC q4w SC injection depot) at doses of 64 mg, 96 mg, or 128 mg 
(0.18, 0.27, or 0.36 mL). 
Subjects who are receiving either 4 mg, 8 mg, or 12 mg CAM2038 q1w at the end of the Titration Phase 
will be randomized to continue their respective CAM2038 q1w SC dosing (4 mg, 8 mg, or 12 mg), or to 
corresponding placebo q1w for a total treatment duration of 12 weeks (12 injections in the Double-Blind 
Phase). Subjects who are receiving 16 mg, 24 mg or 32 mg CAM2038 q1w SC at the end of the Titration 
Phase will be randomized to CAM2038 q4w (64 mg, 96 mg or 128 mg, respectively) or to 
corresponding placebo q4w for a total treatment duration of 12 weeks (3 injections in the Double-Blind 
Phase). 
Reference Therapy, Dosage and Mode of Administration: 
 
Placebo in the Double-Blind Phase: 
Subjects randomized to Group 1 who are on 4 mg, 8 mg, or 12 mg CAM2038 q1w after the Titration 
Phase will receive 12 weekly SC CAM2038 placebo injections with matching or near-matching 
volumes to CAM2038 (0.64 mL) or CAM2038 q1w (0.16, 0.24 mL).  Subjects randomized to Group 
2 who are on 16 mg, 24 mg, or 32 mg CAM2038 q1w after the Titration Phase will receive 3 
monthly SC CAM2038 placebo injections with matching or near-matching volumes to CAM2038 


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q4w (0.18, 0.27, or 0.36 mL). 
 
Buprenex Test Dose in the Titration Phase 
On Day 1 of the Titration Phase, subjects will receive a test dose consisting of an IM injection of 
Buprenex 0.30 mg (1.0 mL). 
Rescue Medication in the Titration and Double-Blind Phases and Open Label Extension Phase: 
Oral hydrocodone/acetaminophen, 5 mg/325 mg tablets, q4-6 h prn. The maximum daily dose is 15 
mg/975 mg/day (three tablets) for subjects whose screening MED was 40-79 mg/day or 30 mg/1950 
mg/day (six tablets) for subjects whose screening MED was ≥ 80 mg/day. Subjects cannot take more 
than an average of one rescue tablet per day, in the week prior to randomization. 
Criteria for Evaluation: 
Primary Efficacy Endpoint: 
The primary efficacy endpoint is the change from baseline in WAAPI and the primary timepoint will be 
Week 12 of the Double-Blind Phase.   
 
Secondary Efficacy Endpoints: 
The secondary efficacy endpoints are as follows: 
▪ 
Change from baseline in the WAWPI scores at Week 12 of the Double-Blind Phase, based on 
an NRS-11. 
▪ 
Percentage of subjects with a 30% or greater decrease in API from baseline to Week 12 of the 
Double-Blind Phase. 
▪ 
Rescue medication usage (number of days used and total dose) during the Double-Blind Phase. 
▪ 
Change from baseline to Week 12 of the Double-Blind Phase in EuroQoL Group 5-dimension 
5-level self-report questionnaire (EQ-5D-5L) score. 
▪ 
Change from baseline to Week 12 of the Double-Blind Phase in Work Productivity and Activity 
Impairment (WPAI) score. 
▪ 
Time to loss of efficacy, defined as discontinuation of study drug for lack of efficacy.  
Safety Endpoints: 
• 
Occurrence of AEs throughout the study. 
• 
Concomitant medication usage throughout the study.  
Exploratory Endpoints: 
• 
Change from baseline to Week 12 of the Double-Blind Phase in Clinical Global Impression of
Improvement (CGI-I) scale (as assessed by the Investigator). 
• 
Change from baseline to Week 12 of the Double-Blind Phase in Patient Global Impression of 
Improvement (PGI-I) scale (as assessed by the subject 


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Table of Contents 
Clinical Trial Protocol HS-16-555 ........................................................................................................... 1 
1. 
SPONSOR AND KEY PERSONNEL CONTACT INFORMATION ............................................. 2 
2. 
PROTOCOL SYNOPSIS ................................................................................................................. 3 
Table of Contents.................................................................................................................................... 13 
3. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................... 18 
4. 
INTRODUCTION .......................................................................................................................... 20 
4.1. 
Background .............................................................................................................................. 20 
4.1.1. 
CAM2038 q1w (Once Weekly) .............................................................................................. 20 
4.1.2. 
CAM2038 q4w (Once Monthly) ............................................................................................ 21 
4.1.3. 
Completed CAM2038 Phase 2 and Phase 3 Studies ............................................................ 22 
4.2. 
Study Rationale ........................................................................................................................ 23 
4.3. 
Dose Rationale ......................................................................................................................... 24 
Table 1: Conversion from Daily Morphine to Once Weekly CAM2038 Doses ............................. 24 
Table 2: Conversion from Once Weekly CAM2038 to Once Monthly CAM2038 Dose .............. 25 
Table 3: Opioid Conversion to Morphine Equivalent Dose ............................................................ 25 
4.3.1. 
Rationale for repeat-site injections ....................................................................................... 26 
5. 
STUDY OBJECTIVES .................................................................................................................. 27 
5.1. 
Primary Objective .................................................................................................................... 27 
5.2. 
Secondary Objectives ............................................................................................................... 27 
5.3. 
Open Label Safety Extension Objectives ................................................................................. 27 
5.3.1. 
Primary Objectives of Open Label Safety Extension ......................................................... 27 
5.3.2. 
Secondary Objectives of Open Label Safety Extension ...................................................... 27 
6. 
INVESTIGATIONAL PLAN ......................................................................................................... 28 
6.1. 
Overall Study Design and Plan ................................................................................................ 28 
6.1.1. 
Transition Phase ..................................................................................................................... 28 
6.1.2. 
Open Label Titration Phase .................................................................................................. 29 
6.1.3. 
Double-Blind Phase ................................................................................................................ 29 
Figure 1: Overview of Study Design .................................................................................................. 30 
6.1.4. 
Follow-up Phase for Subjects Not Transitioning to the Open Label Safety Extension 
Phase .............................................................................................................................................. 30 
6.1.5. 
Open Label Safety Extension ................................................................................................ 31 
Figure 2: Overview of Open-Label Extension for Subjects Continuing from Double-Blind Phase 
Study2 ............................................................................................................................................. 32 


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Figure 3: Overview of Open Label Extension for De Novo Subjects ............................................. 33 
6.2. 
Discussion of Study Design ..................................................................................................... 33 
7. 
SELECTION OF STUDY POPULATION .................................................................................... 35 
7.1. 
Inclusion Criteria ...................................................................................................................... 35 
7.2. 
Exclusion Criteria ..................................................................................................................... 35 
7.3. 
Criteria for Entry into the Open-Label Titration Phase ............................................................ 37 
7.4. 
Criteria for Randomization into the Double-Blind Phase ........................................................ 37 
7.5. 
Inclusion and Exclusion Criteria for Open Label Safety Extension (For Subjects Continuing 
from the Randomized Double-Blind Phase) ........................................................................................... 38 
7.5.1. 
Inclusion Criteria for Existing Subjects Entering from The Randomized Double-Blind 
Phase .............................................................................................................................................. 38 
7.5.2. 
Exclusion Criteria for Existing Subjects Entering from The Randomized Double-blind 
Phase .............................................................................................................................................. 38 
7.6 
. Inclusion and Exclusion Criteria for Open Label Safety Extension           (De Novo Subjects)
 
38 
7.6.1. Inclusion Criteria for De Novo Subjects .............................................................................. 38 
7.6.2. Exclusion Criteria for De Novo Subjects ............................................................................. 39 
7.7. 
Removal of Subjects from Therapy or Assessment ................................................................. 39 
8. 
TREATMENTS .............................................................................................................................. 41 
8.1. 
Treatment Administration ........................................................................................................ 41 
8.1.1. Transition Phase (after Screening to test dose/Day 1) ........................................................ 41 
8.1.2. Test Dose (Day 1 of Titration) ............................................................................................... 41 
8.1.3. Titration Phase ....................................................................................................................... 41 
8.1.4. Double-Blind Phase ................................................................................................................ 42 
8.1.6. Rescue Medications ................................................................................................................ 43 
8.1.7. Open Label Safety Extension ................................................................................................ 43 
8.1.7.1. 
Dosing Schedule .................................................................................................................. 44 
8.2. 
Identity of Investigational Product(s) ....................................................................................... 45 
8.2.1. Description of CAM2038 q1w, CAM2038 q4w, and Placebo SC Injection Products ...... 45 
8.2.2. Description of the Buprenex Test Dose ................................................................................ 45 
8.2.3. Description of the IR Morphine ............................................................................................ 45 
8.2.4. Description of the Hydrocodone/Acetaminophen ............................................................... 45 
8.2.5. Handling, Storage, and Accountability ................................................................................ 46 
8.2.6. Dispensing and Administration ............................................................................................ 46 


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8.3. 
Method of Assigning Subjects to Treatment Groups ............................................................... 46 
8.4. 
Selection of Dose ..................................................................................................................... 47 
8.5. 
Selection and Timing of Dose .................................................................................................. 47 
8.6. 
Blinding .................................................................................................................................... 47 
8.7. 
Prior and Concomitant Medications and Therapy .................................................................... 48 
8.8. 
Treatment Compliance and Monitoring Diversion ................................................................... 49 
9. 
STUDY PROCEDURES AND ASSESSMENTS .......................................................................... 50 
Table 5:   Schedule of Assessments for Screening, Transition, and Titration Phases .................. 51 
Table 6:   Schedule of Assessments for Subjects Randomized to Once Weekly Injections .......... 53 
Table 7:   Schedule of Assessments for Subjects Randomized to Once Monthly Injections ........ 55 
Table 8a:   Schedule of Assessments for Subjects Enrolled from the Randomized Double-Blind 
Phase to The Open Label Safety Extension Phase Weekly Dose.............................................. 57 
Table 8b:   Schedule of Assessments for Subjects Enrolled from the Randomized Double-Blind 
Phase to The Open Label Safety Extension Phase Monthly Dose ............................................ 59 
Table 9:   Schedule of Assessments for Screening, Transition, and Titration Phases for De Novo 
Subjects .......................................................................................................................................... 61 
Table 10a:   Schedule of Assessments for De Novo Subjects Enrolled in Open Label Extension 
for Weekly Patients ....................................................................................................................... 63 
Table 10b:   Schedule of Assessments for De Novo Subjects Enrolled in Open Label Extension 
for Monthly Patients ..................................................................................................................... 65 
9.1. 
Demographics and Other Baseline Characteristics .................................................................. 67 
9.1.1. Informed Consent ................................................................................................................... 67 
9.1.2. Demographics ......................................................................................................................... 67 
9.1.3. Medical History ...................................................................................................................... 67 
9.1.4. Medication History ................................................................................................................. 67 
9.1.5. Contraceptive Requirements ................................................................................................. 67 
9.2. 
Eligibility Review and Randomization .................................................................................... 68 
9.3. 
Efficacy Assessments ............................................................................................................... 68 
9.3.1. Numerical Rating Scale (NRS-11) ........................................................................................ 68 
9.3.2. Rescue Medications ................................................................................................................ 68 
9.3.3. EuroQoL Group 5-Dimension 5-Level Self-Report Questionnaire (EQ-5D-5L): 
Descriptive System ........................................................................................................................ 68 
9.3.4. Work Productivity and Activity Impairment (WPAI) ....................................................... 68 
9.3.5. Clinician Global Impression of Improvement (CGI-I) Scale ............................................. 69 


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9.3.6. Patient Global Impression of Improvement (PGI-I) Scale ................................................. 69 
9.4. 
Pharmacokinetic assessments ................................................................................................... 69 
9.5. 
Safety Assessments .................................................................................................................. 69 
9.5.1. Adverse Events and Serious Adverse Events ....................................................................... 69 
9.5.2. Adverse Drug Reaction .......................................................................................................... 70 
9.5.3. Unexpected Adverse Drug Reaction ..................................................................................... 70 
9.5.4. Assessment of Adverse Events by the Investigator ............................................................. 70 
9.5.5. Serious Adverse Event ........................................................................................................... 71 
9.5.6. Serious Adverse Event Reporting – Procedures for Investigators .................................... 72 
9.5.7. Pregnancy ................................................................................................................................ 73 
9.5.8. Expedited Reporting .............................................................................................................. 73 
9.5.9. Clinical Laboratory Assessments .......................................................................................... 73 
Table 11:  Clinical Laboratory Assessments .................................................................................... 74 
9.5.10. 
Vital Signs ........................................................................................................................... 75 
9.5.11. 
12-Lead Electrocardiogram (ECG) .................................................................................. 75 
9.5.12. 
Physical Examination ......................................................................................................... 75 
9.5.13. 
Injection Site Examination ................................................................................................ 75 
9.5.14. 
Treatment Identification Card .......................................................................................... 76 
9.5.15. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ........................................................ 76 
9.5.16. 
Urine Drug Screen .............................................................................................................. 76 
9.5.17. 
Clinical Opiate Withdrawal Scale (COWS) ..................................................................... 76 
9.5.18. 
Subjective Opiate Withdrawal Scale (SOWS) ................................................................. 76 
9.5.19. 
Other Safety Considerations ............................................................................................. 76 
9.6. 
Efficacy and Safety Variables .................................................................................................. 77 
9.6.1. Primary Efficacy Endpoint ................................................................................................... 77 
9.6.2. Secondary Efficacy Endpoints .............................................................................................. 77 
9.6.3. Safety Endpoints ..................................................................................................................... 77 
9.6.4. Exploratory Endpoints .......................................................................................................... 77 
10. 
DATA QUALITY ASSURANCE ........................................................................................... 78 
10.1. 
Data Collection ......................................................................................................................... 78 
10.2. 
Study Auditing and Monitoring ............................................................................................... 78 


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11. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ........................ 79 
11.1. 
Statistical and Analytical Plans ................................................................................................ 79 
11.2. 
Analysis Populations ................................................................................................................ 79 
11.3. 
Planned Analyses ..................................................................................................................... 79 
11.3.1. 
Demographics and Baseline Characteristics .................................................................... 80 
11.3.2. 
Primary Efficacy Analysis ................................................................................................. 80 
11.3.3. 
Missing Value Imputation ................................................................................................. 80 
11.3.4. 
Sensitivity Analysis ............................................................................................................. 80 
11.3.5. 
Analysis of Secondary Efficacy Endpoints ....................................................................... 80 
11.3.6. 
Analysis of Pharmacokinetics ........................................................................................... 81 
11.3.7. 
Analysis of Safety ............................................................................................................... 81 
11.4. 
Determination of Sample Size ................................................................................................. 82 
12. 
STUDY ADMINISTRATION AND INVESTIGATOR RESPONSIBILITIES ..................... 82 
12.1. 
Regulatory and Ethical Considerations .................................................................................... 82 
12.1.1. 
Ethical Conduct of the Study ............................................................................................ 82 
12.1.2. 
Ethics Approval .................................................................................................................. 82 
12.1.3. 
Subject Informed Consent ................................................................................................. 83 
12.2. 
Privacy and Confidentiality ...................................................................................................... 83 
12.3. 
Study and Site Closure ............................................................................................................. 84 
12.4. 
Regulatory Documents and Records Retention ........................................................................ 84 
12.5. 
Delegation of Responsibilities and Adequate Resources ......................................................... 85 
12.6. 
Protocol Amendments .............................................................................................................. 85 
12.7. 
Financial Disclosure ................................................................................................................. 85 
13. 
SPONSOR APPROVAL PAGE .............................................................................................. 86 
14. 
INVESTIGATOR PROTOCOL AGREEMENT PAGE ......................................................... 87 
15. 
REFERENCES ......................................................................................................................... 88 
16. 
APPENDICES .......................................................................................................................... 91 
Appendix 1: Agents Associated with Potential QTcF Interval Prolongation ................................ 91 
Appendix 2: CAM2038 Administration Sites ................................................................................... 99 
 
 
 
 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Definition of Term 
AE 
Adverse event 
API 
Average pain intensity 
ATC 
Around-the-clock 
BMI 
Body mass index 
BPN 
Buprenorphine 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CGI-I 
Clinical Global Impression of Improvement scale 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CLBP 
Chronic low back pain 
CNS 
Central nervous system 
COWS 
Clinical Opiate Withdrawal Scale 
CRF 
Case Report Form (may include electronic data capture systems or paper forms) 
CS 
Clinically significant 
CSA 
Clinical Study Agreement 
Css,av 
Average concentration during a dosage interval at steady state 
Css,trough 
Trough concentration during a dosage interval at steady state 
CYP3A4 
Cytochrome P450 3A4 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EEW 
Enriched-enrollment withdrawal 
EQ-5D-5L 
EuroQoL Group 5-dimension 5-level self-report questionnaire 
FC 
FluidCrystal 
FDA 
Food and Drug Administration 
G 
Gauge 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IFU 
Instructions for user 
IM 
Intramuscular 
IMMPACT 
Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials 
IR 
Immediate-release 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 


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Abbreviation 
Definition of Term 
IV 
Intravenous 
MED 
Morphine equivalent dose 
MMRM 
Mixed Model Repeated Measures 
Ms 
milliseconds 
NCS 
Not clinically significant 
norBPN 
Norbuprenorphine 
NRS-11 
11-Point numerical rating scale 
PGI-I 
Patient Global Impression of Improvement scale 
PK 
Pharmacokinetic 
Prn 
As needed 
q1w 
Once weekly 
q4-6h 
Every 4 to 6 hours 
q4w 
Once monthly 
QID 
Four times daily 
QTcF 
QT interval corrected using Fridericia’s formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SL 
Sublingual 
SOC 
System Organ Class 
SOWS 
Subjective Opiate Withdrawal Scale 
TID 
Three time daily 
ULN 
Upper limit of normal 
US 
United States 
WAAPI 
Weekly Average of (Daily) Average Pain Intensity 
WAWPI 
Weekly Average of (Daily) Worst Pain Intensity 
WHO 
World Health Organization 
WPAI 
Work Productivity and Activity Impairment 
WPI 
Worst pain intensity 


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4. 
INTRODUCTION 
4.1. 
Background 
Opioids are recommended for the management of moderate to severe pain that cannot be well-controlled 
using non-opioid analgesics or other interventions (American Academy of Pain Medicine, 2013; Chou et 
al, 2009). Buprenorphine (BPN) is an opioid with mixed agonist-antagonist properties that is currently 
available in injectable and buccal formulations to treat moderate to severe (acute) pain (e.g., Buprenex) and 
transdermal and buccal formulations to treat chronic pain (e.g., BuTrans® and Belbuca™). 
CAM2038 (buprenorphine FluidCrystal [FC] subcutaneous [SC] injection depot) once weekly (q1w) and 
once monthly (q4w), hereafter referred to as CAM2038 q1w and CAM2038 q4w, respectively, are ready-
to-use, extended-release BPN products with a target of q1w or q4w SC dosing posology, respectively. 
CAM2038 q1w and CAM2038 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 CAM2038 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 from ambient 
temperature prior to administration. In addition, the injection volumes for CAM2038 q1w and q4w are 
relatively low (from 0.15 to 0.64 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 
patient compliance. 
 
4.1.1. 
CAM2038 q1w (Once Weekly) 
SC CAM2038 q1w has so far been investigated after single and repeated doses in 7 clinical trials in 
opioid-dependent subjects and healthy volunteers. An initial Phase 1/2 study assessed pharmacokinetics 
(PK), pharmacodynamics, and safety in opioid-dependent subjects (Study HS-07-307). The results 
showed that CAM2038 q1w was well tolerated, both locally and systemically. Importantly, no treatment-
emergent serious adverse events (SAEs) were observed and drug-related local tolerability findings were 
limited to 4 of 42 subjects (9.5%). Three subjects experienced mild injection site pain and 1 patient 
exhibited transient injection site inflammation (mild) and injection site pruritus (moderate). 
 
Two additional clinical Phase 1 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 sublingual (SL) BPN (i.e., at steady state) and single dose of intravenous (IV) 
BPN (Studies HS-11-426 and HS-13-487). These two 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., 8 mg, 16 mg, or 24 mg doses). 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 products, IV and SL BPN. Local tolerability was very good with no adverse events (AEs) 


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reported in Study HS-11-426 (Nsafety=60) related to injection site tolerability. Similarly, local 
tolerability of CAM2038 q1w was also very good in Study HS-13-487, featuring 4 repeat injections of 
CAM2038 q1w into the buttock site (1 subject reported 1 AE of injection site pain). 
Based on these studies, the following main conclusions were drawn regarding the clinical properties of 
CAM2038 q1w: 
▪ 
Extended BPN release over one week 
▪ 
Dose proportionality and flexible/multiple dosing options 
▪ 
Six- to 8-fold higher bioavailability versus SL BPN 
▪ 
BPN plasma concentrations over 7 days within ranges of those produced by corresponding SL BPN 
doses at steady state (i.e., approved 8 mg, 16 mg or 24 mg doses) 
▪ 
Less peak/trough fluctuation compared to SL BPN 
▪ 
Repeated-dose administration suggest time-independent PK 
▪ 
Good safety and systemic tolerability in subjects 
▪ 
Safety in healthy volunteers comparable to 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. SC administration of CAM2038 q1w has been 
shown to be well tolerated both systemically and locally in the non-clinical studies. The treatment-related 
findings have been limited to clinical observations in agreement with, and considered related to, known 
pharmacological effects of the drug substance BPN, and to reversible, local inflammatory reactions at the 
SC site of injection. The latter findings were similar to the physiological response to a foreign body. The 
FC-related injection site findings appeared to be reversible and self-limiting, and only apparent at the 
immediate vicinity of test article deposition. In summary, non-clinical data have indicated no systemic 
toxicity associated with CAM2038 q1w or the FC injection depot vehicle. 
4.1.2. 
CAM2038 q4w (Once Monthly) 
SC CAM2038 q4w has been investigated in 5 studies, including one bridging clinical Phase 1 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 a 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 
▪ 
Six- to 8-fold higher bioavailability versus SL BPN, comparable to CAM2038 q1w 
▪ 
BPN plasma concentrations over 4 weeks comparable to CAM2038 q1w over one week, and to SL 
BPN over 24 hours at steady state (i.e., for approved 8 mg, 16 mg, or 24 mg doses) 
▪ 
Predicted average concentration during a dosage interval at steady state (Css,av) and trough 
concentration during a dosage interval at steady state (Css,trough) values for CAM2038 q4w similar to 
CAM2038 q1w 
▪ 
Safety profile comparable to IV and SL BPN treatments 
▪ 
Good local tolerability 


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The most commonly reported drug-related AEs after CAM2038 q1w and CAM2038 q4w administration 
in Study HS-13-487 were nausea (63% of subjects), dizziness (54% of subjects), and vomiting (39% of 
subjects). The local tolerability was good, with 9 subjects experiencing 10 AEs that were assessed as 
related to CAM2038 q4w (injection site reactions, injection site pain, injection site induration, and 
application site bruise). Two SAEs were reported by 2 subjects after treatment with 192 mg CAM2038 
q4w. The first SAE was an event of withdrawal reaction and the second SAE was an event of dehydration 
due to nausea and vomiting. Both SAEs were assessed as related to CAM2038 q4w (withdrawal reaction 
was also assessed as related to the concomitant treatment with naltrexone) and the event of withdrawal 
reaction qualified for reporting as a suspected unexpected serious adverse reaction. 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 publicly 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 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. 
4.1.3. 
Completed CAM2038 Phase 2 and Phase 3 Studies 
There are four completed Phase 2 and Phase 3 clinical studies of CAM2038, HS-11-421, HS-13-478, HS-
15-549 and HS-14-499. Please refer to the Investigator’s Brochure for more detailed investigative study 
and safety information. 
 
HS-11-421 (completed) 
This was a randomized, double-blind, double-dummy, active-controlled, parallel group, multicenter study, 
designed to evaluate the non-inferiority of CAM2038 compared to an existing standard of care (SL 
BPN/naloxone [NX]) in initiation and maintenance treatment with BPN in subjects with opioid use 
disorder. The study involved 4 phases: Screening, Phase 1 (weekly visits, for 12 weeks), Phase 2 (monthly 
visits, for 3 months), and Follow-up. 
 
A total of 428 subjects were randomized in the study, whereof 213 subjects were treated with CAM2038 
and 215 subjects with SL BPN/NX. The study has been completed with no significant unusual or 
unexpected safety signals or concerns reported. 
 
HS-15-549 (completed) 
This was a Phase 2, open-label, partially randomized, 3-treatment group study designed to evaluate the 
steady state PK of BPN and norbuprenorphine (norBPN) following multiple weekly SC administrations of 
CAM2038 q1w at different injection sites (Group 1), following multiple monthly SC administrations of 
CAM2038 q4w (Group 2) in opioid-dependent subjects with a history of chronic non-cancer pain and 
following multiple monthly SC administrations of CAM2038 q4w (Group 3) in opioid-dependent subjects 
with a history of chronic non-cancer pain who were currently taking 24 mg of SL BPN daily. The trial 
involved up to 4 phases: Screening, Treatment, Follow- up and Open Label Safety Extension. 
Approximately 55 subjects were to be enrolled. The study has been completed and there were no unusual 
safety signals or concerns identified. 
 
HS-13-478 (completed) 


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This was a Phase 2 multi-site, randomized, double-blind, repeat-dose Phase 2 study to evaluate the degree 
and duration of action of multiple doses of CAM2038 q1w in blocking the effects of a mu opioid receptor 
agonist (hydromorphone) in subjects with moderate or severe opioid use disorder. The study involved 4 
phases: Screening, Qualification, Treatment, and Follow-up. In the treatment Phase, subjects received one 
of the following treatments (based on a randomization in a 1:1 ratio, stratified by gender and blinded): 
Group A received CAM2038 q1w 24 mg SC injection (22 subjects) and Group B received CAM2038 q1w 
32 mg SC injection (25 subjects). 
Each of the Hydromorphone Challenge Sessions in the Qualification Phase and Treatment Phase consisted 
of the injection of 3 doses of IM hydromorphone (0 mg [placebo], 6 mg and 18 mg) administered once 
daily over 3 consecutive days in randomized blinded order. Subjects were randomized in a 1:1:1:1:1:1 ratio 
to 1 of 6 treatment sequences according to two 3 × 3 William squares. 
 
HS-14-499 (completed) 
This was a Phase 3, open-label, multicenter, 12-month (48-week) safety study in subjects with opioid use 
disorder, consistent with standard practice for long-term safety studies. This safety study utilized 
CAM2038 q1w and CAM2038 q4w and had 3 phases: Screening, Treatment, and Follow-up. The trial is 
completed and ended when at least 100 subjects have been exposed to CAM2038 for 48 weeks.  There 
were no unusual safety signals or concerns identified in the study.  
4.2. 
Study Rationale 
Chronic low back pain (CLBP) is a significant cause of pain and disability costs worldwide (Volinn et al, 
2009; Vos et al, 2012). While most subjects with CLBP show significant improvements within 3 months, a 
proportion of subjects experience persistent pain (≥3 months) and may have limited quality of life and 
physical function (Shekelle et al, 1995; Thomas et al, 1999). Management of CLBP may be achieved 
through several modalities, including opioid pharmacotherapy. Despite their proven efficacy, the use of 
opioids is often limited due to concerns regarding safety and tolerability and concerns pertaining to drug 
abuse and diversion that may arise with long-term therapy for treatment of persistent pain. However, for 
many subjects with CLBP, opioid therapy may be the only effective treatment.  BPN is an effective 
analgesic with a potency 25 to 50 times that of morphine (Jasinski et al, 1978; Cowan et al, 1977). Dose-
dependent analgesia has been observed with intramuscular (IM) doses up to 10 mg. Respiratory depression 
is minimized due to the well-characterized ceiling effect at higher doses (Hans and Robert, 2009). 
Clinically, there is also a less marked effect of BPN on gastrointestinal transit times, with a lower 
incidence of constipation relative to full mu-opioid receptor agonists (Mercadente, 2009). In addition, the 
slow dissociation of BPN from receptors results in a long duration of effect and minimizes withdrawal 
symptoms upon discontinuation (Sittl et al, 2005). Transdermal BPN has proven effective in subjects with 
chronic cancer and non-cancer pain, with a reduction in the need for additional oral analgesics and 
improved quality of life (Mercadente, 2009; Dahan et al, 2005; and Griessinger et al, 2005). 
 
A number of treatment goals have been proposed for improved patient therapy, many of which are based 
on World Health Organization (WHO) recommendations, including providing a stable plasma drug 
concentration to ensure long lasting and effective pain relief, formulations that provide a long duration of 
action, and an improved quality of life. By using the transdermal formulation of BPN, the rate of drug 
delivery can be controlled and stable plasma concentrations achieved. However, transdermal BPN 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 (Tompkins et al, 2014; 
Belbuca™ Prescribing Information, October 2015). Transdermal systems may also be accidently 
ingested, particularly by children. Traditional opioid therapies intended for the treatment of chronic pain 
(e.g., modified or extended-release formulations of full µ-opioid receptor agonists such as morphine, 


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oxycodone, hydrocodone, and hydromorphone) are even more subject to diversion and abuse, resulting in 
significant public health concerns (Sittl et al, 2005 and Likar et al, 2003). 
 
The sustained and stable BPN plasma concentration associated with administration of CAM2038 q1w and 
q4w may provide an ideal treatment modality for many CLBP subjects. The PK profile of CAM2038 q1w 
indicates that a rapid and long-acting release of BPN should lead to rapid and smooth onset of action, in 
combination with a prolonged and stable treatment effect for at least 7 days following a single dose of 
CAM2038 q1w or up to 4 weeks following a single dose of CAM2038 q4w. Thus, the PK profiles of 
CAM2038 q1w may help to improve tolerability during initiation of treatment. Like transdermal 
formulations, CAM2038 may also be suitable for those subjects with difficulty swallowing. 
The profiles of CAM2038 provide an alternative to existing oral opioid medications, with the potential 
added benefit of obtaining consistent and stable plasma levels of BPN. This profile removes the need to 
take daily medications and helps to prevent diversion and accidental pediatric exposures, which continue 
to be important public health goals of the Food and Drug Administration (FDA) and Center for Disease 
Control and Prevention (Frieden and Houry, 2016). Furthermore, the route of administration (i.e., depot 
injection) of CAM2038 may reduce the risks of diversion and abuse, even when compared to transdermal 
opioid formulations. 
While the efficacy of transdermal and transmucosal BPN in managing pain and improving function has 
previously been demonstrated in subjects with CLBP (Salinas et al, 2012; Rauck et al, 2016), the 
anesthetic efficacy of BPN administered as CAM2038 q1w or CAM2038 q4w SC injections has not yet 
been evaluated. The present study will be conducted to evaluate the efficacy and safety of CAM2038 
compared to placebo in subjects with moderate to severe CLBP over a period of 12 weeks during the 
Double-Blind Phase. In addition, the safety of CAM2038 will be evaluated from the Open-Label Titration 
Phase and throughout the Open Label Safety Extension Phase. 
4.3. 
Dose Rationale 
The 4-mg weekly starting dose of CAM2038 q1w correspond to a daily morphine equivalent dose (MED) 
of 28.5 mg, using a more conservative conversion factor of 50 from BPN to morphine; thus, representing 
safe and suitable starting doses for subjects receiving ≥30 mg of morphine daily. In this study, subjects 
will be titrated to effect. An indicative a priori transition from daily morphine dose to weekly CAM2038 
doses and monthly CAM2038 dose is given in Table 1 and Table 2 below, respectively: 
 
Table 1: Conversion from Daily Morphine to Once Weekly CAM2038 Doses 
 
Daily Morphine Dose (mg) 
Daily Titration Morphine 
Dose, 75 % (mg) 
Starting Once Weekly Dose 
40 to <80 
30 to 60 
4 mg CAM2038 
80 to 120 
60 to 90 
8 mg CAM2038 
>120 to 160 
90 to 120 
16 mg CAM2038 
>160 to 320 
120 to 240 
24 mg CAM2038 
>320 
>240 
32 mg CAM2038 


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Table 2: Conversion from Once Weekly CAM2038 to Once Monthly CAM2038 Dose 
 
Once Weekly Dose 
Corresponding Once Monthly CAM2038 Dose 
4 mg CAM2038 
No corresponding monthly dose. Subjects will be kept on 
CAM2038 once weekly. 
8 mg CAM2038 
No corresponding monthly dose. Subjects will be kept on 
CAM2038 once weekly. 
12 mg CAM2038 
No corresponding monthly dose. Subjects will be kept on 
CAM2038 once weekly. 
16 mg CAM2038 
64 mg CAM2038 
24 mg CAM2038 
96 mg CAM2038 
32 mg CAM2038 
128 mg CAM2038 
 
The MED will be calculated using the conversion factor for each opioid as described in Table 3 
(McPherson, 2009). Subjects taking methadone are allowed to screen; however, the down titration process 
should be discussed with the Medical Monitor. 
Table 3: Opioid Conversion to Morphine Equivalent Dose 
 
Equianalgesic Opioid Dosing 
Drug 
Equianalgesic Doses (mg) 
Parenteral 
Oral 
Sublingual 
Sublingual Buprenorphine 
NA 
NA 
1.5 
Belbuca™ buccal film 
NA 
0.3 
NA 
Morphine 
10 
30 
NA 
Codeine 
100 
200 
NA 
Hydrocodone 
NA 
30 
NA 
Hydromorphone 
1.5 
7.5 
NA 
Meperidine 
100 
300 
NA 
Oxycodone 
10* 
20 
NA 
Oxymorphone 
1 
10 
NA 
Tramadol 
100* 
120 
NA 
 
 
Morphine (PO) 
Equivalents 
 
*Fentanyl Patch 25mcg/hr (One 
patch q3 days)  
NA 
60 mg / d 
NA 
Butrans patch 10mcg/hr  
(One patch q week) 
NA 
80 mg / d 
NA 
*Methadone 20 mg PO qd 
NA 
   40 mg / d 
NA 
* Contact Medical Monitor to discuss 


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4.3.1. 
Rationale for repeat-site injections 
A 9-month study in beagle dogs has been conducted to characterize the chronic systemic toxicity of 
CAM2038 q1w and CAM2038 q4w SC administration in beagle dogs. Assessments included evaluation of 
local injection site tolerability and toxicokinetic evaluation at steady-state. Corresponding vehicle placebos 
and saline were used as controls. A total of 8 injection sites on the back were used. Injection sites were 
rotated as follows: 
• 
For the q1w: CAM2038 q1w (32 mg/injection), vehicle placebo and saline injections were 
administered once every week. The injection sites were rotated so that each site was re-used once 
every eighth week over the course of the study. 
• 
For the q4w: CAM2038 q4w (128, 160 or 192 mg/injection), vehicle placebo and saline. Injections 
were administered once every 4 weeks. The injection sites were rotated so that each site was used 
once, except for the last three-monthly injections which were all administered at one site. 
 
The beagle dogs tolerated 39 weekly SC doses of CAM2038 q1w drug product at 32 mg/dose or the 
CAM2038 q1w placebo control, or 10 doses given once every 4-weeks of CAM2038 q4w drug products at 
128, 160, or 192 mg/dose or the CAM2038 q4w placebo control. The CAM2038 drug products and 
placebo controls had no discernible effect on dermal irritation (erythema, or eschar), overall food 
consumption, ophthalmologic parameters, clinical pathology endpoints (hematology, coagulation, clinical 
chemistry, and urinalysis), or organ weights. 
 
Injection site reactions were limited to the presence of Grade 1 edema/swelling, which was considered to 
represent the injection depot matrix (IDM). Most animals given the BPN-containing CAM2038 drug 
product formulations or the corresponding placebo controls had Grade 1 (“very slight”) IDM at the sites of 
injection following dosing. There were no observed differences noted between the sites dosed with BPN-
containing CAM2038 drug products and placebo controls. 
 
Additionally, there was no apparent increase in the severity of IDM swelling with repeated injections at the 
same injection site. Discernable swelling associated with the IDM generally resolved between 60 and 144 
days after dosing administration. 
 
This study demonstrated that repeat injections could be safely performed at the same site every 4 weeks 
with the highest volumes and doses of CAM2038, without any associated deleterious effects. 


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5. 
STUDY OBJECTIVES 
 
5.1. 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of long-acting SC injectable depots of BPN 
(CAM2038 once-weekly [q1w] and CAM2038 once- monthly [q4w]) compared to placebo on average 
pain intensity (API) scores, as measured on an 11-point, numerical rating scale (NRS-11) in subjects 
currently taking daily opioids for moderate to severe CLBP. 
 
5.2. 
Secondary Objectives 
The secondary objectives of the study are: 
▪ Change from baseline in the weekly average of daily worst pain intensity (WAWPI) scores at 
Week 12 of the Double-Blind Phase based on the NRS-11. 
▪ To evaluate the safety and tolerability of treatment with CAM2038 q1w and CAM2038 q4w in 
subjects currently taking opioids for moderate to severe CLBP. 
 
5.3. 
Open Label Safety Extension Objectives 
5.3.1. Primary Objectives of Open Label Safety Extension 
The primary objective of the open label extension phase is: 
 
To evaluate the safety and tolerability of treatment with CAM2038 q1w and CAM2038 q4w up to 
52 weeks in subjects with moderate to severe chronic pain requiring daily treatment with opioids. 
 
5.3.2. Secondary Objectives of Open Label Safety Extension 
The secondary objectives of the open label extension phase are: 
 
Evaluate the steady-state PK of BPN for CAM2038 q1w and CAM2038 q4w in subjects with 
moderate to severe chronic pain requiring daily treatment with opioids 
 
Evaluate the efficacy and safety of CAM2038 q1w and CAM2038 q4w administration for up to 52 
weeks in the treatment of subjects with moderate to severe chronic pain requiring daily treatment 
with opioids.


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6. 
INVESTIGATIONAL PLAN 
 
6.1. 
Overall Study Design and Plan 
This is a Phase III, placebo-controlled, multicenter study with an enriched-enrollment withdrawal (EEW) 
design to evaluate the efficacy and safety of CAM2038 in opioid-experienced subjects with moderate to 
severe CLBP that requires continuous, around-the-clock (ATC) opioid treatment ≥ 40 mg MED. An 
overview of the study design is provided in Figure 1. The study includes 5 phases: A Screening Phase (up 
to 2 weeks), a Transition Phase (up to 2 weeks), an Open Label Titration Phase (up to 10 weeks), a Double-
Blind Treatment Phase including a Final Study Visit (12 weeks), and a Follow-up Phase (4 weeks) The 
overall duration of participation of the core phase is up to 30 weeks, from the Screening Phase through the 
Follow-up Phase. Subjects who complete the Double-Blind Treatment Phase will be offered the 
opportunity to continue treatment in an Open Label Safety Extension Phase for up to 60 weeks. In 
addition, so called “de novo” subjects may be enrolled in the Open Label Safety Extension Phase. These 
subjects may proceed directly from the Open Label Titration Phase to the Open Label Safety Extension 
Phase without participating in the Double-Blind Treatment Phase.  
Subjects will record their API at Screening and prior to the test dose on a paper diary at the site. 
Throughout the study, after subjects receive their first CAM2038 injection, they will record their WPI and 
API using the NRS-11 in an electronic diary. Subjects will be instructed to record their WPI and API once 
daily between 18:00 and 23:59 (i.e., 6:00 pm and 11:59 pm). Subjects will be instructed to make all 
attempts to record their pain scores at the same time of day throughout the study. In addition, subjects will 
be instructed to record their pain intensity in the electronic diary on the NRS-11 “at that moment” prior to 
taking rescue medication. Rescue medication use will also be recorded in the electronic diary. 
Table 5, Table 6, and Table 7 provide additional information on the baseline, efficacy, and safety 
assessments included in the study. Efficacy endpoints and statistical analyses are described further in 
Section 9.6 and Section 11.3, respectively. 
 
6.1.1. Transition Phase 
Following Screening and confirmation of eligibility, subjects will enter a Transition Phase of up to 2 
weeks during which their current opioid dose will be down-titrated by approximately 25% per day to: 
• 
≤80 mg/day MED (for subjects whose opioid dose at screening is > 80 mg MED)  
• 
or to ≤40 mg/day MED (for subjects whose opioid dose at screening is between 40-79 mg/day 
MED).  
Following the down titration, subjects will be transitioned to an immediate-release (IR) morphine for at 
least 2 days before they enter the Open-Label Titration Phase, as follows: 
• 
15 mg 4 times daily [QID] for subjects whose screening MED was ≥80 mg/day 
• 
15 mg 3 times daily [TID] for subjects whose screening MED was 40-79 mg/day. 
 
Subjects who were previously on BPN prior to Screening will not need to participate in the morphine IR 
phase. However, subjects who were previously on BPN will be required to refrain from taking BPN for 


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12-24 hours as a washout prior to starting open label titration on CAM2038. 
 
6.1.2. Open Label Titration Phase 
Following the morphine IR treatment, subjects will enter the Titration Phase.  On Day 1 of the Titration 
Phase, subjects will return to the clinic after a washout of at least a 12-hour from their last morphine IR 
dose, or 12-24 hours from their last BPN dose. Subjects who report a CLBP of ≥5 on the API scale and 
have a Clinical Opiate Withdrawal Scale (COWS) score of ≥5, will receive a BPN test dose (Buprenex 
0.30 mg IM injection) at the clinical site. After the Buprenex test dose, subjects will be assessed for any 
changes in QTcF (Fridericia’s corrected QTc) and withdrawal. Subjects who tolerate the BPN test dose, do 
not show an increase >30 ms in QTcF within 1 hour after the test dose, and have a COWS score of <5 
within 15 minutes after the test dose will receive the first dose of SC CAM2038 q1w within 4 hours (+30 
minutes) after the test dose (4 mg CAM2038 for subjects whose screening MED was between 40 mg/day 
and 79 mg/day; and 8 mg CAM2038 for subjects whose screening MED was ≥80 mg/day). 
During the first week of the Titration Phase, subjects who experience significant pain may, at the 
discretion of the investigator, receive an additional 4 mg (for subjects whose screening MED was 40-79 
mg/day) or 8 mg CAM2038 (for subjects whose screening MED was ≥80 mg/day), on Day 3, 4 or 5. Dose 
adjustments will be made by increasing or decreasing the dose level of CAM2038 q1w at the scheduled 
weekly visits (doses of 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, or 32 mg per week). Subjects who require doses 
>32 mg/week will be discontinued from the study. 
Rescue medication, consisting of hydrocodone/acetaminophen 5 mg/325 mg every 4 to 6 hours (q4-6h), 
may be taken as needed (prn) up to 15 mg/975 mg/day (three tablets) for subjects whose screening opioid 
dose was between 40 and 79 mg/day MED or 30 mg/1950 mg/day (six tablets) for subjects whose 
screening opioid dose was ≥80 mg/day MED. The goal of the Titration Phase is to achieve a stable dose of 
CAM2038 q1w that produces analgesia, by the end of the 10–week period.  
Eligible subjects will receive CAM2038 titrated to a dose that meets the following criteria (see also 
Section 7.4): 
• 
Provides analgesia (i.e., 7-day mean API ≤4) 
• 
The API is at least 2 points below the value at the start of CAM2038 titration 
• 
The dose of CAM2038 is well-tolerated for 7 days before randomization (no adverse effects that 
require a change in study dosing or interruption) 
• 
Subject does not require, on average, more than one dose of rescue medication per day over the 7 
days before randomization 
 
6.1.3. Double-Blind Phase 
Subjects who are stabilized and responding to their CAM2038 q1w dose (4, 8, 12, 16, 24, or 32 mg/week) 
at the end of the Titration Phase and who fulfill the pre-defined randomization criteria will be randomized 
to one of two treatment groups in the 12-week Double-Blind Phase: 
▪ Group 1: CAM2038 q1w or CAM2038 q4w SC injections 
▪ Group 2: placebo q1w or placebo q4w SC injections 


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During the Double-Blind Phase, all subjects who are receiving 4, 8 or 12 mg CAM2038 q1w at the end of 
the Titration Phase will be randomized to continue their respective CAM2038 q1w dosing of 4 mg, 8 mg 
or 12 mg CAM2038, or to matching placebo q1w for a total treatment duration of 12 weeks. Subjects who 
are receiving 16 mg, 24 mg or 32 mg CAM2038 q1w at the end of the Titration Phase will be randomized 
to CAM2038 q4w (64 mg, 96 mg or 128 mg, respectively) or to matching placebo q4w for a total 
treatment duration of 12 weeks. 
 
Figure 1: Overview of Study Design 
 
1One booster is allowed on Day 3-5 after the first CAM2038, 4 or 8 mg injection. If booster is taken, the next dose on week 2 will 
be 8 or 12 mg, otherwise stay at 8 mg. Then titration is weekly up to 10 weeks. Final Study Visit is 1 week after the last CAM2038 
q1w dose for q1w subjects and 4 weeks after the last q4w dose for q4w subjects. Follow-up is within 4 weeks after the Final study 
visit. 
IR = immediate release; MED=morphine equivalent dose; q1w=once weekly; q4w=once monthly; R= randomization. There will 
be a Final Study Visit or Early Termination and one Follow-up Call. 
 
Rescue medication, hydrocodone/acetaminophen 5 mg/325 mg q4-6h prn, will be allowed during the 
Double-Blind Phase (up to three tablets or 15 mg/975 mg/day for subjects whose MED at screening was 
between 40-79 mg/day and up to six tablets or 30 mg/1950 mg/day for subjects whose MED at screening 
was ≥80 mg/day).Whenever subjects take rescue medication, they must record their pain intensity “at that 
moment” prior to taking rescue medication in the electronic diary. 
 
6.1.4. Follow-up Phase for Subjects Not Transitioning to the Open Label Safety Extension 
Phase 
A Final Study Visit will take place 1 week after the last CAM2038/placebo q1w dose or 4 weeks after the 
last CAM2038/placebo q4w dose. At the Final Study Visit (or early termination), subjects will be 
transitioned back to standard care or to their treatment prior to study entry. Subjects will then be contacted 


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at Follow-up, within 4 weeks after the Final Study Visit, to assess AEs and concomitant medications. 
 
Subjects transitioning from the Randomized Double-Blind Phase to the Open Label Safety Extension 
Phase are encouraged to do so at the Final Study Visit of the randomized Double-Blind Phase or as soon as 
possible thereafter. 
 
6.1.5. Open Label Safety Extension  
Subjects who complete the Double-Blind Phase will be offered the opportunity to continue treatment in an 
open label safety extension for a total duration of up to 60 weeks. Subjects who consent to the Open Label 
Extension will not be required to participate in the post-double-blind Follow-up Phase but will be 
transitioned at their Final Study Visit or as soon as possible thereafter, to open label active treatment, in 
the Open Label Extension. With the Open Label Safety Extension Phase, total duration of exposure to 
CAM2038 is up to 60 weeks. Enrollment in the Open Label Safety Extension Phase will continue until a 
sufficient number of subjects have been recruited to obtain at least 52 weeks of safety information in 
approximately 100 subjects. Due to the double-blind design, all subjects will need to receive at least 1 
week of CAM2038 q1w before proceeding to the Open Label Safety Extension Phase.  
 
Subjects completing the Double-Blind Phase on 4 mg, 8 mg or 12 mg CAM2038/placebo q1w will 
continue on the same dose of active treatment (open-label CAM2038) without need for titration. Subjects 
completing the Double-Blind Phase on 64 mg, 96 mg or 128mg CAM2038/placebo q4w will begin open-
label treatment at the corresponding equivalent weekly dose last received by the subject prior to transition 
to the monthly dosing regimen. The subject may transition to monthly dosing upon return to the clinic in 1 
week following the initial dose. At the Investigator’s discretion, the transition period may be extended or 
the patient down-titrated, in case of poor tolerability. The subjects will continue in the Open Label Safety 
Extension Phase until the total exposure to CAM2038 (including the Titration and Double-Blind Phases) is 
at least 52 weeks.  
 
Once the required number of subjects for the Double-Blind phase of the trial has been recruited, 
enrollment for the Double-Blind phase will be closed, and remaining subjects offered the opportunity to 
proceed directly to the long-term safety extension without having to participate in a double-blind treatment 
phase. However, to be eligible to proceed to the safety extension, subjects must meet the following 
criteria: 
• 
Have CAM2038 titrated to a dose that provides analgesia (i.e., 7-day mean API ≤4) 
• 
The dose of CAM2038 is well-tolerated for 7 days before randomization (no adverse effects that 
require a change in study dosing or interruption) 
• 
Subject does not require, on average, more than one dose of rescue medication per day over the 
previous 7 days 
The opening of recruitment of subjects for the safety extension is to ensure that a sufficient number of 
subjects are enrolled to provide required long-term safety data to support the clinical development of 
CAM2038 for the indication of chronic pain requiring daily treatment with opioids. 
 
These so called “de novo” subjects may have CLBP or other severe chronic pain disorders (such as 
osteoarthritis) and will not be required to participate in the Double-Blind Phase. The de novo subjects will 
undergo the same screening procedures, down titration, morphine IR and CAM2038 up-titration as 
required for subjects going through the Double-Blind Phase of the study. The CAM2038 dosing titration 
and rescue medication requirements for the safety extension for subjects whose opioid doses at screening 


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are > 80 mg/day MED, and 40-79 mg/day MED, respectively, shall be the same as described for the 
subjects participating in the Double-Blind Phase. De novo subjects may also be subjects who have 
completed the core study more than 28 days ago or newly identified subjects with a chronic pain indication 
treated with daily opioids. 
 
Subjects in the Open Label Safety Extension Phase will return to the study clinic for their regular weekly 
or monthly CAM2038 injections until the end of the study. At the Month-4 safety extension visit (Visit 
Week 23 for de novo subjects and Visit Weeks 35-36 for subjects transitioned from randomized Double-
Blind Phase), PK sampling for CAM2038 steady state PK will be performed on all subjects who provide 
additional consent for the PK sampling. Blood samples will be collected prior to administration (within 
45 minutes); and at approximately 2 hours, 6 hours, 24 hours, 72 hours, 168 hours, 336 hours, and 672 
hours after administration to measure plasma levels of BPN and norBPN for subjects receiving both 
CAM2038 qlw and CAM2038 q4w treatments. Actual dates and times of dosing of IMP during the safety 
extension phase, as well as, blood sampling for PK measurement will be recorded. 
 
The study design schematics for the Open Label Safety Extension Phase are presented in Error! 
Reference source not found. and Figure 3 below. 
 
Figure 2: Overview of Open-Label Extension for Subjects Continuing from Double-Blind 
Phase Study2 
1 One booster is allowed at the discretion of the investigator, on Day 3-5 after the first 4 or 8 mg injection CAM2038 for subjects experiencing 
significant pain. Then titration is weekly up to 10 weeks.  Follow up is within 4 weeks after the Open Label Treatment Phase 
 
2 Figure 2 represents entire participation of subjects, who continue on from the randomized double blind of the study through the extension. 
However, subjects will not be required to participate in the Double-Blind Phase follow-up period and may proceed directly into the Open-Label 
Safety Extension Phase. A maximum gap of 28 days is allowed between the end of the Double-Blind Phase and the start of the Open-Label Safety 


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Extension Phase 
Figure 3: Overview of Open Label Extension for De Novo Subjects 
 
 
 
 
 
 
 
6.2. 
Discussion of Study Design 
Chronic pain may result from a number of different conditions with different underlying etiologies; 
however, to increase sensitivity of the study, eligible subjects will be subjects with moderate to severe 
CLBP who require ATC opioid treatment. The design selected to meet the objectives of the study is a 12-
week randomized, double-blind, placebo-controlled, EEW study in subjects with moderate to severe 
CLBP that requires continuous, ATC opioid treatment and, despite prior dose escalation, did not receive 
adequate pain relief. 
The overall design is consistent with previous studies of modified-release opioid analgesics, Initiative on 
Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations (Weaver 
and Schnoll, 2002; Yarlas et al, 2013 and Dworkin et al, 2005), and the FDA Guidance for Industry – 
Analgesic Indications: Developing Drug and Biological Products (2014) (Dworkin et al, 2008). The 
Double-Blind Phase will be 12 weeks in duration, which is consistent with FDA guidance and previous 
studies demonstrating efficacy of opioid formulations. The frequency of visits is considered to be 
adequate for dosing, monitoring subject’s compliance with study requirements, and not overly 
burdensome for subjects. 
1One booster is allowed at the discretion of the investigator, on Day 3-5 after the first 4 or 8 mg injection CAM2038 for subjects experiencing 
significant pain. Then titration is weekly up to 10 weeks.  Follow up is within 4 weeks after the Open Label Treatment Phase. 
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CAM2038 is being evaluated for the management of pain severe enough to require daily, ATC, long-term 
opioid treatment and for which alternative treatment options are inadequate. Two dosage formulations are 
being studied (4 mg, 8 mg and 12 mg q1w) and (16 mg, 24 mg and 32 mg q4w). 
The study will utilize an EEW approach as an enrichment strategy to enhance the probability of including 
“responders” and to minimize early discontinuations due to AEs (Dworkin et al, 2012 and FDA CDER, 
2014). According to FDA guidance (2014), an enrichment design may be particularly well suited for 
demonstrating efficacy of alternative dosage forms of an established analgesic. In addition, according to 
FDA guidance, the titrate-to-effect design may improve subject retention and provide a more realistic 
picture of efficacy and safety (Dworkin et al, 2012). The use of fixed opioid doses may permit a more 
rigorous assessment of dose-response, but the limited number of doses may reduce success of the trial, as 
they are not optimized to meet the subjects’ needs. 
During the Titration Phase, subjects will be dosed with CAM2038 q1w until a stabilized dose and 
adequate analgesic effect has been achieved for at least 2 consecutive weeks prior to randomization to the 
Double-Blind Phase, in accordance with pre-defined randomization criteria. Subjects whose pain is 
controlled on 4 mg, 8 mg or 12 mg CAM2038 q1w during the Titration Phase, will be maintained on 4 
mg, 8 or 12 mg CAM2038 q1w, or corresponding placebo during the Double-Blind Phase. Subjects 
whose pain is controlled on 16 mg CAM2038 q1w or higher during the Titration Phase will be 
transitioned to CAM2038 q4w/placebo during the Double- Blind Phase. 
Although there are inherent differences in the PK profiles for weekly and monthly administered products, 
the CAM2038 q1w and q4w formulations are similar with respect to steady state maximum plasma 
concentration and trough plasma concentration of BPN. Based on these similarities, the CAM2038 
products are expected to be interchangeable when subjects go from weekly to monthly dosing regimens. 
Rescue medication, hydrocodone/acetaminophen 5 mg/325 mg, will be provided to help minimize opioid 
withdrawal symptoms in subjects during the Titration Phase and the Double-Blind Phase (particularly in 
subjects randomized to placebo). Randomization will be used to avoid bias in the assignment of subjects 
to treatment, to increase the likelihood that known and unknown subject attributes (e.g., demographics 
and baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity of 
statistical comparisons across treatment groups. 
A placebo control will be used to establish the frequency and magnitude of changes in clinical endpoints 
that may occur in the absence of active treatment, as well as to minimize subject and investigator bias. 
Double-blinded treatment in the Double-Blind Phase will be used to reduce potential bias of subjects and 
investigators during data collection and evaluation of clinical endpoints. 
During the Double-Blind Phase, the pharmacist will be unblinded to the randomization code to permit 
dispensation of the CAM2038 or placebo q1w and CAM2038 or placebo q4w syringes to an unblinded 
staff member who will perform the injections. All other site study personnel, including the investigator and 
study coordinator, as well as the subjects, will remain blinded to treatment during the Double-Blind Phase 
of the study. The unblinded staff member will be instructed not to discuss the trial with the blinded staff to 
ensure the blind is maintained. 
The opening of recruitment of subjects for the safety extension is to ensure that a sufficient number of 
subjects are enrolled to provide required long-term safety data to support the clinical development of 
CAM2038 for the indication of chronic pain requiring daily treatment with opioids. 
 
 


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7. 
SELECTION OF STUDY POPULATION 
Approximately 875 subjects will be screened to obtain approximately 340 randomized subjects (170 
subjects per treatment group). The study comprises two treatment arms: a group of approximately 170 
subjects receiving SC CAM2038 q1w or CAM2038 q4w and a group of approximately 170 subjects 
receiving SC placebo q1w or q4w. Approximately 85 study sites in the United States will be utilized. 
Subjects who discontinue prematurely may be replaced at the discretion of the Medical Monitor and the 
Principal Investigator, in order to maintain study power. 
The study population will consist of adult males and females with moderate to severe CLBP currently 
requiring treatment with daily opioids ≥ 40 mg MED. 
For the extension phase, approximately 140 subjects will be enrolled to obtain 100 completed subjects. 
 
7.1. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria in order to be eligible for participation in the 
study: 
1. Written informed consent provided prior to the conduct of any study-related procedures. 
2. Male or non-pregnant, non-lactating female subject, greater than or equal to 18 years old. 
3. Body mass index (BMI) between 18 and 38 kg/m2, inclusive. 
4. Treated with daily opioids for moderate to severe CLBP for a minimum of 3 months prior to 
Screening. 
5. On a stable dose of ≥40 mg/day of oral morphine or MED during the 14 days prior to Screening. 
6. Systolic blood pressure ≥100 mmHg and diastolic blood pressure ≥60 mmHg. 
7. Female subject of childbearing potential who is willing to use a reliable method of contraception 
during the entire study (Screening Visit to final Follow-up; see Section 9.1.5). To be considered not of 
childbearing potential, female subjects must be surgically sterile (hysterectomy or bilateral 
oophorectomy, or bilateral tubal ligation with surgery at least 6 weeks before Screening). 
8. Male subject who is willing to use reliable contraception. 
9. Willing and able to comply with all study procedures and requirements. 
 
7.2. 
Exclusion Criteria 
Subjects will not be eligible for participation in the study if any of the following 
exclusion criteria are met: 
 
1. Positive for hepatitis B surface antigen, hepatitis C RNA, or antibodies to human immunodeficiency 
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2. Clinically 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 the study, 
including the following: 
a)  Severe respiratory insufficiency, respiratory depression, airway obstruction, gastrointestinal 
motility disorders, biliary tract disease, severe hepatic insufficiency, or planned surgery. 
b) Bipolar disorder 
3. Current diagnosis of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition– defined 
moderate to severe substance use disorder (including alcohol), other than caffeine or nicotine. 
4. Female subject planning to become pregnant during the study. 
5. Surgical procedure(s) for CLBP within 6 months prior to Screening. 
6. Concomitant disease(s) that could prolong the QTcF interval, such as autonomic neuropathy (caused 
by diabetes or Parkinson’s disease), HIV, cirrhosis, Long QT Syndrome, or family history of Long QT 
Syndrome. 
7. QTcF >450 ms for males and >470 ms for females, or clinically significant electrocardiogram (ECG) 
abnormality at Screening, at the investigator’s discretion. 
8. Currently taking medications that have the potential to prolong the QTcF interval or may require such 
medications during the course of the study (Appendix 1) and has clinically significant abnormalities 
on screening ECG readings, as determined by the investigator. 
9. A nerve or plexus block, including epidural steroid injections or facet blocks, within 1 month prior to 
Screening or botulinum toxin injection in the lower back region within 3 months of Screening. 
10. History of chemotherapy or confirmed malignancy (except basal cell carcinoma) within the past 2 
years. 
11. Any other acute or chronic pain condition that could interfere with the subject’s ability to report their 
CLBP accurately and consistently and/or interfere with the study staff’s ability to assess the subjects 
CLBP. 
12. An active or pending workman’s compensation, insurance claim, or litigation related to back pain (i.e., 
primary claim is back pain). 
13. Clinically significant history, in the opinion of the investigator, of suicidal ideation or current evidence 
that the subject is actively suicidal. 
14. Clinically significant history of major depressive disorder that is poorly controlled with medication, 
per investigator judgment. 
15. Hypersensitivity or allergy to BPN, other opioids, or excipients of CAM2038. 
16. Hypersensitivity or allergy to acetaminophen. 
17. Use of 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 


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(e.g., ritonavir, indinavir, and saquinavir) within the 30 days prior to Screening, 
18. Use or planned use of natural supplements that can affect CYP3A4, such as St. John’s Wort, 
throughout the study. 
19. Has a major bleeding disorder, such as hemophilia, or treated with high levels of anticoagulants per the 
investigator’s discretion 
20. Current or confirmed past diagnosis of Sphincter of Oddi dysfunction. 
21. Has a significant hepatic disease, as indicated by Screening clinical laboratory assessment results 
(aspartate aminotransferase, alanine aminotransferase, or lactate dehydrogenase values ≥3 × the upper 
limit of normal [ULN]) or has a creatinine value >1.5 × ULN). 
22. Is an employee of the investigator or the trial site, with direct involvement in the proposed trial or 
other studies under the direction of the investigator or trial site or is a family member of the 
investigator or of an employee of the investigator. 
23. Has any pending legal action that could prohibit participation or compliance in the study. 
 
7.3. 
Criteria for Entry into the Open-Label Titration Phase 
In order to be entered into the Titration Phase, subjects must meet the following criteria: 
1. After at least a 12-hour washout from the last IR morphine dose, subject must have a COWS 
≥5 and an API pain score over the past 24 hours ≥5 in order to receive a test dose of Buprenex. 
2. Passed all baseline criteria, including a normal QTcF, had no change in QTcF >30 ms at 1 hour after the 
test dose with Buprenex, and had a COWS score >5 after the test dose with Buprenex. 
Note: 
• 
Subjects on BPN at Screening are required to participate in the down titration and will undergo a 
washout period prior to the test dose and first on-study treatment.  Subjects entering the study on 
BPN will not transition to IR Morphine, but will refrain from taking their BPN for 12 -24 hours 
prior to the test dose to achieve the desired washout period.       
• 
Subjects on BPN at Screening are still required to follow the same Day 1 procedures (e.g., 
confirmation of pain scores, COWS assessment and Buprenex test dose) as non-BPN subjects. 
7.4. 
Criteria for Randomization into the Double-Blind Phase 
For randomization into the Double-Blind Phase, subjects must meet the following criteria at the 
completion of the Open Label Titration Phase: 
1. Been on a stable dose of CAM2038 q1w for at least 2 consecutive weeks. 
2. CAM2038 titrated to a dose that provides analgesia (i.e., 7-day API score of ≤4 and at least 2 points 
below the value at the start of Titration Phase) and is well tolerated for 7 days before randomization. 
3. Requires no more than an average of one hydrocodone/acetaminophen 5 mg/325 mg/day during the 
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4. Demonstrated study medication (CAM2038) compliance ≥80% during the previous 14 days. 
5. Demonstrated daily compliance with pain intensity scoring for ≥11 of the previous 14 days, including 
the last 3 days prior to randomization. 
7.5. 
Inclusion and Exclusion Criteria for Open Label Safety Extension 
(For Subjects Continuing from the Randomized Double-Blind Phase) 
7.5.1. Inclusion Criteria for Existing Subjects Entering from The Randomized Double-
Blind Phase 
Subjects who are participating in the Double-Blind Phase of the Study must meet all of the following 
inclusion criteria in order to be eligible for participation in the Open Label Safety Extension Phase: 
1. Completed Double-Blind Phase of the study 
2. Signed Informed Consent for Safety Extension 
 
7.5.2. Exclusion Criteria for Existing Subjects Entering from The Randomized Double-
blind Phase 
1. Clinically 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 the study. 
7.6 . 
Inclusion and Exclusion Criteria for Open Label Safety Extension          
 
(De Novo Subjects) 
7.6.1. Inclusion Criteria for De Novo Subjects 
Subjects who are not participating in the Double-Blind Phase of the study must meet all of the following 
inclusion criteria in order to be eligible for participation in the study: 
1. Written informed consent provided prior to the conduct of any study-related procedures. 
2. Male or non-pregnant, non-lactating female subject, greater than or equal to 18 years old. 
3. BMI between 18 and 38 kg/m2, inclusive. 
4. Treated with daily opioids for moderate to severe chronic pain disorder such as CLBP or 
osteoarthritis for a minimum of 3 months prior to Screening. 
5. On a stable dose of ≥40 mg/day of oral morphine or MED during the 14 days prior to Screening. 
6. Systolic blood pressure ≥100 mmHg and diastolic blood pressure ≥60 mmHg. 
7. Female subject of childbearing potential who is willing to use a reliable method of contraception 
during the entire study (Screening Visit to final Follow-up; see Section 9.1.5). To be considered 
not of childbearing potential, female subjects must be surgically sterile (hysterectomy or bilateral 


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oophorectomy, or bilateral tubal ligation with surgery at least 6 weeks before Screening). 
8. Male subject who is willing to use reliable contraception. 
9. Willing and able to comply with all study procedures and requirements. 
 
7.6.2. Exclusion Criteria for De Novo Subjects 
Same exclusion criteria as for subjects participating in the randomized Double-Blind Treatment Phase 
(see Section 7.2).  
7.6.3. Criteria for Entry into the Titration Phase (for De Novo subjects) 
1. After at least a 12-hour washout from the last IR morphine dose, subject should have a COWS ≥ 5 and 
an API pain score over the past 24 hours ≥ 5 in order to receive a test dose of Buprenex. 
2. Passed all baseline criteria, including a normal QTcF, had no change in QTcF >30 ms at 1 hour after 
the test dose with Buprenex, and had a COWS score <5 after the test dose with Buprenex. 
Note: 
• 
Subjects on BPN at Screening are required to participate in the down titration and will undergo a 
washout period prior to the test dose and first on-study treatment.  Subjects entering the study on 
BPN will not transition to IR Morphine, but will refrain from taking their BPN for 12 -24 hours 
prior to the test dose to achieve the desired washout period.       
• 
Subjects on BPN at Screening are still required to follow the same Day 1 procedures (e.g., 
confirmation of pain scores, COWS assessment and Buprenex test dose) as non-BPN subjects. 
 
7.6.4. Criteria for Enrollment into the Open Label Treatment Phase (for De Novo 
subjects) 
1. Been on a stable dose of CAM2038 q1w for at least 2 consecutive weeks. 
2. CAM2038 titrated to a dose that provides analgesia (i.e., 7-day API score of ≤4 and at least 2 points 
below the value at the start of Titration Phase) and is well tolerated for 7 days before randomization. 
3. Requires no more than an average of one hydrocodone/acetaminophen 5 mg/325 mg/day during the 
last 7 days prior to randomization. 
 
 
7.7. 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, including the Titration, Double-Blind Phases, and Open-
Label Safety Extension Phase, 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 
o Every attempt should be made to collect samples for a urine toxicology test and BPN blood 
concentration if a subject experiences a SAE or is discontinued from the study due to an AE. 
The investigator will remain blinded to the results until the study blind is broken. 


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▪ 
At the request of the Sponsor, regulatory agency, or Institutional Review Board (IRB) 
▪ 
Subject is lost to follow-up 
▪ 
Subject treatment allocation is unblinded 
▪ 
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 visits and procedure 
▪ 
Major protocol violation 
▪ 
Pregnancy 
▪ 
Use of unacceptable concomitant medication(s) 
▪ 
It is not considered in the best interest of the subject to continue 
▪ 
Administrative reasons (e.g., termination of enrollment or study) 
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 in as much detail as possible, although the subject is not obligated to provide such 
reason(s). 
In the event that a subject is discontinued while at the clinical site, the early termination procedures shown 
in the Schedule of Assessments (Table 6 , Table 7, Table 8, and Table 10) should be performed prior to 
discharge from the clinical site. For any case of early discontinuation, whether or not the subject is at the 
clinical site, the investigator should ask the subject to return for the early termination procedures, provided 
that the subject has not withdrawn consent for those procedures. If the subject has not withdrawn consent 
for procedures, the sponsor can hire a third-party vendor to locate the subject so that the early termination 
procedures can be performed. If subject refuses to complete early termination procedures, this information 
will be recorded. 
 
 


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8. 
TREATMENTS 
 
8.1. Treatment Administration 
 
8.1.1. Transition Phase (after Screening to test dose/Day 1) 
 
Following Screening and confirmation of eligibility, subjects will enter a Transition Phase of up to 2 
weeks during which their current opioid dose will be down-titrated by approximately 25% per day to ≤80 
mg/day MED for subject whose screening MED was ≥80 mg/day; or to ≤40 mg/day MED for subject 
whose screening MED was between 40 mg and 79 mg/day. With exception to subjects down-titrating their 
BPN dosing, subjects will be transitioned to an IR morphine (15 mg QID or 15 mg TID, respectively) for 
at least 2 days before they enter the Open Label Titration Phase. Following the morphine IR treatment, 
subjects will enter the Titration Phase. Subjects who were previously on BPN prior to Screening will not 
need to participate in the morphine-IR phase, but will refrain from taking BPN for 12-24 hours as a 
washout phase. 
 
8.1.2. Test Dose (Day 1 of Titration) 
Subjects are required to refrain from their previous IR morphine treatment for at least 12 hours in order to 
receive the Buprenex test dose at the clinical site (i.e., Day 1 of the Titration Phase). Subjects will be 
required to have an API score over the previous 24 hours ≥ 5, recorded on a paper diary and a COWS 
score ≥ 5 in order to receive the test dose of Buprenex. The COWS assessment can be performed up to 48 
hours after the initial COWS assessment. At that time, subjects will receive an IM injection of 0.30 mg 
(1.0 mL) Buprenex and will be assessed for any changes in QTcF or withdrawal. ECGs will be taken 15 
minutes before and 15 minutes and 1 hour after the test dose. COWS will be assessed at 15 minutes after 
the test dose. 
 
8.1.3. Titration Phase 
After administration of the Buprenex test dose on Day 1, subjects who tolerate the test dose, do not show 
an increase of > 30 ms in QTcF within 1 hour, and have a COWS score of < 5 within 15 minutes after the 
test dose will receive their first dose of CAM2038 q1w within 4 hours (+ 30 minutes) after the test dose. 
Subjects whose screening opioid dose was between 40 mg and 79 mg/day MED will be started on 4 mg 
CAM2038 q1w. Subjects whose screening opioid dose was ≥80 mg/day MED will be started on 8 mg 
CAM2038 q1w. During the first week of the Titration Phase, subjects who experience significant pain 
may, at the discretion of the investigator receive a second dose of CAM2038 at their respective dose (4 mg 
for subjects whose screening MED was 40-79 mg/day; 4 or 8 mg CAM2038 q1w for subjects whose 
screening Med was ≥80 mg/day) on Day 3, 4, or 5. Subjects will then attend clinic visits every week for 
dosage adjustment. Dose adjustments will be made by increasing or decreasing the dose level of 
CAM2038 q1w at the scheduled weekly visits (doses of 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, or 32 mg per 
week). 
 
The maximum dose within a 7-day period cannot exceed 32 mg.  Subjects who require doses higher than 
32 mg/week will be discontinued from the study. The dosing of CAM2038 q1w will be titrated with the 
purpose of achieving a stable dose of CAM2038 q1w by the end of the 10-week Titration Phase. 
 


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8.1.4. Double-Blind Phase 
Subjects who are receiving 4, 8 or 12 mg CAM2038 q1w at the end of the Titration Phase will be 
randomized to continue their respective 4 mg, 8 mg or 12 mg CAM2038 q1w dosing, or to corresponding 
placebo q1w for a total treatment duration of 12 weeks (12 injections in the Double-Blind Phase). Subjects 
who are receiving 16 mg, 24 mg or 32 mg CAM2038 q1w at the end of the Titration Phase will be 
randomized to CAM2038 q4w (64 mg, 96 mg or 128 mg, respectively) or to corresponding placebo q4w 
for a total treatment duration of 12 weeks (3 injections in the Double-Blind Phase). 
The dose conversions between CAM2038 q1w and CAM2038 q4w are shown below. 
▪ 
4 mg CAM2038 q1w = 4 mg CAM2038 q1w or placebo q1w 
▪ 
8 mg CAM2038 q1w = 8 mg CAM2038 q1w or placebo q1w 
▪ 
12 mg CAM2038 q1w = 12 mg CAM2038 q1w or placebo q1w 
▪ 
16 mg CAM2038 q1w = 64 mg CAM2038 q4w or placebo q4w 
▪ 
24 mg CAM2038 q1w = 96 mg CAM2038 q4w or placebo q4w 
▪ 
32 mg CAM2038 q1w = 128 mg CAM2038 q4w or placebo q4w 
 
 
CAM2038/placebo q1w must not be administered into a previously injected site for at least 4 weeks. 
CAM2038/placebo q4w must not be administered in a site previously injected with CAM2038/placebo 
q4w or with CAM2038/placebo q1w. 
During the entire Double-Blind Phase, subjects will be instructed to record their pain intensity ratings 
before taking rescue medication. Rescue medication will consist of hydrocodone/acetaminophen 5 mg/325 
mg tablets, q4-6h prn, not to exceed a total of 6 tablets or a total dosage of hydrocodone/acetaminophen 30 
mg/1950 mg/day for subjects whose screening opioid dose was ≥80 mg/day. For subjects whose screening 
opioid dose was between 40 and 79 mg/day MED, the maximum allowable rescue medication will be 15 
mg/975 mg/day (three tablets). This dosage limit will provide analgesic rescue medication at a maximum 
dose to prevent liver toxicity. 
In addition, at any time during the Double-Blind Phase, if the subject requires rescue medication above the 
maximum allowable (hydrocodone/acetaminophen 30 mg/1950 mg/day (six tablets) for subjects whose 
screening MED was ≥80 mg/day; or 15mg/975 mg/day (three tablets) for subjects whose screening MED 
was between 40 and 79 mg/day), the subject should be asked if they want to continue with the maximum 
dose of rescue medication or would like to withdraw from the study. If circumstances surrounding 
discontinuation or withdrawal are unclear, the Medical Monitor should be consulted. If the subject decides 
to withdraw, the subject should have a final on-treatment visit and then have procedures and assessments 
completed for any remaining study visits, as specified in the protocol. 
Telephone or other contacts made by the site are allowed throughout the course of the study. Subjects 
should return to the study center according to the schedule specified in this protocol. 
One week after the last dose of CAM2038/placebo q1w or 4 weeks after the last dose of 
CAM2038/placebo q4w, the subjects will attend a Final Study Visit. At the Final Study Visit (or early 
termination), subjects will be transitioned back to standard care or their treatment prior to study entry. 
Within 4 weeks after the Final Study Visit, subjects will be contacted by phone to assess AEs and review 
concomitant medications. 
 


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8.1.5. Subjects Randomized to Placebo in the Double-Blind Phase 
At the start of the Double-Blind Phase, approximately half of the subjects (170) will be randomized to 
placebo. These subjects may experience increases in their pain scores and require rescue medication. Sites 
are encouraged to keep these subjects in the study as long as possible. However, subjects may withdraw 
consent for participation at any time and for any reason. Subjects who discontinue prematurely may be 
replaced at the discretion of the Medical Monitor and the Principal investigator, in order to maintain study 
power. 
 
8.1.6. Rescue Medications 
Hydrocodone/acetaminophen 5 mg/325 mg will be used as a rescue medication throughout the study. 
Rescue medication will be allowed prn during the Open Label Titration Phase and the Double-Blind Phase 
up to 30 mg/1950 mg/day of hydrocodone (5 mg)/acetaminophen (325 mg). However, the subject may not 
use, on average, more than one dose of rescue medication per day over the 7 days before randomization. 
Throughout the study, subjects will be instructed to record their pain intensity “at that moment” on the 
electronic diary prior to taking rescue medication. 
8.1.7. Open Label Safety Extension 
Once the required number of subjects for the Double-Blind phase of the trial has been recruited 
(approximately 340), enrollment for the Double-Blind Phase will be closed and remaining subjects with 
CLBP will be offered the opportunity to proceed directly to the Open Label Safety Extension Phase 
without having to participate in the Double-Blind Phase. However, to be eligible to proceed to the Open 
Label Safety Extension Phase, subjects must meet the following criteria: 
• 
The analgesic dose of CAM2038 is well-tolerated for 7 days before entry into open label study (no 
adverse effects that require a change in study dosing or interruption) 
The opening of recruitment for subjects with CLBP for the safety extension only after enrollment for the 
randomized Double-Blind Phase of the study is complete, is to ensure that eligible subjects with CLBP are 
enrolled into the pivotal randomized Double-blind phase first. However, other subjects with chronic pain 
requiring daily treatment with opioids, who do not qualify for the randomized Double-Blind Phase of the 
study but are eligible for the safety extension phase may be enrolled directly into the safety extension 
phase (so called de novo subjects). These subjects will not be required to wait for recruitment for the 
randomized Double-Blind Phase to be completed prior to enrolling into the safety extension. The purpose 
of the safety extension is to ensure that sufficient data is obtained, to provide at least 52 weeks of exposure 
safety information in at least 100 subjects.  These long long-term safety data are required to support the 
clinical development of CAM2038 for the indication of chronic pain requiring daily treatment with 
opioids. 
 
De novo subjects proceeding directly to the open label extension, will undergo the same screening 
procedures, down titration, morphine IR, Buprenex test dose, and CAM2038 up-titration similar to the 
requirement for subjects enrolling into the randomized Double-Blind Phase of the study. The CAM2038 
dosing titration and rescue medication requirements for the safety extension for subjects whose opioid 
doses at screening are > 80 mg/day MED, and 40-79 mg/day MED, respectively, shall be the same as 
described for the subjects participating in the Double-Blind Phase. 
 
Subjects in the safety extension will return to the study clinic for their regular weekly or monthly 
CAM2038 injections until the end of the study.  
 


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Starting at the fourth monthly safety extension visit, PK sampling for CAM2038 steady state PK will 
be performed in subjects who have provided additional consent for the PK sampling. PK sample can 
be done at any visit timepoint after the subject has stabilized but no later than 4 week prior to EOT 
visit. Effort will be made to ensure that a sufficient number of subjects are included to cover the range 
of CAM2038 doses in the safety extension phase. 
Blood samples will be collected prior to administration (within 45 minutes); and at approximately 2 
hours, 6 hours, 24 hours, 72 hours, 168 hours, 336 hours, and 672 hours to measure plasma levels of 
BPN and norBPN for subjects receiving both CAM2038 qlw and CAM2038 q4w treatments. Actual 
dates and times of dosing of IMP during the safety extension phase as well as blood sampling for PK 
measurement will be recorded. 
 
8.1.7.1. Dosing Schedule 
 
The dose titration schedule below provides guidance regarding titration of subject dosing upon enrollment 
into the open label extension portion of the study following participation in the double-blind 
randomization.    
 
• 
All subjects will be started on the weekly CAM2038 regimen during the open label extension.  
• 
Subjects completing the randomized double-blind phase on 4 mg, 8 mg, or 12mg 
CAM2038/placebo q1w will continue the same dose of active treatment (open label CAM2038) 
without need for titration.  
• 
Subjects completing the randomized double-blind phase on 64 mg, 96mg, or 128mg 
CAM2038/placebo q4w will begin open label treatment at the corresponding equivalent weekly 
dose last received by the subject prior to transition to the monthly dosing regimen. The subject 
may transition to monthly dosing upon return to the clinic in 1 week following the initial dose. At 
the investigator’s discretion, the transition period may be extended or the patient down-titrated, in 
case of poor tolerability.   
• 
Additional details are presented in Table 4 below: 
 
Table 4 Open-Label Extension Dose Schedule for Randomized Double-Blind Rollover 
Randomized Double-Blind Dose 
 
 
Titration Schedule  
 
4mg CAM2038 q1w 
Remain at 4mg weekly 
8mg CAM2038 q1w  
 
Remain at 8mg weekly 
2mg CAM2038 q1w   
Remain at 12mg weekly 
64mg monthly* 
Start at 16mg q1w   
96mg monthly* 
Start at 24mg q1w 
128mg monthly* 
Start at 32mg q1w   
*Please note:  
• 
16 mg CAM2038 q1w is the dosing equivalent of 64 mg CAM2038 q4w   
• 
24 mg CAM2038 q1w is the dosing equivalent of 96 mg CAM2038 q4w  


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• 
32 mg CAM2038 q1w is the dosing equivalent of 128 mg CAM2038 q4w 
 
8.2. Identity of Investigational Product(s) 
The following treatments will be used during the study: 
▪ 
CAM2038 (BPN FC Injection depot for q1w administration), 6.25 mg/mL: 4 mg (BPN 
base), 0.64 mL SC injection.* 
▪ 
CAM2038 (BPN FC Injection depot for q1w administration), 50 mg/mL: 8 mg, 12 
mg, 16 mg, 24 mg, and 32 mg (BPN base), 0.16, 0.24, 0.32, 0.48, and 0.64 mL SC 
injection. 
▪ 
CAM2038 (BPN FC Injection depot for q4w administration), 356 mg/mL: 64 mg, 96 
mg, and 128 mg (BPN base), 0.18, 0.27, and 0.36 mL SC injection. 
▪ 
Placebo: 0.16, 0.32, 0.48 and 0.64 mL SC injections for q1w or q4w administration. 
* CAM2038 6.25 mg/mL has been interchangeably referred to as CAM2048 during its development. 
The active ingredient is the same as for CAM2038 q1w. It also has the same excipients, as the 
CAM2038 q1w. For the purposes of this protocol, all reference to CAM2048 shall be considered to 
refer to and interchangeable with CAM2038 q1w 
 
8.2.1. Description of CAM2038 q1w, CAM2038 q4w, and Placebo SC Injection Products 
CAM2038 q1w will be supplied as a pre-filled syringe with safety device and plunger containing the 
following: BPN, soybean phosphatidylcholine, glycerol dioleate, and anhydrous ethanol. 
CAM2038 q4w will be supplied as a pre-filled syringe with safety device and plunger containing the 
following: BPN, soybean phosphatidylcholine, glycerol dioleate, and N-Methyl-2- pyrrolidone. 
Placebo SC injections will be supplied as matching (for CAM2038 q1w) or nearly matching (by volume 
and color for CAM2038 q4w) pre-filled syringes with safety devices and plungers containing the 
following: soybean phosphatidylcholine, glycerol dioleate, and ethanol. 
More information regarding the CAM2038 q1w and CAM2038 q4w and matching or nearly matching 
placebo injections can be found in the Instructions for User (IFU). 
 
8.2.2. Description of the Buprenex Test Dose 
Buprenex (BPN hydrochloride) will be sourced centrally and will be given as 1 mL deep IM injection 
corresponding to 0.3 mg BPN according to the prescribing information. 
 
8.2.3. Description of the IR Morphine 
Morphine sulfate IR will be supplied as 15-mg tablets for oral administration. 
 
8.2.4. Description of the Hydrocodone/Acetaminophen 
Hydrocodone/Acetaminophen will be supplied as 5 mg/325 mg for oral administration. 
 


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8.2.5. 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. 
The CAM2038 drug products, IR morphine, Buprenex, and hydrocodone/acetaminophen 5 mg/325 mg as 
rescue medication should be stored in a secured area at room temperature (59° to 77° F or 15° to 25° C) and 
in accordance with the product labeling and all applicable laws, regulations and local/institutional 
requirements. 
 
Detailed drug accountability records must be maintained, including the dates shipments are received, the 
quantity of material received, the dates dispensed and the running inventory. The unused quantities will be 
returned to the Sponsor’s drug supply vendor at the end of the trial. All unused supplies will be checked 
against the drug accountability records during the study and/or at the end of the study. Subjects will be 
instructed to return all unused study drugs to the clinical site. The investigator or designee must maintain an 
inventory record of all rescue medications dispensed to subjects. 
Mishandling, potential theft, significant loss of clinical supplies at the site, or other suspected diversion 
must be reported to the Sponsor within 24 hours of first knowledge of the issue. If diversion is confirmed or 
suspected (e.g., excessive use of rescue medications), the study staff will be required to complete a clinical 
supply product complaint form, including documenting if a subject sold drug or gave drug to a friend or 
relative, if there was a discrepancy in drug accountability and suspected diversion, if a subject had drug 
stolen, or if there was diversion or theft by site staff or others. 
BPN (Schedule III), morphine sulfate (Schedule II), and hydrocodone/acetaminophen 5 mg/325 mg (Schedule 
II) are controlled substances and 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. 
 
8.2.6. Dispensing and Administration 
Only eligible subjects participating in the study will receive the study drug. Only authorized research site 
staff may supply or administer the study drugs. Once dispensed, study drug may not be relabeled or 
reassigned for use by other subjects. 
During the Double-Blind Phase, the pharmacist will be unblinded to the randomization code to permit 
dispensation of the CAM2038/placebo q1w and CAM2038/placebo q4w syringes to an unblinded staff 
member who will perform the injections. All other site study personnel, including the investigator and study 
coordinator, as well as the subjects, will remain blinded to treatment until the study is unblinded by the 
study sponsor. The unblinded staff member will be instructed not to discuss the trial with the blinded staff 
to ensure the blind is maintained. 
Injections will be administered in different SC sites, to avoid injecting into the same exact site (Appendix 
2). Detailed instructions for use will be provided in the IFU. 
 
8.3. Method of Assigning Subjects to Treatment Groups 
Randomization will be used to avoid bias in the assignment of subjects to treatments, to increase the 
likelihood that known and unknown subject attributes (e.g., demographics, baseline characteristics) are 
evenly balanced across treatment groups, and to enhance the validity of statistical comparisons across 


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treatment groups. 
Subjects who provide written informed consent will be assigned a unique number in the screening process. 
This number will be used to identify the subject throughout the study. 
Subjects who meet the eligibility criteria will be randomized in a 1:1 ratio (Group 1: active CAM2038 SC 
injections or Group 2: placebo SC injections). Randomization will be stratified based on double blind 
dosing regimen. Subjects randomized at a titration dose of either 4, 8 or 12 mg will remain on weekly 
doses. Subjects randomized at a titration dose of 16, 24, or 32 mg will transition to monthly dosing. 
Therefore, there will be four different dose types. 
• 
A1 – Active weekly 
• 
B1 – Placebo weekly 
• 
A4 – Active monthly 
• 
B4 – placebo monthly 
Due to the size of the study, it is expected that subjects will be balanced for various other baseline factors, 
including age. 
Once any subject number or randomization number is assigned, it cannot be reassigned to any other subject. 
This study will use central randomization, as described in Section 9.2. 
 
8.4. Selection of Dose 
The study will include the following doses based on each subject’s individual analgesia needs and 
tolerability: 
• 
CAM2038 q1w 6.25 mg/mL: 4 mg (BPN base); 0.64 mL SC injection 
• 
CAM2038 q1w 50 mg/mL: 8 mg, 12 mg, 16 mg, 24 mg, and 32 mg (BPN base); 0.16, 
0.24, 0.32, 0.48, and 0.64 mL SC injection 
• 
CAM2038 q4w, 356 mg/mL: 64 mg, 96 mg, and 128 mg (BPN base); 0.18, 0.27, and 
0.36 mL SC injection. 
Dose adjustments will be allowed during the Open Label Titration Phase only. 
Rescue medication is oral hydrocodone/acetaminophen, 5 mg/325 mg tablets, q4-6 h prn. The maximum daily 
dose is 30 mg/1950 mg/day. Subjects cannot take more than one rescue tablet per day, on average, in the 
week prior to randomization. 
On Day 1 of the Titration Phase, subjects will receive a test dose consisting of a single IM injection of 0.30 
mg (1.0 mL) Buprenex and will be assessed for any changes in QTcF or withdrawal prior to any 
administration of CAM2038. 
 
8.5. Selection and Timing of Dose 
Subjects will be randomized to receive either CAM2038 or placebo at individualized doses. No fasting or 
special dietary requirements are required for the study. 
 
8.6. Blinding 


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In order to reduce the potential for bias in the study, treatment group assignments will be double-blinded 
during the Double-Blind Phase. The subject, investigational site personnel, Sponsor, and Sponsor designees 
directly involved in the conduct and/or monitoring of this study will not be aware of the treatment group 
assignments. 
 
There is a slight difference in color and fill volume between the placebo and active CAM2038 q4w; however, 
the viscosity is the same. In order to maintain the blind given the differences in color and fill volume, the 
following will be implemented during the Double-Blind Phase: 
▪ 
The Injecting Clinician and any other staff involved in the injection process will not participate in 
subject evaluations, nor discuss any information regarding the injections with the subjects or other 
study staff. 
▪ 
To keep the subjects blinded, appropriate steps will be taken to ensure that the subject is unable to 
view the syringe at any time. 
▪ 
The study staff will not ask the Injecting Clinician or any other staff involved in the injection process for 
information regarding subject group assignment that might inadvertently unblind the study staff. 
Under normal circumstances, the blind will not be broken until all participants have completed treatment. In 
case of emergency, and only if the information is required by the investigator to ensure subject’s safety in 
managing a medical condition, the treatment may be unblinded at the site by using a code break module. 
The code break module will be provided by the Sponsor or designee. If possible, the investigator should 
contact the Sponsor prior to unblinding and after any actions have been taken. Whenever a treatment 
sequence is prematurely unblinded, the reason, date, and time of the unblinding and the individual who 
broke the blind must be documented. Individual code breaks will result in withdrawal of the subject from 
the study. 
 
8.7. Prior and Concomitant Medications and 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 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 up to 2 weeks (for CAM2038 q1w) or at 
least 2 months (for CAM2038 q4w) following the last CAM2038 injection. Therefore, subjects 
requiring analgesic emergency treatment or anesthesia for surgery should ideally be treated with a 
non-opioid analgesic. Opioids may be used with caution, but as higher doses may be required for 
analgesic effect, there may be a higher potential for toxicity with opioid administration. The clinical 
course should 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. 
BPN is metabolized via CYP3A4. Because CYP3A4 inhibitors may increase plasma concentrations 
of BPN, 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 prohibited 
for at least 30 days prior to Screening. Interactions with CYP3A4 inducers have not been 
investigated; therefore, CYP3A4 inducers (e.g., phenobarbital, carbamazepine, phenytoin, and 
rifampicin) are prohibited for at least 30 days prior to Screening. 


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▪ 
Concomitant use of other narcotic anesthetics, benzodiazepines, phenothiazines, other tranquilizers, 
or other central nervous system (CNS) depressants (including alcohol and sedative/hypnotics) may 
cause respiratory and CNS depression. Use of these substances should be minimized during treatment 
with CAM2038. If these sedatives are required during the study, the Medical Monitor must be 
consulted. Subjects should be advised of the danger of concomitant use of sedatives while 
participating 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. 
The following concomitant medications and therapies may be permitted during the study: 
▪ 
Nonsteroidal anti-inflammatory drugs will be permitted occasionally for headache, 
fever, or other indications, aside from CLBP, for no more than 3 consecutive days and 
no more than the maximum daily recommended dose 
▪ 
Other non-opioid analgesics are permitted, but subjects must be on a stable dose 
(±20% dose and timing of administration) for at least 30 days prior to enrollment 
▪ 
Rescue medication 
▪ 
Anti-constipation medications 
▪ 
Aspirin at doses ≤325 mg/day for cardiovascular prophylaxis 
The following medications and therapies are permitted, but must remain stable (±20% dose 
and timing of administration) throughout the duration of the subject’s participation in the 
study: 
▪ 
Muscle relaxants 
▪ 
Hypnotics (eszopiclone, zolpidem, zaleplon) 
▪ 
Antidepressants 
▪ 
Anticonvulsants 
▪ 
Physical therapy 
▪ 
Biofeedback therapy 
▪ 
Acupuncture therapy 
▪ 
Herbal remedies (except products that can affect CYP3A4, such as St. John’s Wort) 
On a case-by-case basis, the investigator is permitted to allow the use of some concomitant 
medications, for example, to treat an AE, as long as the investigator determines that the 
medication will not affect the subject’s safety or study integrity (e.g., topical medications). 
Wherever possible, the investigator should obtain approval from the Sponsor’s Medical 
Monitor prior to administering the medication. 
 
8.8. Treatment Compliance and Monitoring Diversion 
Because CAM2038 is administered by study personnel, no compliance procedures are necessary. Diversion 
will be monitored and recorded by reconciling the number of tablets of rescue medication dispensed against 
the number of tablets returned at each visit and diary entries. Any suspected or confirmed diversion will be 
documented and reported. 
 
 
 
 


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9. 
STUDY PROCEDURES AND ASSESSMENTS 
All study assessments will be performed at the visits and time points outlined in the Schedule of 
Assessments (Table 5, Table 6, and Table 7).  Open-label safety extension assessments for existing subjects 
enrolled from the randomized Double-Blind Phase is present in Table 8.  Table 9 and Table 10 presents the 
schedule of assessments for de novo subjects in Open Label Safety Extension Phase.  The following sections 
outline the details and procedures associated with the assessments. 
 
 


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Table 5:   Schedule of Assessments for Screening, Transition, and Titration Phases 
 
Study Period/Phase: Screening 
Transition Phase1 
Open-Label Titration Phase2 
Week: W-2 to -1 
W0 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
Day: D-14 to -1 D1 up to 10-
12 days3 
2 to 4 
days 
 
 
 
 
 
 
 
 
 
 
Informed Consent4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria Review 
X 
 
 
X5 
 
 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs7 
X 
 
 
X8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Laboratory Assessments 
X 
 
 
X 
 
 
 
X9 
 
 
 
 
 
Pregnancy Test10 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Hepatitis B/C, HIV11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Treatment Identification Card 
X 
Down-Titrate Opioid Dose 
X 
 
1 Subjects on BPN at screening will participate in the down titration but will not transition to morphine IR. Subjects will washout and refrain from their BPN treatment for 12-24 hours 
prior to the test dose on Day 1. 
2 Titration Phase visit window is ±3 days. 
3 Telephone contact. 
4 Subjects must voluntarily provide written informed consent prior to any study-related procedures being performed. 
5 Prior to starting the Titration Phase, all Inclusion/Exclusion and other relevant criteria must be met. 
6 A complete physical examination of all major body systems (including height, weight, and BMI) will be performed. 
7 Includes body temperature, blood pressure, pulse rate, pulse oximetry and respiration rate. 
8 Vital signs and ECG will be measured 15 minutes (allowable window up to 60 minutes) before the Buprenex test dose, 15 minutes (allowable window of between 15-30 minutes) and 1 
hour (allowable window of between 60-90 minutes) after the test dose, and 1 hour (allowable window of between 60-90 minutes) and 24 hours (allowable window of ±3 hours) after the 
first CAM2038 q1w dose. Vital signs and ECG will thereafter be assessed weekly during the Titration Phase. 
9 An additional sample for assessment of electrolytes will be taken 4 weeks after the first dose of CAM2038 q1w. Refer to Table 11 for a list of laboratory analytes. 
10 A serum pregnancy test will be performed at Screening. An “in-office” urine pregnancy test will be required every other week during the Titration (for women of childbearing potential). 
11 It is the Investigator’s responsibility to understand and comply with the laws and regulations that apply to HIV, Hepatitis B, and Hepatitis C testing of blood samples. Hepatitis B/C and 
HIV testing is required unless the site’s IRB prohibits such testing. 


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Study Period/Phase: Screening 
Transition Phase1 
Open-Label Titration Phase2 
Week: W-2 to -1 
W0 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
Day: D-14 to -1 D1 up to 10-
12 days3 
2 to 4 
days 
 
 
 
 
 
 
 
 
 
 
IR Morphine12 
X 
Buprenex Test Dose 
X13 
COWS/SOWS 
X14 
X 
CAM2038 q1w SC Injection15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection Site Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense, Collect, and Record Rescue 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Daily Diary Pain Rating (NRS-11) 
X 
X16 
Daily 
Daily 
Daily 
Daily 
Daily 
Daily 
Daily 
Daily 
EQ-5D-5L 
X 
X 
X 
X 
WPAI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS17 
X 
X 
X 
X 
X 
X 
Concomitant Medications/Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE=Adverse Event; BMI=Body Mass Index; C-SSRS-Columbia Suicide Severity Rating Scale; COWS=Clinical Opiate Withdrawal Scale; D=day; 
ECG=electrocardiogram; EQ-5D-5L=EuroQoL Group 5-dimension 5-level self-report questionnaire; HIV=Human Immunodeficiency Virus; IM=intramuscular; NRS-11=11-point 
numerical rating scale; q1w=once weekly; SC=subcutaneous; SOWS=Subjective Opiate Withdrawal Scale; W=week; WPAI=Work Productivity and Activity Impairment. 
 
12 IR morphine (15 mg QID for subjects with screening MED of ≥80 mg/day; or 15 mg TID for subjects with screening MED between 40 mg and 79 mg/day) for at least 2 days prior to 
Day 1 of the Titration Phase. A 12-hour washout from the last IR morphine dose is required before the Buprenex test dose is given. 
13 One IM injection of 0.3 mg (1.0 mL) Buprenex. 
14 COWS/SOWS will be assessed before the test dose, 15 min (allowable window of between 15-30 minutes) after the test dose, and 24 hours (allowable window of ±3 hour) after the first 
4 mg or 8 mg CAM2038 dose.  If COWS score is not ≥5, the COWS can be repeated for up to 48 hours. 
15 The first dose of either 4 mg or 8 mg CAM2038 q1w will be administered within 4 hours (+30 minutes) after the test dose. During the first week of the Titration Phase, subjects who 
experience significant pain may, at the discretion of the investigator, receive an additional CAM2038 at their respective dose (4mg or 8 mg) on Day 3, 4 or 5. Dose adjustments will be 
made by increasing or decreasing the dose level of CAM2038 q1w at the scheduled weekly visits (doses of 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, or 32 mg per week). Subjects who require 
doses >32 mg/week will be discontinued from the study. 
16 Electronic diary dispensed after test dose. 
17 ‘Screening’ version at Screening and ‘Since Last Visit’ version every other week during the Titration Phase. 
18 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. 


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Table 6:   Schedule of Assessments for Subjects Randomized to Once Weekly Injections 
 
Study Period/Phase: 
Double-Blind Phaseab 
Final 
Study 
Visitc 
Follow-up 
Phased 
Month: 
M4 
M5 
M6 
M7 
Week: 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
27 
Eligibility Criteria Review 
Xe 
Physical Examinationf 
X 
Vital Signsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
Xh 
X 
X 
X 
X 
Clinical Laboratory Assessments 
X 
X 
Pregnancy Testi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
COWS/SOWSj 
X 
X 
CAM2038/placebo q1w SC Injectionk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection Site Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense, Collect, and Record Rescue 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xl 
 
a Double-Blind Phase visit window is ±3 days. 
b The first day of the Double-Blind Phase is defined as baseline. 
c This visit is defined as the twelfth week of the Double-Blind Phase in the analyses of data. 
d Telephone contact only. 
e Prior to enrollment into the Double-Blind Phase, all Inclusion/Exclusion and other relevant criteria must be met. 
f A complete physical examination of all major body systems (including height, weight, and BMI) will be performed. 
g Includes body temperature, blood pressure, pulse rate, pulse oximetry and respiration rate and will be performed at every visit, prior to treatment, and 1-hour post-study treatment 
(allowable window of 60-90 minutes). 
h ECGs will be assessed at Week 11, prior to treatment and 1-hour post-dose (allowable window of 60-90 minutes). 
i A serum pregnancy test will be performed at the Final Study Visit/Early Termination. An “in-office” urine pregnancy test will be required weekly (for women of childbearing 
potential). 
j COWS/SOWS will be assessed before dosing. 
k Subjects who are receiving 4 mg, 8 mg or 12 mg CAM2038 q1w will randomize to CAM2038/placebo q1w with weekly injections throughout the Double-Blind Phase. 
l Rescue medication will not be dispensed at this visit. 
 


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Study Period/Phase: 
Double-Blind Phaseab 
Final 
Study 
Visitc 
Follow-up 
Phased 
Month: 
M4 
M5 
M6 
M7 
Week: 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
27 
Daily Electronic Diary Pain Rating (NRS- 
11) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EQ-5D-5L 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
WPAI 
X 
X 
X 
X 
C-SSRSm 
X 
X 
X 
X 
CGI-I Scale 
X 
X 
X 
X 
PGI-I Scale 
X 
X 
X 
X 
Concomitant Medications/Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Eventsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adjust Opioid Treatment 
Xo 
 
 BMI=Body Mass Index; CGI-I=Clinical Global Impression Improvement; C-SSRS=Columbia Suicide Severity Rating Scale; COWS=Clinical Opiate Withdrawal Scale; 
ECG=electrocardiogram; EQ-5D-5L=EuroQoL Group 5-dimension 5-level self-report questionnaire; ET=Early Termination; NRS-11=11-point numerical rating scale; PGI-I= 
Patient Global Impression of Improvement; q1w=once weekly; q4w=once monthly; SC=subcutaneous; SOWS=Subjective Opiate Withdrawal Scale; WPAI=Work Productivity and 
Activity Impairment.
 
m Since Last Visit’ version to be used. 
n 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. 
o At the Final Study Visit (or ET) subjects will be transitioned back to standard care or their treatment prior to study entry. 


Clinical Trial Protocol 
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Braeburn Pharmaceuticals 
CONFIDENTIAL 
Protocol Amendment 9 / Version: 10.0 
12-APR-2018 
Page 55 of 99 
 
 
 
Table 7:   Schedule of Assessments for Subjects Randomized to Once Monthly Injections 
 
Study Period/Phase: 
 
Double-Blind Phaseab 
 
Final Study Visitc 
 
Follow- up Phased 
Month: 
M4 
M5 
M6 
Week: 
11 
15 
19 
23 
27 
Eligibility Criteria Review 
Xe 
Physical Examinationf 
X 
Vital Signsg 
X 
X 
X 
X 
ECGh 
X 
X 
X 
X 
Clinical Laboratory Assessments 
X 
X 
Pregnancy Testi 
X 
X 
X 
X 
COWS/SOWSj 
X 
CAM2038 q4w/placebo SC Injectionk 
X 
X 
X 
Injection Site Examination 
X 
X 
X 
X 
Dispense, Collect, and Record Rescue Medications 
X 
X 
X 
Xl 
Daily Electronic Diary Pain Rating (NRS-11) 
X 
X 
X 
X 
EQ-5D-5L 
X 
X 
X 
X 
WPAI 
X 
X 
X 
X 
 
aDouble-Blind Phase ±7 days 
b The first day of the Double-Blind Phase is defined as baseline. 
c This visit is defined as the twelfth week of the Double-Blind Phase in the analyses of data. 
d Telephone contact only. 
e Prior to enrollment into the Double-Blind Phase, all Inclusion/Exclusion and other relevant criteria must be met. 
f A complete physical examination of all major body systems (including height, weight and BMI) will be performed. 
g Includes body temperature, blood pressure, pulse rate pulse oximetry and respiration rate and will be performed at every visit, prior to treatment, 1-hour post-treatment 
(allowable window of 60-90 minutes) and at 6-10 hours (tmax) after the first CAM2038/placebo q4w dose. 
h ECGs will be assessed at Week 11, prior to treatment and at 6-10 hours (tmax) after the first CAM2038/placebo q4w dose. 
i A serum pregnancy test will be performed at the Final Study Visit/Early Termination. An “in-office” urine pregnancy test will be required monthly (for women of childbearing 
potential). 
j COWS/SOWS will be assessed before dosing and 6-10 hours (tmax) after the first dose of CAM2038/placebo q4w. 
k Subjects who are receiving 16, 24, or 32 mg CAM2038 will be randomized to CAM2038/placebo q4w (64, 96, or 128 mg) and receive 3 doses with CAM2038/placebo q4w 
(Weeks 11, 15 and 19) 
l Rescue medication will not be dispensed at this visit. 


Clinical Trial Protocol 
HS-16-555 
Braeburn Pharmaceuticals 
CONFIDENTIAL 
Protocol Amendment 9 / Version: 10.0 
12-APR-2018 
Page 56 of 99 
 
 
Study Period/Phase: 
 
Double-Blind Phaseab 
 
Final Study Visitc 
 
Follow- up Phased 
Month: 
M4 
M5 
M6 
Week: 
11 
15 
19 
23 
27 
C-SSRSm 
X 
X 
X 
X 
CGI-I Scale 
X 
X 
X 
X 
PGI-I Scale 
X 
X 
X 
X 
Concomitant Medications/Procedures 
X 
X 
X 
X 
X 
AEsn 
X 
X 
X 
X 
X 
Adjust Opioid Treatment 
 
 
 
Xo 
 
AE=Adverse Events; BMI=Body Mass Index; CGI-I=Clinical Global Impression Improvement; C-SSRS=Columbia Suicide Severity Rating Scale; COWS=Clinical Opiate 
Withdrawal Scale; ECG=electrocardiogram; EQ-5D-5L=EuroQoL Group 5-dimenstion 5-level self-report questionnaire; ET=Early Termination; NRS-11=11-point numerical 
rating scale; PGI-I= Patient Global Impression of Improvement; q1w=once weekly; q4w=once monthly; SC=subcutaneous; SOWS=Subjective Opiate Withdrawal Scale; 
WPAI=Work Productivity and Activity Impairment.
 
m Since Last Visit’ version to be used. 
n 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. 
o At the Final Study Visit (or ET) subjects will be transitioned back to standard care or their treatment prior to study entry. 


Clinical Trial Protocol 
HS-16-555 
Braeburn Pharmaceuticals 
CONFIDENTIAL 
Protocol Amendment 9 / Version: 10.0 
12-APR-2018 
Page 57 of 99 
 
 
 
Table 8a:   Schedule of Assessments for Subjects Enrolled from the Randomized Double-Blind Phase to The Open Label 
Safety Extension Phase Weekly Dose 
 
a Open Label Safety Extension Phase visit window is ±3 days for the CAM2038 q1w visit. 
b Telephone contact only. 
c Study treatment may vary depending on subject’s titration schedule.  
d This includes weeks 24, 25, 26, 28, 29, 30, 32, 33, 34, 36, 37, 38, 40, 41, 42, 44, 45, 46, 48, 49, 50, 52, 53, 54, 56, 57, 58, and 59. 
e EOT is week 60 for weekly subjects. 
f A complete physical examination of all major body systems (including height, weight, and BMI) will be performed. 
g Includes body temperature, blood pressure, pulse rate, pulse oximetry and respiration rate and will be performed, prior to treatment during the monthly visit, and 1-hour post-
study treatment (allowable window of 60-90 minutes). 
h ECGs will be assessed quarterly prior to treatment 
i A serum pregnancy test will be performed at the Final Study Visit/Early Termination. An “in-office” urine pregnancy test will be required weekly (for women of childbearing 
potential). 
j COWS/SOWS will be assessed before dosing. 
k Subjects who are receiving 4 mg, 8 mg or 12 mg CAM2038 q1w at enrollment into the Open Label Safety Extension Phase will return to the study site every week for 
administration of CAM2038 q1w throughout the Open Label Safety Extension Phase. Exact times when CAM2038 injection is administered must be recorded. 
Study Phase 
Open Label Extensiona 
End of 
Study 
Follow-Up 
Phaseb 
Month 
M7 
M8 
M9 
M10 
M11 
M12 
M13 
M14 
M15 
 
 
 
Study Treatment Week: 
W23c 
27 
31 
35 
39 
43 
47 
51 
55 
All Other Weekly 
Treatment Visitsd 
EOTe 
Up to 4 
weeks after 
EOT 
Eligibility Criteria Review 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationf 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
ECG 
Xh 
 
 
X 
 
 
X 
 
 
 
X 
 
Clinical Laboratory  
Assessments 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Pregnancy Testi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
COWS/SOWSj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
CAM2038 q1w SC Injectionk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Injection Site Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


Clinical Trial Protocol 
HS-16-555 
Braeburn Pharmaceuticals 
CONFIDENTIAL 
Protocol Amendment 9 / Version: 10.0 
12-APR-2018 
Page 58 of 99 
 
 
 
 
l Rescue Medication will not be dispensed at this visit 
m Blood samples will be collected prior to administration (within 45 minutes); and at approximately 2 hours, 6 hours, 24 hours, 72 hours, 168 hours, 336 hours, and 672 hours 
post administration to measure plasma levels of BPN and norBPN for subjects receiving both CAM2038 qlw and CAM2038 q4w treatments. Actual dates and times of dosing 
of IMP during the safety extension phase as well as blood sampling for PK measurement will be recorded. 
n 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. 
o At the Final Study Visit (or EOT) subjects will be transitioned back to standard care or their prior treatment. 
Study Phase 
Open Label Extensiona 
End of  
Study 
Follow-Up  
Phaseb 
Month 
M7 
M8 
M9 
M10 
M11 M12 
 
M13 
M14 
M15 
All Other Weekly 
Treatment Visitsd 
 
 
Study Treatment Week: 
W23c 
27 
31 
35 
39 
43 
47 
52 
56 
 
 EOTe 
Up to 4 weeks 
after EOT  
Dispense, Collect, and 
Record Rescue Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xl 
 
Daily Electronic Diary Pain 
Rating (NRS- 11) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Steady State PK Samplingm 
 
 
 
X 
 
 
 
 
 
 
 
 
EQ5DL 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
WPAI 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
C-SSRS 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
CGI-I Scale 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
PGI-I Scale 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Concomitant 
Medications/Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adjust Opioid Treatment 
 
 
 
 
 
 
 
 
 
 
Xo 
 


Clinical Trial Protocol 
HS-16-555 
Braeburn Pharmaceuticals 
CONFIDENTIAL 
Protocol Amendment 9 / Version: 10.0 
12-APR-2018 
Page 59 of 99 
 
 
Table 8b:   Schedule of Assessments for Subjects Enrolled from the Randomized Double-Blind Phase to The Open Label 
Safety Extension Phase Monthly Dose 
 
a Open Label Safety Extension Phase visit window is ±3 days for the CAM2038 q1w visit and ±7 days for the CAM2038 q4w visit. 
b Telephone contact only. 
c Study treatment may vary depending on subject’s titration schedule.  All subjects receive a weekly dose at week 23. 
d EOT is 4 weeks after the last monthly injection. 
e A complete physical examination of all major body systems (including height, weight, and BMI) will be performed. 
f Includes body temperature, blood pressure, pulse rate, pulse oximetry and respiration rate and will be performed, prior to treatment during the monthly visit, and 1-hour post-
study treatment (allowable window of 60-90 minutes). 
g ECGs will be assessed every quarterly prior to treatment 
h A serum pregnancy test will be performed at the Final Study Visit/Early Termination. An “in-office” urine pregnancy test will be required monthly (for women of childbearing 
potential). 
i COWS/SOWS will be assessed before dosing. 
jSubjects who are receiving 16, 24, or 32 mg CAM2038 at enrollment into the Open Label Treatment Phase will return to the study site every 4 weeks to be administered 
CAM2038 q4w (64, 96, or 128 mg) throughout the Open Label Safety Extension Phase. Exact times when CAM2038 injection is administered must be recorded. 
k Rescue Medication will not be dispensed at this visit 
 
Study Phase 
Open Label Extensiona 
End of 
Study 
Follow-Up 
Phaseb 
Month 
M7 
M8 
M9 
M10 
M11 
M12 
M13 
M14 
M15 
 
 
Study Treatment Week: 
W23-24c 27-28 
31-32 
35-36 
39-40 
43-44 
47-48 
51-52 
55-56 
EOTd 
Up to 4 weeks 
after EOT 
Eligibility Criteria Review 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examinatione 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECG 
Xg 
 
 
X 
 
 
X 
 
 
X 
 
Clinical Laboratory Assessments 
X 
 
 
X 
 
 
X 
 
 
X 
 
Pregnancy Testh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
COWS/SOWSi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CAM2038 q1w SC Injectionj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Injection Site Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense, Collect, and Record 
Rescue Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xk 
 
Study Phase 
Open Label Extensiona 
End of  
Studyd 
Follow-Up  
Phaseb 


Clinical Trial Protocol 
HS-16-555 
Braeburn Pharmaceuticals 
CONFIDENTIAL 
Protocol Amendment 9 / Version: 10.0 
12-APR-2018 
Page 60 of 99 
 
 
  
 
 
l Study treatment may vary depending on subject’s titration schedule.  All subjects receive a weekly dose at week 23. 
m Blood samples will be collected prior to administration (within 45 minutes); and at approximately 2 hours, 6 hours, 24 hours, 72 hours, 168 hours, 336 hours, and 672 hours 
post administration to measure plasma levels of BPN and norBPN for subjects receiving both CAM2038 qlw and CAM2038 q4w treatments. Actual dates and times of dosing 
of IMP during the safety extension phase as well as blood sampling for PK measurement will be recorded. 
n 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. 
o At the Final Study Visit (or EOT) subjects will be transitioned back to standard care or their prior treatment. 
Month 
M7 
M8 
M9 
M10 
M11 
M12 
M13 
M14 
M15 
 
 
Study Treatment Week: 
W23-24l 
27-28 
31-32 
35-36 
39-40 
43-44 
47-48 
51-52 
55-56 
EOT 
Up to 4 weeks after 
EOT 
Daily Electronic Diary Pain Rating 
(NRS- 11) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Steady State PK Samplingm 
 
 
 
X 
 
 
 
 
 
 
 
EQ5DL 
X 
 
 
X 
 
 
X 
 
 
X 
 
WPAI 
X 
 
 
X 
 
 
X 
 
 
X 
 
C-SSRS 
X 
 
 
X 
 
 
X 
 
 
X 
 
CGI-I Scale 
X 
 
 
X 
 
 
X 
 
 
X 
 
PGI-I Scale 
X 
 
 
X 
 
 
X 
 
 
X 
 
Concomitant 
Medications/Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adjust Opioid Treatment 
 
 
 
 
 
 
 
 
 
Xo 
 


Clinical Trial Protocol 
HS-16-555 
Braeburn Pharmaceuticals 
CONFIDENTIAL 
Protocol Amendment 9 / Version: 10.0 
12-APR-2018 
Page 61 of 99 
 
 
 
Table 9:   Schedule of Assessments for Screening, Transition, and Titration Phases for De Novo Subjects 
 
Study Period/Phase: Screening 
Transition 
Phasea 
Open-Label Titration Phaseb 
Week: W-2 to -1 
W0 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
Day: D-14 to -1 D1 up to 
12 
daysc 
2 to 4 
days 
Informed Consentd 
X 
Eligibility Criteria Review 
X 
Xe 
Demographic Data 
X 
Medical and Medication History 
X 
Physical Examinationf 
X 
Vital Signsg 
X 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Laboratory Assessments 
X 
Xi 
 
X 
Pregnancy Testj 
X 
X 
X 
X 
X 
X 
Hepatitis B/C, HIVk 
X 
Urine Drug Screen 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
a Subjects on BPN at screening will not participate in the down titration and morphine IR phases, but will washout and refrain from their BPN treatment for 12-24 hours prior to 
the test dose on Day 1. 
b Titration Phase visit window is ±3 days. 
c Telephone contact. 
d Subjects must voluntarily provide written informed consent prior to any study-related procedures being performed. 
e Prior to starting the Titration Phase, all Inclusion/Exclusion and other relevant criteria must be met. 
f A complete physical examination of all major body systems (including height, weight, and BMI) will be performed. 
g Includes body temperature, blood pressure, pulse rate, pulse oximetry and respiration rate. 
h Vital signs and ECG will be measured 15 minutes (allowable window up to 60 minutes) before the Buprenex test dose, 15 minutes (allowable window of between 15-30 
minutes) and 1 hour (allowable window of between 60-90 minutes) after the test dose, and 1 hour (allowable window of between 60-90 minutes) and 24 hours 
(allowable window of±3 hour) after the first CAM2038 q1w dose. Vital signs and ECG will thereafter be assessed weekly during the Titration Phase. 
i An additional sample for assessment of electrolytes will be taken 4 weeks after the first dose of CAM2038 q1w. Refer to Table 11 for a list of laboratory analytes. 
j A serum pregnancy test will be performed at Screening. An “in-office” urine pregnancy test will be required every other week during the Titration Phase. (for women of 
childbearing potential). 
k It is the investigator’s responsibility to understand and comply with the laws and regulations that apply to HIV, Hepatitis B, and Hepatitis C testing of blood samples. Hepatitis 
B/C and HIV testing is required unless the site’s IRB prohibits such testing. 


Clinical Trial Protocol 
HS-16-555 
Braeburn Pharmaceuticals 
CONFIDENTIAL 
Protocol Amendment 9 / Version: 10.0 
12-APR-2018 
Page 62 of 99 
 
 
Study Period/Phase: Screening 
Transition 
Phasea 
Open-Label Titration Phaseb 
Week: W-2 to -1 
W0 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
Day: D-14 to -1 D1 up to 
12 
daysc 
2 to 4 
days 
Dispense Treatment Identification Card 
X 
Down-Titrate Opioid Dose 
X 
IR Morphinel 
X 
Buprenex Test Dose 
Xm 
COWS/SOWS 
Xn 
X 
CAM2038 q1w SC Injectiono 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection Site Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense, Collect, and Record Rescue 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Daily Diary Pain Rating (NRS-11) 
X 
Xp 
Daily 
Daily 
Daily 
Daily 
Daily 
Daily 
Daily 
Daily 
EQ-5D-5L 
X 
X 
X 
X 
WPAI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRSq 
X 
X 
X 
X 
X 
X 
Concomitant Medications/Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEsr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
 
l IR morphine (15 mg QID for subjects with screening MED of ≥80 mg/day; or 15 mg TID for subjects with screening MED between 40 mg and 79 mg/day) for at least 2 days 
prior to Day 1 of the Titration Phase. A 12-hour washout from the last IR morphine dose is required before the Buprenex test dose is given. 
m One IM injection of 0.3 mg (1.0 mL) Buprenex. 
n COWS/SOWS will be assessed before the test dose, 15 min (allowable window of between 15-30 minutes) after the test dose, and 24 hours (allowable window of ±3 hour) 
after the first 4 mg or 8 mg CAM2038 dose.  If COWS score is not ≥5, the COWS can be repeated for up to 48 hours. 
o The first dose of either 4 mg or 8 mg CAM2038 q1w will be administered within 4 hours (+30 minutes) after the test dose. During the first week of the Titration Phase, 
subjects who experience significant pain may, at the discretion of the investigator, receive an additional CAM2038 at their respective dose (4mg or 8 mg) on Day 3,4 or 5. Dose 
adjustments will be made by increasing or decreasing the dose level of CAM2038 q1w at the scheduled weekly visits (doses of 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, or 32 mg per 
week). Subjects who require doses >32 mg/week will be discontinued from the study. 
p Electronic diary dispensed after test dose. 
q ‘Screening’ version at Screening and ‘Since Last Visit’ version every other week during the Titration Phase. 
r 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. 


Clinical Trial Protocol 
HS-16-555 
Braeburn Pharmaceuticals 
CONFIDENTIAL 
Protocol Amendment 9 / Version: 10.0 
12-APR-2018 
Page 63 of 99 
 
 
Table 10a:   Schedule of Assessments for De Novo Subjects Enrolled in Open Label Extension for Weekly Patients  
 
Study Phase 
Open Label Treatmenta 
EOTb 
Follow
-up 
Phase 
Open Label Treatment Week: 
11 
15 19 
23 
27 
31 
35 
39 
43 
47 
51 
55 
All Other Weekly 
Treatment Visitsc 
EOT 
Up to 4 
weeks 
after 
EOT 
Eligibility Criteria Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationd 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
ECG 
Xf 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Clinical Laboratory Assessments 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Pregnancy Testg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
COWS/SOWSh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
CAM2038 SC Injectioni 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Injection Site Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense, Collect, and Record Rescue 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xj 
 
 
a Open Label Safety Extension Phase visit window is ±3 days for theCAM2038 q1w visit and ±7 days for the CAM2038 q4w visit 
b Telephone contact within 4 weeks after EOT for AEs and Conmeds. 
c This includes weeks 12, 13, 14, 16, 17, 18, 20, 21, 22, 24, 25, 26, 28, 29, 30, 32, 33, 34, 36, 37, 38, 40, 41, 42, 44, 45, 46, 48, 49, 50, 52, 53, 54, 55, 57, 58 
and 59. 
d A complete physical examination of all major body systems (including height, weight, and BMI) will be performed. 
e Includes body temperature, blood pressure, pulse rate, pulse oximetry and respiration rate and will be performed prior to treatment at each monthly visit and 1hr post-study 
treatment (allowable window of between 60-90 minutes). 
f ECGs will be assessed quarterly prior to treatment 
g A serum pregnancy test will be performed at the Final Study Visit/Early Termination. An “in-office” urine pregnancy test will be required weekly (for women of childbearing 
potential). 
h COWS/SOWS will be assessed before dosing. 
i Subjects who are receiving 4 mg, 8 mg or 12 mg CAM2038 q1w at enrollment into the Open Label Safety Extension Phase will return to the study site every week for 
administration of CAM2038 q1w throughout the Open Label Safety Extension Phase. Exact times when CAM2038 injection is administered must be recorded 
j Rescue Medication will not be dispensed at this visit 


Clinical Trial Protocol 
HS-16-555 
Braeburn Pharmaceuticals 
CONFIDENTIAL 
Protocol Amendment 9 / Version: 10.0 
12-APR-2018 
Page 64 of 99 
 
 
Study Phase 
Open Label Treatmenta 
EOTb 
Follow
-up 
Phase 
Open Label Treatment Week: 
11 
15 19 
23 
27 
31 
35 
39 
43 
47 
51 
55 
All Other Weekly 
Treatment Visitsc 
EOT 
Up to 4 
weeks 
after 
EOT 
Daily Electronic Diary Pain Rating (NRS- 
11) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Steady State PK Samplingk 
 
 
 
Xk 
 
 
 
 
 
 
 
 
 
 
 
EQ5DL 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
WPAI 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
C-SSRSl 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
CGI-I Scale 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
PGI-I Scale 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Concomitant medications / Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEsm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adjust Opioid Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xn 
 
 
k At week 23 or later, PK sample will be done. Blood samples will be collected prior to administration (within 45 minutes); and at approximately 2 hours, 6 hours, 24 hours, 
72 hours, 168 hours, 336 hours, and 672 hours post administration to measure plasma levels of BPN and norBPN for subjects receiving both CAM2038 qlw and CAM2038 q4w 
treatments. Actual dates and times of dosing of IP during the safety extension phase as well as blood sampling for PK measurement will be recorded. 
l ‘Since Last Visit’ version to be used. 
m 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. 
n At the Final Study Visit (or EOT) subjects will be transitioned back to standard care or their prior treatment prior to study entry 


Clinical Trial Protocol 
HS-16-555 
Braeburn Pharmaceuticals 
CONFIDENTIAL 
Protocol Amendment 9 / Version: 10.0 
12-APR-2018 
Page 65 of 99 
 
 
 
Table 10b:   Schedule of Assessments for De Novo Subjects Enrolled in Open Label Extension for Monthly Patients  
 
Study Phase 
Open Label Treatmenta 
EOTb 
Follow
-up 
Phase 
Open Label Treatment Week: 
11 
15 
19 
23 
27 
31 
35 
39 
43 
47 
51 
55 
EOT 
Up to 4 
Weeks 
after EOT 
Eligibility Criteria Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationc 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
Xe 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Clinical Laboratory Assessments 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Pregnancy Testf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
COWS/SOWSg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CAM2038 SC Injectionh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Injection Site Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense, Collect, and Record Rescue 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xi 
 
Daily Electronic Diary Pain Rating (NRS- 
11) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
a Open Label Safety Extension Phase visit window is ±3 days for the CAM2038 q1w visit and ±7 days for the CAM2038 q4w visit 
b Telephone contact within 4 weeks after EOT for AEs and Conmeds. 
c A complete physical examination of all major body systems (including height, weight, and BMI) will be performed. 
d Includes body temperature, blood pressure, pulse rate, pulse oximetry and respiration rate and will be performed prior to treatment at each monthly visit and 1hr post-study 
treatment (allowable window of between 60-90 minutes). 
e ECGs will be assessed quarterly prior to treatment 
f A serum pregnancy test will be performed at the Final Study Visit/Early Termination. An “in-office” urine pregnancy test will be required monthly (for women of childbearing 
potential). 
g COWS/SOWS will be assessed before dosing. 
h Subjects who are receiving 16, 24, or 32 mg CAM2038 at enrollment into the Open Label Safety Extension Phase will return to the study site every 4 weeks to be 
administered CAM2038 q4w (64, 96, or 128 mg) throughout the Open Label Safety Extension Phase. Exact times when CAM2038 injection is administered must be recorded 
i Rescue Medication will not be dispensed at this visit 


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Study Phase 
Open Label Treatmenta 
EOTb 
Follow
-up 
Phase 
Open Label Treatment Week: 
11 
15 
19 
23 
27 
31 
35 
39 
43 
47 
51 
55 
EOT 
Up to 4 
Weeks 
after EOT 
Steady State PK Samplingj 
 
 
 
Xj 
 
 
 
 
 
 
 
 
 
 
EQ5DL 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
WPAI 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
C-SSRSk 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
CGI-I Scale 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
PGI-I Scale 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Concomitant medications / Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEsl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adjust Opioid Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
 
j At week 23 or later but no later than 4 weeks prior to a subject’s scheduled EOT visit, PK draws will begin. Blood samples will be collected prior to administration 
(within 45 minutes); and at approximately 2 hours, 6 hours, 24 hours, 72 hours, 168 hours, 336 hours, and 672 hours post administration to measure plasma levels of BPN and 
norBPN for subjects receiving both CAM2038 qlw and CAM2038 q4w treatments. Actual dates and times of dosing of IP during the safety extension phase as well as blood 
sampling for PK measurement will be recorded. 
k ‘Since Last Visit’ version to be used 
l 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. 
m At the Final Study Visit (or EOT) subjects will be transitioned back to standard care or their prior treatment prior to study entry 


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9.1. Demographics and Other Baseline Characteristics 
9.1.1. 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 informed consent form (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. 
 
9.1.2. Demographics 
The following demographics will be recorded: age (birth date), sex, race, and ethnicity. A complete 
psychosocial history will be obtained including education, employment status, marital/significant other 
status, residential status, and legal status/arrest history. 
 
9.1.3. Medical History 
The complete medical history, up to the previous 5 years, will include histories of acute, chronic, or 
infectious disease; surgical or oncologic histories; and any reported conditions affecting major body systems 
or are the source of the subjects’ chronic pain. All findings on medical history will be evaluated by the 
investigator for clinical significance. 
 
9.1.4. Medication History 
All medications (prescription and non-prescription, herbal medications/natural health products, or 
investigational drugs) taken by the subjects during the 30 days prior to Screening will be recorded in the 
source documentation as medication history. A brief substance abuse history will also be collected. 
 
9.1.5. Contraceptive Requirements 
Female subjects of childbearing potential must be using and willing to continue using medically 
acceptable contraception during the study from Screening through study completion. Examples of 
medically acceptable forms of contraception: 
▪ 
True abstinence (at the discretion of the investigator. 
▪ 
Intrauterine device in place for at least 3 months. 
▪ 
Non-surgical permanent sterilization (e.g., Essure procedure) at least 3 months prior to 
dosing. 
▪ 
Barrier method (condom or diaphragm) with spermicide for at least 14 days before Screening and 
through study completion. 
▪ 
Stable hormonal contraceptive use for at least 3 months prior to dosing and through study 
completion. 
Female subjects of non-childbearing potential are not required to use contraception or undergo pregnancy 


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tests; however, they must have been 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 amenorrhoeic for at least 2 years without 
another cause or amenorrhoeic for at least 1 year without another cause and a documented follicle 
stimulating hormone level ≥50 mIU/mL. 
 
9.2. Eligibility Review and Randomization 
At the Screening Visit, the investigator or designee must document that the subject meets all inclusion 
and no exclusion criteria via a signed note or eligibility and clinical stability checklist. In addition, 
subjects must fulfill the criteria for entry into the Transition Phase, the Titration Phase, the Double-Blind 
Phase and the Open Label Safety Extension Phase. Randomization will be accomplished centrally using 
an Interactive Response Technology managed by the Sponsor. 
 
9.3. Efficacy Assessments 
Details regarding primary, secondary, and exploratory endpoints are provided in Section 9.6 and discussed 
further in Section 11.3 (Statistical Analysis). The following sections provide an overview of the efficacy 
assessments included in the study. 
 
9.3.1. Numerical Rating Scale (NRS-11) 
The NRS-11 is an 11-point scale with anchors at 0 (no pain) and 10 (worst pain imaginable). Subjects 
will record their API at Screening and test dose Day 1 on paper and their WPI and API scores over the 
past 24 hours daily in an electronic diary. Subjects should record their “pain at that moment” on their 
electronic diary immediately prior to taking rescue medication. Study personnel and subjects will 
undergo training on how to complete this assessment. 
 
9.3.2. Rescue Medications 
The number of rescue doses taken per day and proportion of days rescue medication was taken will be 
recorded using an electronic diary. Subjects will be instructed on the proper use and timing of rescue 
medication. Subject’s pain intensity will be recorded in the electronic diary whenever the subject takes 
rescue medication. 
 
9.3.3. EuroQoL Group 5-Dimension 5-Level Self-Report Questionnaire (EQ-5D-
5L): Descriptive System 
The EuroQoL Group 5-dimension 5-level self-report questionnaire (EQ-5D-5L) descriptive system is 
a generic, multidimensional, health-related, quality-of-life instrument. The profile allows participants 
to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and 
mood using a 5-level scale. These combinations of attributes will be converted into a weighted health-
state Index Score according to the United States population-based algorithm, with higher scores 
indicating better quality of life. 
 
9.3.4. Work Productivity and Activity Impairment (WPAI) 
The Work Productivity and Activity Impairment (WPAI) is a self-administered instrument used to 
measure the effect of general health and symptom severity on work productivity and regular activities, 
and yields 4 types of scores: Absenteeism (work time missed)=Question (Q)2/(Q2+4))*100); 


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Presenteeism (impairment at work/reduced on-the-job effectiveness)=(Q5/10)*100); Work Productivity 
Loss (overall work impairment/absenteeism plus presenteeism)=(Q2/(Q2+Q4)+[(1-
Q2/(Q2+Q4))x(Q5/10)])*100); and Activity Impairment=(Q6/10)*100. Scores range from 0 to 1 for each 
of the above 4 types; higher scores indicate greater impairment. 
 
9.3.5. Clinician Global Impression of Improvement (CGI-I) Scale 
The Clinician Global Impression of Improvement (CGI-I) scale is a 7-point scale that requires the 
clinician to assess how much the subject's CLBP has improved or worsened relative to a baseline state at 
the beginning of the intervention and rated as: 1, very much improved; 2, much improved; 3, minimally 
improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse (Guy, 1976). 
 
9.3.6. Patient Global Impression of Improvement (PGI-I) Scale 
The Patient Global Impression of Improvement (PGI-I) scale is a 7-point scale that requires the subject to 
assess how much the his/her CLBP has improved or worsened relative to a baseline state at the beginning 
of the intervention and rated as: 1, much worse; 2, worse; 3, a little worse; 4, no change; 5, a little better; 
6, better; or 7, much better. 
 
9.4. Pharmacokinetic assessments 
 
Venous blood samples (6 mL each) will be collected, as indicated in Tables 8 and 10. Samples will be 
collected, processed, and shipped according to instructions provided in the Study MOP. The actual date and 
time of each blood sample collection will be recorded. 
 
The plasma concentrations of BPN and norBPN will be summarized descriptively. PK parameters of BPN 
will be evaluated and reported separately. 
 
9.5. 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/placebo injections may be 
discontinued as clinically indicated. 
Opioid-naïve subjects will not be permitted into this study, as the study drug is very potent and the doses 
for this study have been selected for opioid-experienced subjects. Opioid-experienced subjects are defined 
as taking ≥40 mg/day of oral morphine or MED, including ATC and rescue medication, for the 
management of their CLBP for the 14 days prior to Screening. 
 
9.5.1. Adverse Events and Serious Adverse Events 
The following definitions, developed in accordance with the US Code of Federal Regulations (CFR) and 
the International Council for Harmonization (ICH) Clinical Safety Data Management Guidance for 
Industry, E2A, will be used for the purpose of identifying AEs in this clinical study. 
 
An AE is defined as any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE 
can therefore be any unfavorable and/or unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational medicinal product, whether 
or not related to the investigational medicinal product. All AEs, including observed or volunteered 


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problems, complaints, or symptoms, are to be recorded on the appropriate CRF. 
AEs, will be monitored and documented from the time of informed consent until the final Follow-up. AEs 
that have been designated as possibly related to study drug will be followed until resolution or stabilization. 
Subjects should be instructed to report any AE that they experience to the investigator. Investigators should 
make an assessment of AEs at each visit and record the event on the appropriate AE CRF. 
Wherever possible, a specific disease or syndrome, rather than individual associated signs and symptoms, 
should be identified by the investigator and recorded on the CRF. However, if an observed or reported 
sign or symptom is not considered a component of a specific disease or syndrome by the investigator, it 
should be recorded as a separate AE on the CRF. Additionally, the condition that led to a medical or 
surgical procedure (e.g., surgery, endoscopy, tooth extraction, or transfusion) should be recorded as an 
AE, not the procedure. 
Any medical condition already present at Screening should not be reported as an AE, unless the medical 
condition or signs or symptoms present at Screening changes in severity or seriousness at any time during 
the study. In this case, it should be reported as an AE. 
Clinically significant abnormal laboratory or other examination (e.g., ECG) findings that are detected 
during the study or are present at Screening and significantly worsen during the study should be 
reported as AEs. The investigator will exercise his or her medical and scientific judgment in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically significant. Clinically 
significant abnormal laboratory values occurring during the clinical study will be followed until repeat 
tests return to normal, stabilize, or are no longer clinically significant. Any abnormal test that is 
determined to be an error does not require reporting as an AE. 
 
 
9.5.2. Adverse Drug Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be considered an 
adverse drug reaction. “Responses” to a medicinal product means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility, i.e., the relationship cannot be ruled out. 
 
9.5.3. Unexpected Adverse Drug Reaction 
An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity of which is 
not consistent with the applicable product information. 
9.5.4. Assessment of Adverse Events by the Investigator 
The investigator will assess the severity (intensity) of each AE as mild, moderate, or severe, and will also 
categorize each AE as to its potential relationship to study drug using the categories of related, possibly 
related, or not related. 
Assessment of Severity: 
Mild – An event that is easily tolerated and generally not interfering with normal daily activities.  
Moderate – An event that is sufficiently discomforting to interfere with normal daily activities.  
Severe – An event that is incapacitating with inability to work or perform normal daily activities.  
Causality Assessment: 
The relationship of an AE to the administration of the study drug is to be assessed according to the 
following definitions: 


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No (unrelated, not related, no relation) – The time course between the administration of study drug and the 
occurrence or worsening of the AE rules out a causal relationship and another cause (concomitant drugs, 
therapies, complications, etc.) is suspected. 
Possibly related – An event that follows a reasonable temporal sequence from administration of the study 
drug, but that may be due to another cause and could also be reasonably explained by the subject’s clinical 
state or other modes of therapy administered to the subject. 
Yes (related) – The time course between the administration of study drug and the occurrence or worsening 
of the AE is consistent with a causal relationship and no other cause (concomitant drugs, therapies, 
complications, etc.) can be identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the study 
drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 
The following factors should also be considered: 
▪ 
The temporal sequence from study drug administration- 
o The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event. 
▪ 
Underlying, concomitant, intercurrent diseases- 
o Each report should be evaluated in the context of the natural history and course of the CLBP 
being treated and any other disease the subject may have. 
▪ 
Concomitant drug- 
▪ 
The other drugs the subject is taking or the treatment the subject receives should be examined to 
determine whether any of them might be recognized to cause the event in question.  
▪ 
Known response pattern for this class of study drug- 
o Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 
▪ 
Exposure to physical and/or mental stresses- 
o The exposure to stress might induce adverse changes in the recipient and provide a 
logical and better explanation for the event. 
▪ 
The pharmacology and PK of the study drug- 
o The known pharmacologic properties (absorption, distribution, metabolism, and 
excretion) of the study drug should be considered. 
 
9.5.5. Serious Adverse Event  
An AE or adverse reaction is considered serious if, in the view of either the investigator or Sponsor, it 
results in any of the following outcomes: 
▪ 
Death 
▪ 
A life-threatening AE 
o NOTE: An AE or adverse reaction is considered “life-threatening” if, in view of the 


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investigator or Sponsor, its occurrence places the subject at immediate risk of death. It does 
not include an event that, had it occurred in a more severe form, might have caused death. 
▪ 
Requires hospitalization or prolongation of existing hospitalization 
o NOTE: Any hospital admission with at least one overnight stay will be considered an 
inpatient hospitalization. An emergency room visit without hospital admission will not be 
recorded as a SAE under this criterion, nor will hospitalization for a procedure scheduled or 
planned before signing of informed consent. However, unexpected complications and/or 
prolongation of hospitalization that occur during elective surgery should be recorded as AEs 
and assessed for seriousness. Admission to the hospital for social or situational reasons (i.e., 
no place to stay, live too far away to come for hospital visits) will not be considered 
inpatient hospitalizations. 
▪ 
A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions 
▪ 
A congenital anomaly/birth defect 
▪ 
An important medical event 
NOTE: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed above. Examples of such 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 hospitalizations, or the development of drug dependency. 
All AEs requiring hospitalization or prolongation of a pre-existing hospitalization should be reported as 
SAEs, unless they occur after the final Follow-up or 30 days after early termination AND are not 
considered to be drug-related by the investigator. 
Hospitalizations meeting the following criteria will not be reported as an SAE but must be recorded 
on the appropriate CRF: study specified hospitalization, short-term administrative hospitalization for 
procedures, tests or treatments of conditions that would not otherwise constitute an SAE, or elective 
hospitalizations. 
 
9.5.6. Serious Adverse Event Reporting – Procedures for Investigators 
Initial Reports 
All SAEs occurring from the time of informed consent through Follow-up (or 30 days following early 
termination) must be reported to Medpace Clinical Safety within 24 hours of the knowledge of the 
occurrence (this refers to any AE that meets any of the aforementioned serious criteria). Serious AEs that 
have been designated as possibly related to study drug will be followed until resolution or stabilization. 
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) system for 
the study. When the form is completed, Medpace Safety personnel will be notified electronically and will 
retrieve the form. If the event meets serious criteria and it is not possible to access the EDC system, send 
an email to Medpace Safety at MedPace-safetynotification@medpace.com or call the Medpace SAE 
hotline (phone number listed below), and fax the completed paper SAE form to Medpace (fax number 
listed below) within 24 hours of awareness. When the EDC system becomes available, the SAE 
information must be entered within 24 hours of the system becoming available. 


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Safety Contact Information: Medpace Clinical Safety 
Medpace SAE hotline – USA: 
Telephone: +1-800-730-5779, ext. 2999 or +1-513-579-9911, ext. 2999 
Facsimile: +1-866-336-5320 or +1-513-579-0444 
e-mail: medpace-safetynotification@medpace.com 
Follow-Up Reports 
The investigator must continue to follow the subject until the SAE has subsided or until the condition 
becomes chronic in nature, stabilizes (in the case of persistent impairment), or the subject dies. 
Within 24 hours of receipt of follow-up information, the investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation (e.g., subject 
discharge summary or autopsy reports) to Medpace Clinical Safety via fax or e-mail. If it is not possible to 
access the EDC system, refer to the procedures outlined above for initial reporting of SAEs. 
 
9.5.7. Pregnancy 
If the subject becomes pregnant during the study or within 30 days of discontinuing study drug, the 
investigator should report the pregnancy to Medpace Clinical Safety within 24 hours of being notified. 
Medpace Clinical Safety will then forward the Exposure In Utero form to the investigator for completion. 
A subject becoming pregnant while on study drug will immediately be withdrawn from the study and early 
termination study procedures will be performed. 
The subject should be followed by the investigator until completion of the pregnancy. If the pregnancy 
ends for any reason before the anticipated date, the investigator should notify Medpace Clinical Safety. At 
the completion of the pregnancy, the investigator will document the outcome of the pregnancy. If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE (i.e., postpartum 
complication, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly), the investigator 
should follow the procedures for reporting an SAE. 
 
9.5.8. Expedited Reporting 
The Sponsor will report all relevant information about suspected unexpected serious adverse reactions that 
are fatal or life-threatening as soon as possible to the FDA, and in any case no later than 7 days after 
knowledge by the Sponsor of such a case, and that relevant follow-up information will subsequently be 
communicated within an additional 8 days. 
All other suspected unexpected serious adverse reactions will be reported to the FDA as soon as possible, 
but within a maximum of 15 days of first knowledge by the Sponsor. 
The Sponsor will also inform all investigators as required. 
 
9.5.9. Clinical Laboratory Assessments 
All protocol-specified laboratory tests on blood and urine samples will be performed at a selected 
central laboratory, with the exception of urine pregnancy tests that are conducted at the study site. 
The central laboratory will generate laboratory reports and forward them to the clinical site in a 
timely manner. It is the responsibility of the investigator to review and sign all 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 


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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 11. 
 
Table 11:  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 
Creatinine phosphokinase 
Total cholesterol (non-fasting) 
Color 
pH 
Specific gravity 
Ketones 
Protein 
Glucose 
Bilirubin 
Nitrite 
Urobilinogen 
Occult blood 
Microscopic examination of 
sediment, only if urinalysis 
dipstick results are abnormal 
Coagulation 
Prothrombin time, International 
normalized ratio 
In addition to the clinical laboratory tests, a serum pregnancy test will be performed at the Screening Visit 
and the Final Study Visit/Early Termination for women of childbearing potential. An “in-office” urine 
pregnancy test will be required every other week during the Titration Phase and weekly/monthly during 
the Double-Blind Phase (for women of childbearing potential). 


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A blood sample for a serology panel testing for hepatitis B surface antigen, hepatitis C RNA, and HIV 
will be performed for all subjects, unless a site’s IRB prohibits such testing. It is the investigator’s 
responsibility to understand and comply with all laws and regulations that apply to the testing of blood for 
HIV and hepatitis B and C. These laws and regulations may include state laws related to written consent, 
separate from the ICF for this study, and pre- and post-test counseling. 
 
The total blood volume to be taken per subject will be approximately 75 mL, as each blood 
collection will be approximately 15 mL. 
Every attempt should be made to collect samples for a urine toxicology test and BPN blood concentration 
if a subject experience an SAE or is discontinued from the study due to an AE. 
 
9.5.10. Vital Signs 
Vital signs will consist of temperature, blood pressure (systolic and diastolic blood pressure, mmHg), 
pulse rate (beats per minute), pulse oximetry and respiratory rate (breaths/min) collected while sitting, 
following a rest period of at least 3 minutes. 
 
9.5.11. 12-Lead Electrocardiogram (ECG) 
12-lead ECGs will be performed after the subject has been resting in a recumbent/supine position for at 
least 3 minutes. The ECG variables will include ventricular heart rate and the PR, QRS, QT, and QTcF 
intervals. The ECGs will be signed and dated by a medically-qualified individual to confirm review of the 
ECG and verify whether any abnormalities are clinically significant. In general, abnormal, clinically 
significant ECGs are expected to be associated with an item recorded in the medical history or with an 
AE. ECGs will be performed at the Screening Visit, 15 minutes before and 15 minutes and 1 hour after the 
Buprenex test dose, 1 and 24 hours, ± 3 hours, after the first CAM2038 q1w dose and then weekly during 
the Titration Phase Double-Blind Phase. For q1w subjects, ECGs will be performed monthly during the 
Double-Blind Phase.  For q4w subjects, ECGs will be performed at 6-10 hours (tmax) after the first 
CAM2038/placebo q4w injection in the Double-Blind Phase, then monthly thereafter, quarterly in the 
Open Label Safety Extension, and at the Final Study Visit/Early Termination. 
Male subjects who have a QTcF >450 ms or post-baseline increases ≥60 ms and female subjects who have 
a QTcF >470 ms or post-baseline increases ≥60 ms will be monitored closely with repeated ECGs until 
their ECGs return to baseline. Any subjects with QTcF ≥500 ms will have their dose withheld and repeat 
ECGs until their ECG values return to baseline. In some cases, the subject will need to be discontinued 
from the study and will not receive any more injections of CAM2038/placebo. The investigator can refer 
the subject to a cardiologist, if necessary. 
 
9.5.12. Physical Examination 
A complete physical examination, including all major body systems (and height, weight, and BMI) will be 
performed at Screening and at the Final Study Visit/Early Termination. 
 
9.5.13. Injection Site Examination 
CAM2038 or placebo injection sites will be examined during each scheduled visit for any signs of adverse 
site reactions, including erythema, pruritus, edema, pain, etc. The pain scale will be completed by the 
subjects within 10 minutes after each injection. The new injection site will also be examined within 15 
minutes after each injection to determine if any site related AEs have occurred. Additionally, the previous 
injection site will be examined in the similar fashion as the current injection site.  Subjects will also be 
queried specifically about local tolerability AEs in connection to the examinations. Injection site 


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examination can only be performed by the blinded site personnel. If an injection site reaction is observed, 
non-identifying pictures of the injection site, accompanied by a ruler adjacent to the injection site, will be 
taken and placed in the subject’s files. 
 
9.5.14. 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. 
 
9.5.15. Columbia-Suicide Severity Rating Scale (C-SSRS) 
The Columbia-Suicide Severity Rating Scale (C-SSRS) will be used to assess both behavior and ideation 
that 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 Screening version (6 months and lifetime 
history) and the Since Last Visit version. 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. 
The C-SSRS is to be administered by the investigator or his/her qualified designee at every visit as 
indicated in the Schedule of Assessments. Note: Qualified designee is defined as an individual who 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. 
 
9.5.16. Urine Drug Screen 
A 12-panel urine drug screen will test for the following drugs of abuse: 
tetrahydrocannabinol/marijuana, cocaine, phencyclidine, morphine, methamphetamines, methadone, 
amphetamines, barbiturates, benzodiazepines, methylenedioxymethamphetamine, oxycodone and 
tricyclic antidepressants. 
 
9.5.17. Clinical Opiate Withdrawal Scale (COWS) 
The study personnel will assess clinical observations indicative of withdrawal using the COWS. This scale 
consists of 11 common opiate withdrawal signs or symptoms, rated on a numeric scale and based on a 
timed period of observation of the subject by the rater. 
 
9.5.18. Subjective Opiate Withdrawal Scale (SOWS) 
Subjects will complete a self-assessment of withdrawal symptoms using the Subjective Opiate Withdrawal 
Scale (SOWS). This form contains 16 questions that rate the intensity of withdrawal from 0 (“Not at all”) 
to 4 (“Extremely”). 
 
9.5.19. 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 after 


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the beginning of the clinical trial or until such time that they are reasonably certain that their ability to 
engage in such activities is not adversely affected. 
 
9.6. Efficacy and Safety Variables 
9.6.1. Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline in WAAPI and the primary timepoint will be 
Week 12 of the Double-Blind Phase.   
 
9.6.2. Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
▪ 
Change from baseline in the WAWPI scores at Week 12 of the Double- Blind Phase, based on an 
NRS-11. 
▪ 
Percentage of subjects with a 30% or greater decrease in API from baseline to Week 12 of the 
Double-Blind Phase. 
▪ 
Rescue medication usage (number of days used and total dose) during the Double-Blind Phase. 
▪ 
Change from baseline to Week 12 of the Double-Blind Phase in EQ-5D-5L score. 
▪ 
Change from baseline to Week 12 of the Double-Blind Phase in Work Productivity and WPAI 
score.  
▪ 
Time to loss of efficacy, defined as discontinuation of study drug for lack of efficacy. 
 
9.6.3. Safety Endpoints 
The safety endpoint are as follows: 
▪ 
Occurrence of AEs throughout the study. 
▪ 
Concomitant medication usage throughout the study. 
 
9.6.4. Exploratory Endpoints 
The safety endpoint are as follows: 
▪ 
Change from baseline to Week 12 of the Double-Blind Phase in Clinical Global Impression of 
Improvement (CGI-I) scale (as assessed by the Investigator). 
▪ 
Change from baseline to Week 12 of the Double-Blind Phase in Patient Global Impression of 
Improvement (PGI-I) scale (as assessed by the subject 
 
 


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10. 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 10.2. 
Actions to ensure the accuracy and reliability of data include the selection of qualified investigator s 
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 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. 
 
10.1. 
Data Collection 
Source documents include, but are not limited to, original documents, data and records such as 
hospital/medical records (including electronic health records), clinic charts, lab results, participant 
diaries, data recorded in automated instruments, microfilm or magnetic media, and pharmacy records. 
This study will use an EDC system. 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. 
 
10.2. 
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, as well as other 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 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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11. STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
 
11.1. 
Statistical and Analytical Plans 
Complete details of the statistical analyses to be performed will be documented in a statistical analysis plan 
(SAP), which will be completed prior to unblinding of the study data from the core study. This document 
will include more detail of analysis populations, summary strategies, and any amendments to the proposed 
analyses listed here, if necessary. A separate SAP will describe the analyses to be performed for the Open 
Label Safety Extension Phase. Any changes to the SAP will be outlined in the final study report. 
 
11.2. 
Analysis Populations 
Four analysis populations will be considered for the randomized Double-Blind Phase of the study: 
• 
Randomized Population: The Randomized Population will consist of all subjects who 
have been assigned random treatment. 
• 
Intent-to-Treat (ITT) Population: The ITT Population will include all randomized subjects. The 
primary efficacy analyses will be based on the ITT Population. 
• 
Safety Population: The Safety Population will include all subjects who have received any study 
medication (CAM2038). Analysis based on this population will group subjects according to the 
treatment they actually received, regardless of the treatment they were randomized to receive. All 
safety analyses will be based on the Safety Population. 
• 
Per-Protocol Population: The Per-Protocol Population will include all ITT subjects with no 
major protocol violations. Major protocol violation criteria will be established prior to the 
database lock and included in the protocol deviation plan.  Protocol deviations will be presented 
in the clinical study report.  Efficacy analyses may also be performed based on the per protocol 
population.   
Analysis populations for the Open Label Safety Extension Phase will include: 
 
• 
Intent-to-Treat (ITT) Population: The ITT Population will include all subjects enrolled into the 
Open Label Safety Extension. Efficacy analyses will be based on the ITT Population. 
• 
Safety Population: The Safety Population will include all subjects who have received any study 
drug. All safety analyses will be based on the Safety Population. 
• 
Per-Protocol Population: The Per-Protocol Population will include all ITT subjects without 
major protocol violations. Major protocol violation criteria will be established prior to the 
database lock. 
• 
PK population: The PK population will include all subjects who have received CAM2038 in the 
treatment phase and from whom at least 1 measurable plasma concentration is obtained. 
Planned analyses for the Open Label Extension will be detailed in the SAP which will be finalized prior to 
Database Lock. 
 
11.3. 
Planned Analyses 


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11.3.1. Demographics and Baseline Characteristics 
A summary of demographics and baseline characteristics will be presented by treatment arm and overall 
for the ITT, Safety and PK Populations. 
Demographic data and baseline clinical characteristics will be summarized. 
Tabular summaries and/or listings will be provided for baseline clinical characteristics, such as BMI, type 
of primary opioid use (e.g., prescription opioid pain relievers, other), medical history, inclusion/exclusion 
criteria, and medication history. 
 
11.3.2. Primary Efficacy Analysis 
The primary analysis will be performed based on the ITT population.  The primary efficacy endpoint 
is the change from baseline in WAAPI and the primary timepoint will be Week 12 of the Double-Blind 
Phase.   
 
11.3.3. Missing Value Imputation 
Unless otherwise stated, all other missing values will not be imputed. 
 
11.3.4. Sensitivity Analysis 
Additional sensitivity analyses may be performed as appropriate. 
 
11.3.5. Analysis of Secondary Efficacy Endpoints 
The secondary efficacy endpoints include: 
▪ 
Change from baseline in the WAWPI scores at Week 12 of the Double-Blind Phase based on an NRS-
11. 
▪ 
Percentage of subjects with a 30% or greater decrease in API from baseline to Week 12 of the 
Double-Blind Phase. 
▪ 
Rescue medication usage (number of days used and total dose) during the Double-Blind Phase. 
▪ 
Change from baseline to Week 12 of the Double-Blind Phase in EQ-5D-5L score. 
▪ 
Change from baseline to Week 12 of the Double-Blind Phase in WPAI score. 
▪ 
Time to loss of efficacy, defined as discontinuation of study drug for lack of efficacy. 
 
Change from Baseline in Weekly Average of Daily Worst Pain Intensity (WAWPI) over 
Time 
This variable will be analyzed via methods similar to those used to analyze the primary efficacy variable. 
 
Use of Rescue Medication 
Percentage of days in the study that rescue medication is used will be calculated for both treatment groups. 
This variable will be analyzed via an analysis of variance model with treatment effects. The estimated 
treatment effects, treatment difference and the two-sided 95% CI of the treatment difference will be 
presented. 
Percent of subjects who used rescue medication will also be calculated for both treatment groups. This 
variable will be analyzed using the Chi-square test. The percentages, the difference of the percentages, and 


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the two-sided 95% CI of the treatment difference will be presented. The 95% CIs of the treatment 
difference will be calculated using normal approximation. 
 
Change from Baseline to Week 12 of the Double-Blind Phase in EQ-5D-5L score 
This variable will be analyzed via methods similar to those used to analyze the primary efficacy variable. 
 
Change from Baseline to Week 12 of the Double-Blind Phase in WPAI score 
This variable will be analyzed via methods similar to those used to analyze the primary efficacy variable. 
 
Time to Loss of Efficacy 
Time to loss of efficacy is defined as discontinuation of study drug for lack of efficacy. Time to loss of 
efficacy will be analyzed via log-rank model with treatment effects. Time to event “survival” curves will 
be presented using the Kaplan-Meier method. Median time to event and the 95% CI of the median times 
will be presented, if estimable. In this time to event analyses, subjects who discontinue the study due to 
any reason other than “lack of efficacy” will be censored at the time they discontinued and subjects who 
completed the study will be censored at the time they completed the study. 
 
11.3.6. Analysis of Pharmacokinetics 
 
Plasma concentration data of BPN and norbuprenorphine (norBPN) will be listed for the PK Population by 
analyte, subject and actual time after last dose. Concentrations below the lower limit of quantification (BLQ) 
will be indicated by BLQ<0.0125 for BPN and BLQ<0.0200 for norBPN in the listings. Individual BPN and 
norBPN plasma concentration-time data will be displayed graphically on linear and semi-logarithmic scales 
by analyte and dose.  
 
Plasma concentrations of BPN and norBPN will be summarized descriptively (n, arithmetic mean, standard 
deviation [SD], geometric mean, geometric CV%, minimum, median and maximum) for the PK Population 
by analyte, dose and scheduled time after last dose. Mean plasma concentration-time data will be displayed 
graphically on linear and semi-logarithmic scales by analyte. 
 
Trough concentration during a dosage interval at steady state (Css,trough) of BPN and norBPN will be 
summarized (n, arithmetic mean, standard deviation [SD], geometric mean, geometric CV%, minimum, 
median and maximum) for the PK Population by analyte, dose and scheduled time after last dose.  
 
Model predicted PK parameters of BPN will be evaluated by population PK modeling and reported 
separately. 
 
 
11.3.7. Analysis of Safety 
Exposure will be summarized by treatment group. 
AEs will be coded by primary system organ class (SOC) and preferred term according to the Medical 
Dictionary for Regulatory Activities and summarized by number and percent of subjects in each primary 
SOC and preferred term. Summaries of these AE subsets will be presented for relationship to study drug, 
intensity, seriousness, AEs or SAEs leading to discontinuation, and AEs occurring in 5% or greater of any 
treatment group (by preferred term). Frequencies for deaths and hospitalizations will also be summarized 


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by treatment group and overall. 
Data for clinical laboratory tests, ECG, COWS/SOWS, vital signs, injection site reactions, and physical 
examinations will be summarized using standard descriptive and change from baseline statistics. Shift 
tables and tabular summaries of abnormalities will be provided, where appropriate. 
Medications will be coded using the WHO Drug Dictionary and summarized using descriptive 
statistics. 
By-subject listings will be provided for all safety data. 
 
11.4. 
Determination of Sample Size 
It is estimated that 170 subjects per treatment group will provide 90% power with a 2-sided test at a 5% 
significance level and standard deviation of API at Week 12 of 2.0 to detect a treatment effect of 0.7 
unit (or a standardized effect of 0.35) in change from baseline in the WAAPI scores at Week 12 
(Double-Blind Phase). Considering a titration success rate of 60%, this study will enroll approximately 
875 subjects to obtain 340 subjects achieving a successful dose in order to be randomly assigned to 
study drug treatment in the Double-Blind Phase. 
Additional statistical details will be outlined in the SAP. 
 
12. STUDY ADMINISTRATION AND INVESTIGATOR 
RESPONSIBILITIES 
 
12.1. 
Regulatory and Ethical Considerations 
12.1.1. 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. 
 
12.1.2. 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. 
 


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12.1.3. Subject Informed Consent 
The investigator (or authorized designee) will ensure that the participant 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 is to be provided in a language understandable to the participant and must not include any 
language that waives the participant’s legal rights. 
Prospective participants must also be informed of their right to withdraw consent without prejudice at any 
time during the 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. 
 
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. 
 
 
12.2. 
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 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 


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considered the sole property of the Sponsor. Please refer to the Clinical Study Agreement (CSA) for 
details. 
 
12.3. 
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, treatment codes, and emergency code break envelopes will be 
performed, as applicable. 
 
In addition, the Sponsor reserves the right to temporarily suspend or prematurely discontinue this study at 
any time and for any reason. If such action is taken, the Sponsor will discuss this with the 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. 
 
12.4. 
Regulatory Documents and Records Retention 
The investigator is responsible for creating and/or maintaining all study documentation required by 21 
CFR 50, 54, 56 and 312, ICH E6 section 8, as well as any other documentation defined in the protocol or 
CSA. The investigator must provide key documents to the Sponsor prior to the start of the 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 one of the above 2 timeframes has been satisfied. 
If the investigation does not result in the submission of the data in support of, or as part of, an application 
for a research or marketing permit, records must be retained for a period of 2 years following notification 
by the Sponsor that the entire clinical investigation (not merely the investigator’s portion) is completed, 
terminated, or discontinued or 2 years following withdrawal of the Investigational New Drug 
application/Clinical Trial Authorization or request for marketing approval (New Drug 
Application/Marketing Authorization Application). 
If the investigator retires, relocates, or for other reasons withdraws from the responsibility of keeping 
the 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. 
 


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12.5. 
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 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. 
 
12.6. 
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. 
 
12.7. 
Financial Disclosure 
Clinical investigators are required to provide financial disclosure information for the submission of 
certification or disclosure statements required under 21 CFR § 54. As defined in 21 CFR § 54.2, a Clinical 
investigator is a listed or identified investigator or Sub-investigator who is directly involved in the 
treatment or evaluation of research participants. The term also includes the spouse and each dependent 
child of the investigator. In addition, investigators must promptly update financial disclosure information if 
any relevant changes occur during the course of the investigation and for 1 year following completion of 
the study. 


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13. 
SPONSOR APPROVAL PAGE 
A Phase III, Randomized, Double-Blind, Placebo-Controlled, 
Enriched-Enrollment Withdrawal, Multicenter Study to Evaluate the Efficacy 
and Safety of a Long-Acting Subcutaneous Injectable Depot of Buprenorphine 
(CAM2038) in Subjects with Moderate to Severe Chronic Low Back Pain 
Currently Treated with Daily Opioids 
 
Protocol: Amendment 9 / Version 10.0 
Date: 12-Apr-2018 
 
Braeburn Pharmaceuticals 
 
 
 
Sponsor 
Representative 
(please print or type) 
Sponsor Representative Signature 
Date (DD-MMM-YYYY) 


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14. 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
A Phase III, Randomized, Double-Blind, Placebo-Controlled, 
Enriched-Enrollment Withdrawal, Multicenter Study to Evaluate the Efficacy 
and Safety of a Long-Acting Subcutaneous Injectable Depot of Buprenorphine 
(CAM2038) in Subjects with Moderate to Severe Chronic Low Back Pain 
Currently Treated with Daily Opioids 
 
Protocol: Amendment 9 / Version 10.0 
Date: 12-Apr-2018 
 
Braeburn Pharmaceuticals 
 
I have read this protocol and I agree to conduct the study in accordance with the protocol and 
with all applicable government regulations and International Conference on Harmonization/Good 
Clinical Practice guidance’s. 
 
 
 
Principal Investigator’s 
Name 
(please print or type) 
Principal Investigator’s Signature 
Date (DD-MMM-YYYY) 


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15. REFERENCES 
1. American Academy of Pain Medicine. Use of opioids for the treatment of chronic pain. Available 
at http://www.painmed.org/files/use-of-opioids-for-the-treatment-of-chronic- pain.pdf. 
2. Belbuca™ Prescribing Information, October 2015. 
3. Busner J and Targum SD. The Clinical Impression Scale – applying a research tool in 
clinical practice. Psychiatry (Edgmont). 2007;4(7):28-37. 
4. Chou R, Fanciullo GJ, Fine PG, Miaskowski C, Passik SD, Portenoy RK. Opioids for chronic 
noncancer pain: prediction and identification of aberrant drug-related behaviors: a review of the 
evidence for an American Pain Society and American Academy of Pain Medicine clinical 
practice guideline. J Pain. 2009 Feb;10(2):131-146. 
5. Cowan A, Lewis JW, Macfarlane IR. Agonist and antagonist properties of buprenorphine, a new 
antinociceptive agent. Br J Pharmacol. 1977;60:537-545. 
6. Dahan A, Yassen A, Bijl H, et al. A comparison of the respiratory effects of intravenous 
buprenorphine and fentanyl in humans and rats. Br J Anaesth. 2005;94:825-834. 
7. Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, et al. Core 
outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain. 2005 
Jan;113(1-2):9-19. 
8. Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, et al. Interpreting the 
clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT 
recommendations. J Pain. 2008 Feb;9(2):105-121. 
9. Dworkin RH, Turk DC, Peirce-Sandner S, Burke LB, Farrar JT, Gilron I, et al. Considerations 
for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations. 
Pain. 2012 Jun;153(6):1148-1158. 
10. Food and Drug Administration Center for Drug Evaluation and Research (CDER). Draft 
Guidance for Industry Analgesic Indications: Developing Drug and Biological Products, February 
2014. 
11. Frieden TR and Houry D. Reducing the risks of relief – the CDC Opioid-Prescribing 
Guideline. N Engl J Med. 2016;37:1501-1504. 
12. Griessinger N, Sittl R, Likar R.Transdermal buprenorphine in clinical practice – a post-
marketing surveillance study in 13,179 patients. Curr Med Res Opin. 2005;21:1147-
1156. 


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13. Guy W. Clinical Global Impressions: In ECDEU Assessment Manual for 
Psychopharmacology, 1976; pp. 218-222. Revised DHEW Pub. (ADM). Rockville, MD: National 
Institute for Mental Health. 
14. Hans G and Robert D. Transdermal buprenorphine: a critical appraisal of its role in pain 
management. J Pain Res. 2009;2:117-134. 
15. Jasinski D, Pevnick J, Griffith J. Human pharmacology and abuse potential of the analgesic 
buprenorphine – a potential agent for treating narcotic addiction. JAMA Archive Gen. 
Psychiatry. 1978;35:501-516. 
16. Likar R, Griessinger N, Sadjak A, et al. Transdermal buprenorphine for the treatment of chronic 
cancer and noncancer pain. Wien Med Woschr. 2003;153:317-322. 
17. McPherson ML, Demystifying Opioid Conversion Calculations 1st edition. ASHP. 2009. 
18. Mercadente S, Casuccio A, Tirelli W, Ciarrantano A. Equipotent doses to switch from high doses 
of opioids to transdermal buprenorphine. Support Care Cancer. 2009;17:715-718. 
19. Rauck RL, Potts J, Xiang Q, Tzanis E, Finn A. Efficacy and tolerability of buccal 
buprenorphine in opioid-naive patients with moderate to severe chronic low back pain. 
PostgradMed. 2016 Jan;128(1):1-11. 
20. 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;5:363-369. 
21. Shekelle PG, Markovich M, Louie R. An epidemiologic study of episodes of back pain care. 
Spine. 1995;20:1668-1673. 
22. Sittl R, Likar R, Nautrup BP. Equipotent doses of transdermal fentanyl and transdermal 
buprenorphine in patients with cancer and non-cancer pain: results of a prospective cohort study. 
Clin Ther. 2005; 27:225-237. 
23. Thomas E, Silman AJ, Croft PR, et al. Predicting who develops chronic low back pain in 
primary care: a prospective study. BMJ. 1999;318:1662-1667. 
24. Tompkins DA, Smith MT, Mintzer MZ, Campbell CM, Strain EC. A double blind, within subject 
comparison of spontaneous opioid withdrawal from buprenorphine versus morphine. J 
Pharmacol Exp Ther. 2014 Feb;348(2):217-226. 
25. Volinn E, Fargo JD, Fine PG. Opioid therapy for nonspecific low back pain and the 
outcome of chronic work loss. Pain. 2009;142:194-201. 
26. Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 
diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 
2010. Lancet. 2012;380:2163-2196. 


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27. Weaver MF, Schnoll SH. Opioid treatment of chronic pain in patients with addiction. Pain Palliat 
Care Pharmacother. 2002;16(3):5-26. 
28. Yarlas A, Miller K, Wen W, Dain B, Lynch SY, Pergolizzi JV, Raffa RB, Ripa SR. A randomized, 
placebo-controlled study of the impact of the 7-day buprenorphine transdermal system on health-
related quality of life in opioid-naïve patients with moderate-to-severe chronic low back pain. J 
Pain. 2013 Jan; 14(1):14-23. 
29. Albayaty M, Linden M, Olsson H, Johnsson M, Strandgården K, Tiberg F. Pharmacokinetic 
Evaluation of Once-Weekly and Once-Monthly Buprenorphine Subcutaneous Injection Depots 
(CAM2038) Versus Intravenous and Sublingual Buprenorphine in Healthy Volunteers Under 
Naltrexone Blockade: An Open-Label Phase 1 Study. Adv Ther. 2017 Feb;34(2):560-575. doi: 
10.1007/s12325-016-0472-9. Epub 2017 Jan 9 


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16. APPENDICES 
Appendix 1: Agents Associated with Potential QTcF Interval Prolongation 
Generic Name 
Brand Name (Partial List) 
Drug Class 
Alfuzosin 
Uroxatral® 
Alpha1-blocker antiviral 
Amantadine 
Symmetrel®, Symadine® 
Antiviral 
Amiodarone 
Cordarone®, Pacerone®, Nexterone®, 
Elavil®, Tryptomer®, Tryptizol®, Laroyxl®, 
Saroten®, Sarotex® 
Antiarrhythmic 
Amitriptyline 
Lentizol®, Endep® 
Antidepressant, tricyclic 
Anagrelide 
Agrylin®, Xagrid® 
Phosphodiesterase 3 inhibitor 
Apomorphine 
Apokyn®, Ixense®, Spontane®, Uprima® 
Dopamine agonist 
Aripriprazole 
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® 
Proteasome inhibitor 
Bortezomib 
Velcade®, Bortecad® 
Tyrosine kinase inhibitor 
Bosutinib 
Bosulif® 
Kinase inhibitor 
Certinib 
Zykadia® 
Sedative 
Chloral hydrate 
Aquachloral®, Novo-chlorhydrate®, 
Somnos®, Noctec®, Somnote® 
Antimalarial 
Chloroquine 
Aralen® 
Antipsychotic/Antiemetic 
Chlorpromazine 
Thorazine®, Largactil®, Megaphen® 
Phosphodiesterase 3 inhibitor 
Cilostazol 
Pletal® 
Vasodilator 


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Generic Name 
Brand Name (Partial List) 
Drug Class 
Ciprofloxacin 
Cipro®, Cipro-XR®, Neofloxin® 
Antibiotic 
Citalopram 
Celexa®, Cipramil® 
Antidepressant, selective serotonin 
reuptake inhibitor (SSRI) 
Clarithromycin 
Biaxin®, Prevpac® 
Antibiotic 
Clomipramine 
Anafranil® 
Antidepressant, tricyclic 
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 


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Generic Name 
Brand Name (Partial List) 
Drug Class 
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 
Lexapro, 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) 
SSRI 
Famotidine 
Pepcid®, Fluxid®, Quamatel® 
H2-receptor antagonist 
Felbamate 
Felbatol® 
Anticonvulsant 
Fingolimod 
Gilenya® 
Sphingosine phospate receptor 
modulator 
Flecainide 
Flecaine® 
Antiarrhythmic 
Fluconazole 
Diflucan®, Trican® 
Antifungal 
Fluoxetine 
Prozac, Sarafem, Fontex® 
Antidepressant SSRI 
Foscarnet 
Foscavir® 
Antiviral 
Furosemide 
Lasix®, Fusid®, Frumex® 
Diuretic 
Galantamine 
Reminyl®, Nivolin®, Razodyne-ER® 
Cholinesterase inhibitor 
Gemifloxacin 
Factive® 
Antibiotic 
Granisetron 
Kytril®, Sancuso®, Granisol® 
Antiemetic 
Halofantrine 
Halfan® 
Antimalarial 
Haloperidol 
Haldol®, Aloperidin®, Bioperidolo®, 
Brotopon®, Dozic®, Duraperidol®, Einalon 
S®, Eukystol®, Halosten®, Keselan®, 
Antipsychotic 


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Generic Name 
Brand Name (Partial List) 
Drug Class 
Linton®, Peluces®, Serenace®, Serenase®, 
Sigaperidol® 
Hydrochlorothiazide 
Apo-Hydro®, Aquazide H®, BP Zide®, 
Dichloride®, Hydrodiuril®, HydroSaluric®, 
Hydrochlorol®, Microzide®, Esidrex®, 
Oretic® 
Diuretic 
Hydroxychloroquine 
Plaquenil®, Quineprox® 
Antimalarial/Anti-inflammatory 
Hydroxzine 
Atarax®, Visaril®, Aterax®, Alamon®, 
Durrax®, Equipose®, Masmoran®, 
Orgatrax®, Paxistil®, Quiess®, Tran-Q®, 
Tranquizine® 
Antihistamine 
Ibutilide 
Corvert® 
Antiarrhythmic 
Iloperidone 
Fanapt®, Fanapta®, Zomaril® 
Antipsychotic, atypical 
Imipramine 
Tiofranil® 
Antidepressant, tricyclic 
Indapamide 
Lozol®, Natrilix®, Insig® 
Diuretic 
Isradipine 
Dynacirc® 
Antihypertensive 
Itraconazole 
Sporanox®, Onmel® 
Antifungal 
Ketoconazole 
Nizoral®, Sebizole®, Ketomed®, Keton® 
Kinase inhibitor 
Lapatinib 
Tykerb®, Tyverb® 
Tyrosine kinase 
inhibitor/Antineoplastic agent 
Leuprolide 
Lupron®, Eligard®, Viadur®, Carcinil®, 
Enanton®, Leuplin®, Lucrin®, Procren®, 
Prostap® and others 
Gonadotropin receptor 
agonist/antagonist 
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®, 
Antiemetic 


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Generic Name 
Brand Name (Partial List) 
Drug Class 
Maxolon®, Metozolv®, Plasil®, Pramin®, 
Primperan®, Perinorm® 
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 


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Generic Name 
Brand Name (Partial List) 
Drug Class 
Paroxetine 
Paxil®, Aropax®, Pexeva®, Seroxat®, 
Sereupin® 
Antidepressant, SSRI 
Pasireotide 
Signifor® 
Somatostatin analog 
Pazopanib 
Votrient® 
Tyrosine kinase inhibitor 
Pentamidine 
Pentam® 
Antifungal 
Perflutren lipid 
microspheres 
Definity® 
Imaging contrast agent 
Pimozide 
Orap® 
Antipsychotic 
Posacoanazole 
Noxafil®, Posamol® 
Antifungal 
Procainamide 
Protestyl®, 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®, 
Sertalin Bluefish 
Antidepressant, SSRI 
Sevoflurane 
Ulane®, Sojourn® 
Anesthetic, general 


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Generic Name 
Brand Name (Partial List) 
Drug Class 
Solifenacin 
VESIcare® 
Muscle relaxant 
Sorafenib 
Nexavar® 
Tyrosine kinase inhibitor 
Sotalol 
Betapace®, Sotalex®, Sotacor® 
Antiarrhythmic 
Sunitinib 
Sutent® 
Kinase inhibitor 
Tacrolimus 
Prograf®, Advagraf®, Protopic® 
Immunosuppressant 
Tamoxifen 
Nolvadex® (discontinued 6/13), Istubal®, 
Valodex® 
Antiestrogen 
Telaprevir 
Incivek®, Incivo® 
Antiviral 
Telavancin 
Vibativ® 
Antibiotic 
Telithromycin 
Ketek® 
Antibiotic 
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/Serotonin 
Antagonist Reuptake Inhibitor 
(SARI) 
Trimipramine 
Surmontil®, Rhotrimine®, Stangyl® 
Antidepressant, tricyclic 
Vandetanib 
Caprelsa® 
Anticancer 
Vardenafil 
Levitra® 
Phosphodiesterase 5 inhibitor 
Vemurafenib 
Zelboraf® 
Kinase inhibitor 


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Generic Name 
Brand Name (Partial List) 
Drug Class 
Venlafaxine 
Effexor®, Efexor® 
Antidepressant/Serotonin- 
norepinephrine reuptake inhibitors 
(SNRI) 
Voriconazole 
VFend® 
Antifungal 
Vorinostat 
Zolinza® 
Histone deacetylase inhibitor 
Ziprasidone 
Geodon®, Zeldox® 
Antipsychotic, atypical 
Source: http://www.crediblemeds.org/ 


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Appendix 2: CAM2038 Administration Sites 
 
Thirty-six administration sites have been identified for injection of CAM2038/placebo. 
CAM2038/placebo q1w must not be administered into a previously injected site for 
at least 4 weeks. 
CAM2038/placebo q4w must not be administered in a sited previously injected with 
CAM2038/placebo q4w or CAM2038/placebo q1w for at least 4 weeks. 
The pictorial below will help record the injection site location. The injection site location will be 
recorded in the EDC. 
 
 

SAP_001.pdf: 
BRAEBURN, Inc. 
CONFIDENTIAL 
Version 1.00—31 Aug 2018 
HS-16-555 SAP 
Page 1 of 23 
HS-16-555 
Phase III 
 
A Phase III, Randomized, Double-Blind, Placebo-Controlled, 
Enriched-Enrollment Withdrawal, Multicenter Study to Evaluate 
the Efficacy and Safety of a Long-Acting Subcutaneous Injectable 
Depot of Buprenorphine (CAM2038) in Subjects with a Recent 
History of Moderate to Severe Chronic Low Back Pain Currently 
Treated with Opioids 
 
Statistical Analysis Plan (SAP) 
 
 
Sponsor 
BRAEBURN  
450 Plymouth Road 
Plymouth Meeting, PA  19462 
Tel: (610) 467-8680 
 
 
 
Version 1.00 
 
31 Aug 2018 
 
 
 
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HS-16-555 SAP 
Page 2 of 23 
 
SPONSOR APPROVAL 
The undersigned have reviewed the format and content of this prospective statistical analysis plan (SAP) 
and have approved it to analyze the HS-16-555 data. 
 
 
BRAEBURN   
 
Richard Malamut, MD 
 
 
 
 
Print Name 
 
Signature 
 
Date 
 
 
Susan Franks 
 
 
 
 
Print Name 
 
Signature 
 
Date 
 
 
 
STATISTICIAN 
 
Michael Chen 
 
 
 
 
Print Name 
 
Signature 
 
Date 
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HS-16-555 SAP 
Page 3 of 23 
 
TABLE OF CONTENTS 
1. 
DOCUMENT HISTORY ................................................................................................................................... 5 
2. 
LIST OF ABBREVIATIONS ............................................................................................................................ 5 
3. 
INTRODUCTION .............................................................................................................................................. 6 
4. 
STUDY DESCRIPTION ................................................................................................................................... 7 
4.1 
Study Objectives ........................................................................................................................ 7 
4.2 
Study Treatments ...................................................................................................................... 7 
4.3 
Study Design ............................................................................................................................... 7 
4.4 
Randomization and Blinding ................................................................................................ 7 
5. 
ANALYSIS POPULATIONS ............................................................................................................................ 9 
5.1 
Randomized Population ......................................................................................................... 9 
5.2 
Modified Intent-to-Treat Population ................................................................................. 9 
5.3 
Per Protocol Population ...................................................................................................... 10 
5.4 
Safety Population ................................................................................................................... 10 
6. 
GENERAL CONVENTIONS ......................................................................................................................... 11 
6.1 
Definition of Baseline ........................................................................................................... 11 
6.2 
Changes to Planned Analyses ............................................................................................ 11 
7. 
DESCRIPTION OF THE STUDY POPULATIONS .................................................................................. 12 
7.1 
Disposition ............................................................................................................................... 12 
7.2 
Demographic and Baseline Characteristics .................................................................. 12 
7.3 
Medical History ....................................................................................................................... 12 
8. 
PRIOR AND CONCOMITANT MEDICATIONS ...................................................................................... 13 
9. 
EFFICACY ANALYSES .................................................................................................................................. 14 
9.1 
Primary Efficacy Outcome .................................................................................................. 14 
9.2 
Derivation of the Primary Efficacy Variable ................................................................ 14 
9.3 
Primary Analysis .................................................................................................................... 14 
9.4 
Sensitivity Analyses .............................................................................................................. 15 
9.5 
Secondary Efficacy Endpoints ........................................................................................... 16 
9.5.1 
Change from baseline in the weekly average of daily WPI scores at Week 12 
of the Double-Blind Treatment Phase ........................................................................... 16 
9.5.2 
Proportion of responders with a ≥30% and ≥50% reduction from the Open-
Label Titration Phase baseline in API score over time ........................................... 16 
9.5.3 
Time to loss of efficacy ......................................................................................................... 16 
9.5.4 
Change from baseline to last week of treatment in PGI-I Scale .......................... 17 
9.5.5 
Change from the Open-Label Titration Phase baseline to the last week of 
treatment of the Double-Blind Treatment Phase in WPAI score ....................... 17 
9.5.6 
Change from the Open-Label Titration Phase baseline to the last week of 
treatment of the Double-Blind Treatment Phase in EuroQoL Group EQ-5D-5L 
score ............................................................................................................................................ 17 
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HS-16-555 SAP 
Page 4 of 23 
 
9.5.7 
Rescue medication usage (number of days) during the Double-Blind 
Treatment Phase. ................................................................................................................... 17 
9.6 
Exploratory Efficacy Outcomes ......................................................................................... 17 
9.6.1 
Proportion of responders with a ≥70% reduction from the Open-Label 
Titration Phase baseline to week 12 of the Double-Blind Treatment Phase in 
API score over time ............................................................................................................... 18 
9.6.2 
Change from baseline to Week 12 in CGI-I Scale ....................................................... 18 
9.7 
Interim Analyses .................................................................................................................... 18 
9.8 
Adjustments for Multiplicity .............................................................................................. 18 
9.9 
Power and Sample Size Justification ............................................................................... 18 
10. 
SUMMARIES OF MEASURES OF SAFETY ........................................................................................... 19 
10.1 
Extent of Exposure ................................................................................................................. 19 
10.2 
Adverse Events ........................................................................................................................ 19 
10.3 
Laboratory Assessments ..................................................................................................... 20 
10.4 
Vital Signs ................................................................................................................................. 20 
10.5 
Physical Examinations ......................................................................................................... 20 
10.6 
12-Lead Electrocardiogram (ECG) ................................................................................... 20 
10.7 
Injection-Site Examination ................................................................................................. 21 
10.8 
Urine Drug Screen .................................................................................................................. 21 
10.9 
COWS .......................................................................................................................................... 21 
10.10 SOWS………… ............................................................................................................................. 21 
10.11 C-SSRS………………………………………………………………………………………………………….. 21 
11. 
IDENTIFICATION AND SUMMARY OF PROTOCOL DEVIATIONS .............................................. 21 
12. 
DATA QUALITY ASSURANCE ................................................................................................................ 21 
13. 
REFERENCES .............................................................................................................................................. 22 
14. 
APPENDICES .............................................................................................................................................. 23 
14.1 
Appendix A — Imputation Algorithm for Partial and Missing Dates .................. 23 
 
 
 
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HS-16-555 SAP 
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1. DOCUMENT HISTORY 
Version 
Date  
Changes made since previous version 
0.01 
20 NOV 2017 
Draft 
0.02 
22 NOV 2017 
Draft 
0.03 
27 NOV 2017 
Draft 
1.00 
31 AUG 2018 
Final  
 
2. LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
 
API 
Average pain intensity 
BPN 
Buprenorphine 
C-SSRS 
Columbia–Suicide Severity Rating Scale 
CGI-I 
Clinical Global Impression of Improvement 
CLBP 
Chronic low back pain 
COWS 
Clinical Opiate Withdrawal Scale 
CRF 
Case Report Form (may include electronic data capture systems or paper forms) 
CRO 
Contract research organization 
ECG 
Electrocardiogram 
EERW 
Enriched-enrollment randomized withdrawal 
ITT 
Intent-to-treat 
MedDRA 
Medical Dictionary of Regulatory Activities 
MMRM 
Mixed-model repeated measures 
NRS 
Numerical rating scale 
PGI-I 
Patient Global Impression of Improvement 
q1w 
Once-weekly 
q4w 
Once-monthly 
SAE 
Serious adverse event  
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SOC 
System organ class 
SOWS 
Subjective Opiate Withdrawal Scale 
TEAE 
Treatment-emergent adverse event 
WAAPI 
Weekly average of average pain intensity 
WHO 
World Health Organization 
WPAI 
Work Productivity and Activity Impairment 
WPI 
Worst pain intensity 
 
 
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3. INTRODUCTION 
This statistical analysis plan (SAP) is based on Protocol HS-16-555, Protocol Amendment 9, v 10.0, 12 
April 2018. This SAP defines the analysis plan for the Double-Blind Treatment Phase, including the Open-
Label Titration and Double-Blind Treatment Phases. A separate SAP will be prepared for the Open-Label 
Safety Extension Phase, and therefore, this phase is not discussed any further beyond the objectives in this 
document.  
The purpose of this document is to provide details on study populations and how the variables will be 
derived, how missing data will be handled, and on statistical methodologies to be used to analyze the safety 
and efficacy data from the Double-Blind Treatment Phase.   
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4. STUDY DESCRIPTION 
4.1 
STUDY OBJECTIVES 
Primary Objective: 
The primary objective of this study is to evaluate the efficacy of long-acting subcutaneous (SC) injectable 
depots of buprenorphine (BPN) (CAM2038 once-weekly [q1w] and CAM2038 once-monthly [q4w]) 
compared to placebo on average pain intensity (API) scores, as measured on an 11-point numerical rating 
scale (NRS-11) in subjects currently taking daily opioids for moderate to severe chronic low back pain 
(CLBP). 
Secondary Objectives:  
The secondary objectives of the study are to evaluate: 
x 
The change from baseline in the weekly average of daily worst pain intensity (WPI) scores at Week 
12 of the Double-Blind Treatment Phase, based on an NRS-11; 
x 
The proportion of subjects meeting the clinical responder definition of at least 30% and 50% 
improvement in API from the Open-Label Titration Phase baseline to the end of the Double-Blind 
Treatment Phase; 
x 
Time to loss of efficacy during the Double-Blind Treatment Phase; 
x 
The change from baseline to Week 12 of the Double-Blind Treatment Phase in the Patient Global 
Impression of Improvement (PGI-I) scale (as assessed by each subject); 
x 
The change from the Open-Label Titration Phase baseline to the end of the Double-Blind 
Treatment Phase in quality of life and work productivity measures, using Work Productivity and 
Activity Impairment (WPAI) subject-reported assessments and EuroQoL Group 5-dimension 5-
level self-report questionnaire (EQ-5D-5L) scores; and 
x 
Rescue medication utilization during the Double-Blind Treatment Phase. 
4.2 
STUDY TREATMENTS  
Subjects meeting randomization criteria (Protocol Section 7.4) will be randomized to receive weekly or 
monthly injections in 1 of 2 treatment groups in the Double-Blind Treatment Phase:  
x 
Group 1: CAM2038 SC injections (4 mg, 8 mg or 12 mg q1w; or 64 mg, 96 mg or 128 mg q4w)  
x 
Group 2: Placebo SC injections 
4.3 
STUDY DESIGN 
This is a Phase III, randomized, double-blind, placebo-controlled, enriched-enrollment randomized 
withdrawal (EERW), multicenter study to evaluate the efficacy and safety of CAM2038 q1w and CAM2038 
q4w in subjects currently taking opioids with a recent history of moderate to severe chronic low back pain 
for an extended period.  
4.4 
RANDOMIZATION AND BLINDING 
Randomization will be used to avoid bias in the assignment of subjects to treatment, to increase the 
likelihood that known and unknown subject attributes (e.g., demographics, baseline characteristics) are 
evenly balanced across treatment groups, and to enhance the validity of statistical comparisons across 
treatment groups. 
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During the Open-Label Titration Phase, subjects will be dosed with CAM2038 q1w until a stabilized dose 
and adequate analgesic effect has been achieved for at least 2 consecutive weeks prior to randomization to 
the Double-Blind Treatment Phase, in accordance with pre-defined randomization criteria. Subjects whose 
pain is controlled on 4 mg, 8 mg or 12 mg CAM2038 q1w during the Open-Label Titration Phase will be 
maintained on 4 mg, 8 mg or 12 mg CAM2038 q1w, or corresponding placebo, during the Double-Blind 
Treatment Phase. Subjects whose pain is controlled on 16 mg, 24 mg or 32 mg CAM2038 q1w during the 
Open-Label Titration Phase will be transitioned to CAM2038 64 mg, 96 mg or 128 mg q4w, or 
corresponding placebo, during the Double-Blind Treatment Phase. Subjects will be randomized to either 
active CAM2038 or placebo control in a 1:1 ratio within each of the q1w or q4w regimens.  
Under normal circumstances, the blind will not be broken until all participants have completed treatment. 
In case of emergency, and only if the information is required by the Investigator to ensure subject’s safety 
in managing a medical condition, the treatment may be unblinded at the site by using a code-break module. 
The code-break module will be provided by the Sponsor or designee. If possible, the Investigator should 
contact the Sponsor prior to unblinding and after any actions have been taken. Whenever a treatment 
sequence is prematurely unblinded, the reason, date and time of the unblinding, and the individual who 
broke the blind, must be documented. Individual code breaks will result in withdrawal of the participant 
from the study.  
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5. ANALYSIS POPULATIONS 
5.1 
RANDOMIZED POPULATION 
The Randomized Population will consist of all subjects who have been assigned random treatment. 
5.2 
MODIFIED INTENT-TO-TREAT POPULATION 
The modified Intent-to-Treat (mITT) Population will consist of all randomized subjects with the exception 
of all subjects from Sites 068 and 077 due to persistent non-compliance.  
 
Site 068:  
 
A for-cause audit was performed on 02 Oct 2017 for Site 068 in response to a quality event. There were 
several Critical and Major observations noted during the audit; the deficiencies noted during the audit were 
based on a random sampling of data. Below are some of the observations noted: 
 
 The Critical observations were: 
x 
Subject signatures on revised informed consent forms could not be confirmed as authentic. 
x 
The data on subject diaries could not be attributed to the subjects themselves. 
x 
Subject eligibility could not be confirmed with provided source documents. 
 
The Major observations were: 
x 
Source documentation provided was found to be inadequate and/or unreliable. 
x 
There was inadequate accountability and review by site staff of subject diaries. 
x 
There was inadequate reporting and assessment of adverse events. 
x 
The site did not have appropriate research staff based on qualification, training and experience. 
 
The above observations have led to uncertainty in the integrity and reliability of the data collected at this 
site. Therefore, the data will not be included in the efficacy analysis. 
 
Site 077:  
 
Multiple audits, including a for-cause audit and several quality visits, were conducted by the Sponsor, 
Medpace (the contract research organization [CRO]) and third-party auditors, due to the Site 077 enrolling 
a large number of subjects into the study. These audits and quality visits led to several Critical and Major 
observations noted below: 
 
The Critical observations were: 
x 
Not all subjects spoke, read or comprehended English, and as a result, the Informed Consent (IC) 
process and every study visit was conducted in Spanish or through an interpreter/impartial witness. 
This was not permitted in the protocol and was not documented in the source documentation. 
x 
The study staff were unblinded throughout the entire study. The study staff who administered the 
investigational product also performed the protocol-required assessments at each visit. 
x 
Source documentation was manually changed, allowing several subjects to meet inclusion and 
exclusion criteria for the study. 
x 
The medical records at the site were incomplete or missing.As a result, it could not be determined 
whether the subjects met inclusion criteria to qualify for the study.  
 
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The Major observations were: 
x 
The questionnaires, scales and diaries required to be completed by subjects at each visit could not 
be attributed to the appropriate subjects. 
x 
There was inadequate accountability for and review of subject diaries by site staff. 
x 
The electronic medical records were not validated and contained numerous inconsistencies. 
 
The above observations have led to uncertainty in the integrity and reliability of the data collected at this 
site. Therefore, the data will not be included in the efficacy analysis. 
 
The primary efficacy analyses will be based on the mITT Population. 
5.3 
PER PROTOCOL POPULATION 
The Per Protocol Population will include all subjects in the mITT Population with no major protocol 
violations. Major protocol violation criteria (defined as CSR reportable violations) have been be established 
(prior to database lock) and included in the Protocol Deviation Plan. These protocol violations  will be 
presented in the Clinical Study Report. Efficacy analyses may also be performed based on the Per Protocol 
Population.  
5.4 
SAFETY POPULATION 
The Safety Population will include all subjects who have received any dose of study medication. Analyses 
based on this population will group subjects according to the treatment they received rather than the 
treatment they were randomized to receive. All safety analyses will use the Safety Population. 
 
In the primary safety summaries, data for Sites 068 and 077 mentioned in Section 5.2 will be excluded, due 
to an inability to verify compliance with adverse event reporting requirements, leading to possible under-
reporting of adverse events. However, supportive safety summaries will include the data from Sites 068 
and 077.  
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6. GENERAL CONVENTIONS 
Unless otherwise stated, all 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 decimal places, 
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, SD, median, minimum, maximum and percentages will be presented with one 
decimal place. 
 
Unless otherwise stated, confidence intervals, when presented, will be constructed at the two-sided 95% 
level. For binomial variables, the 95% confidence intervals will be constructed using the normal 
approximation without continuity correction. 
 
Data listings will present all data collected on Case Report Forms (CRFs) by study drug, center and subject 
number. Unless otherwise stated, data will be presented by treatment and overall. 
6.1 
DEFINITION OF BASELINE 
Unless otherwise stated, the randomization baseline will be defined as the last assessment recorded on the 
day of randomization (e.g., weekly average in pain intensity).  
 
Open-label titration pain score baseline is defined as a single assessment prior to entering the Open-Label 
Titration Phase.  
 
Analyses will be conducted using SAS Version 9.2 or higher. 
6.2 
CHANGES TO PLANNED ANALYSES 
Draft versions of the SAP will be numbered sequentially as Version 0.0x. 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 approved version before unblinding.  
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7. DESCRIPTION OF THE STUDY POPULATIONS 
All tables, figures and listings must include population descriptors in the titles (e.g., mITT Population, 
Safety Population, Per Protocol Population). 
7.1 
DISPOSITION 
Subject disposition summaries will be presented by treatment arm and will include the number of subjects 
randomized, the number and percentage of randomized subjects in the primary Safety, mITT, and Per 
Protocol (if applicable) Populations, as well as the number and percentage of subjects who complete the 
study. The summaries will also include the reasons for early discontinuation from the study.  
 
Disposition summaries will be presented for the primary Safety, mITT, and Per Protocol Populations (if 
applicable) separately. 
7.2 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
A summary of demographics and baseline characteristics will be presented by treatment arm and overall 
for the mITT and the primary Safety Population. The demographic characteristics will consist of age, sex, 
ethnicity, and race, and will use descriptive statistics. 
 
Demographic data including age, sex, ethnicity, and race, as well as baseline clinical characteristics, will 
be summarized. Age will be calculated based on the following conditional algorithm:  
x 
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 
 
Since the birth dates capture the months and years only, the days will be imputed as the first day of the 
month before applying the above rules to derive the ages.  
 
Clinical baseline characteristics summarized will include, at minimum, body mass index, current 
employment status, duration of low back pain, and pain score at the beginning of the open-label titration 
phase. Clinical baseline characteristics will be summarized by treatment group and overall. 
7.3 
MEDICAL HISTORY 
Medical history will be coded using the Medical Dictionary of Regulatory Activities (MedDRA). A medical 
history listing will be presented.  
 
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8. 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 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 medication. Concomitant medications are defined as medications with start dates occurring on 
or after the date of first administration of any study treatment component and no more than 30 days after 
the last administration of any study treatment component. Medications 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. 
 
Prior and concomitant medication will be summarized for both Primary and Supportive Safety Populations. 
 
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9. EFFICACY ANALYSES 
Twenty-four hour API, WPI and rescue medication use will be collected daily by electronic diary. Paper 
diary entries will be collected in situations where electronic diary transmission issues occur and where 
electronic diaries are unavailable. For cases where both electronic and paper diaries are available, only the 
data from the electronic source will be used. Pain-related efficacy evaluation will be based on electronic 
diary data only. Additional sensitivity analyses will be conducted with both electronic and paper diary data 
as supportive efficacy.  
9.1 
PRIMARY EFFICACY OUTCOME 
The primary efficacy variable will be the change from baseline in weekly average API (WAAPI), and the 
primary timepoint will be Week 12.  
9.2 
DERIVATION OF THE PRIMARY EFFICACY VARIABLE 
WAAPI scores will be calculated for each weekly interval (i.e., 7-day intervals) relative to randomization 
date (first randomized treatment date) for all subjects (both subjects on q1w and q4w). For example, 
WAAPI at Week 0 will be the average of available (non-missing) APIs captured during the 7 days prior to 
Treatment Day 1 (the first randomized treatment day). WAAPI at Week 1 will be the average for the next 
7 days including the score captured on Day 1. WAAPI at Week 12 (the primary timepoint) will be the 
average for the APIs captured from Day 78 to Day 84. The baseline WAAPI score will be the WAAPI at 
Week 0. The changes from baseline at any post-baseline timepoint will be calculated as baseline minus 
post-baseline, so that a positive change is indicative of improvement. 
9.3 
PRIMARY ANALYSIS 
The primary analysis will be performed based on the mITT Population.  
 
WAAPI over time will be performed by longitudinal data analysis using mixed-model repeated measures 
(MMRM) methods. All post-randomization baseline observations will be utilized; missing values will 
remain as missing (i.e. no attempt will be made to impute missing values, and only observed values will 
be used in the data analysis). The model will include treatment, post-baseline weeks, treatment by week 
interaction as fixed effects, and baseline WAAPI as the covariate. The covariance will assume to be 
unstructured. If the estimates do not converge, SAS default covariance structure (variance components) 
will be assumed. The MMRM with maximum likelihood estimation will utilize the following pseudo- 
SAS code for analysis: 
 
proc mixed data = WAAPI Data method = ml; 
class treatment week subject; 
model Change in WAAPI = treatment week treatment*week baseline; 
repeated week / subject = subject type = un; 
lsmeans treatment / pdiff cl e; 
lsmeans treatment*week /slice = week cl diff; 
ods output diffs = alldiff; 
 
If the estimation under type=un cannot converge, the SAS default (variance components) will be used. 
The estimated treatment effects, treatment differences, and the two-sided 95% confidence intervals of the 
treatment differences at all post-baseline timepoints will be presented. The primary comparison will be 
the treatment difference at Week 12.  
 
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A clear advantage of using MMRM is that this method does not require artificial missing imputations that 
would often create biases. The MMRM method is valid if the “missing at random” assumption holds. The 
trial is designed to minimize missing values: (a) Subjects who discontinue taking study medication are 
permitted to remain in the study, and safety and efficacy data will continue to be collected from these 
subjects; (b) Liberal use of rescue medication is allowed during the study, and data collection will 
continue even after subjects take these medications, and (c) Robust efficacy data collection procedures 
will be used in the trial.  
 
Using the procedures above, it is expected that missing values will be minimal and that “missing at 
random” is a reasonable assumption. Therefore, the “MMRM without missing” imputation is reasonable. 
Sensitivity analyses of missing value imputations will be performed to support the robustness of the 
conclusion (see Section 9.4).  
 
Additional analyses outlined in the sensitivity analyses section (9.4) will be performed to assess the 
robustness of the analysis results. 
9.4 
SENSITIVITY ANALYSES 
 
Missing values sensitivity analyses: 
 
As the MMRM analysis does not impute missing values, sensitivity analyses with various missing value 
imputation methods will be performed. Sensitivity analyses based on the random replace and tipping 
point methods will be performed to assess the robustness of the primary efficacy data.  
 
If all daily ratings are missing for a given week, the missing change from baseline values at a given week 
will be imputed using the following methods. 
 
Random replacement method 
Missing change from baseline in WAAPI at Week J will be imputed with randomly generated values from 
a normal distribution using a seed of 153928221. The normal distribution will be assumed to have a mean 
x and a standard deviation of y, where x and y are the mean and standard deviation of the changes at 
Week J based on all subjects (i.e., subjects from both treatment groups) with non-missing values. It 
should be noted that, if treatment is effective, the results of this missing value imputation method will be 
more conservative (i.e., biased in favor of the control). 
 
Tipping point method 
Missing change values at Week J from placebo subjects will be imputed with the value that is equal to the 
mean changes among placebo subjects at that week. Missing change values from active treatment subjects 
will be imputed with the value that is k% worse than the mean WAAPI from the placebo group at that 
week, where k=0, 5, 10, 20, 30, 40…100, until tipping (i.e., the treatment difference at Week 12 is no 
longer significant at a two-sided significance level of 0.05). 
 
Additional Sensitivity Analyses: 
 
Inclusion of paper diary data from the primary analysis 
The primary efficacy variable will be analyzed including available paper diary data collected. 
 
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Exclusion of weekly average diary entries that do not have at least 5 daily entries during 
randomization baseline week (Week -1) and at the end of treatment (Week 12) 
The primary efficacy variable will be analyzed after treating WAAPI for any giving week as missing if 
average pain scores are available for less than 5 days in that week.) 
 
Exclusion of subjects who do not complete at least 4 weeks of treatment  
The primary efficacy variable will be analyzed in subjects who participate in the study for at least 4 weeks 
of the double-blind period. 
 
Exclusion of subjects who do not complete at least 8 weeks of treatment  
The primary efficacy variable will be analyzed in subjects who participate in the study for at least 8 weeks 
of the double-blind period. 
9.5 
SECONDARY EFFICACY ENDPOINTS 
The secondary efficacy endpoints are as follows: 
x 
Change from baseline in the weekly average of daily WPI scores at Week 12 of the Double-Blind 
Treatment Phase, based on an NRS-11; 
x 
Percentage of subjects with a 30% and 50% or greater decrease in API from the Open-Label 
Titration Phase baseline to Week 12 of the Double-Blind Treatment Phase; 
x 
Time to loss of efficacy, defined as discontinuations from the study or study drug for lack of 
efficacy; 
x 
Change from baseline to Week 12 of the Double-Blind Treatment Phase in the PGI-I scale (as 
assessed by each subject)  
x 
Change from baseline to Week 12 of the Double-Blind Treatment Phase in WPAI scores; 
x 
Change from baseline to Week 12 of the Double-Blind Treatment Phase in EuroQoL Group EQ-
5D-5L scores; and 
x 
Rescue medication days during the Double-Blind Treatment Phase. 
9.5.1 CHANGE FROM BASELINE IN THE WEEKLY AVERAGE OF DAILY WPI 
SCORES AT WEEK 12 OF THE DOUBLE-BLIND TREATMENT PHASE 
This variable, based on an NRS-11, will be analyzed via similar methods to those for the primary efficacy 
variable. 
9.5.2 PROPORTION OF RESPONDERS WITH A ≥30% AND ≥50% REDUCTION 
FROM THE OPEN-LABEL TITRATION PHASE BASELINE IN API SCORE 
OVER TIME  
Percent reduction from the Open-Label Titration Phase baseline in NRS score to a given post-baseline 
week will be derived as 100*(Titration Baseline pain score – Post-Baseline WAAPI) / (Titration Baseline 
pain score). A subject is a responder if the percent reduction is at least 30% and 50%.  
 
This variable will be analyzed using the chi-square test. The percentages, the difference of the 
percentages, and the two-sided 95% confidence interval of the treatment difference will be presented. The 
95% confidence intervals of the treatment difference will be calculated using normal approximation. 
9.5.3 TIME TO LOSS OF EFFICACY 
Lack of efficacy is defined as discontinuation from the study or study drug for lack of efficacy. The time 
will be defined as the following: 
 
 
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Discontinuation Date – Randomization Date + 1  
 
Time to loss of efficacy will be analyzed via a log-rank model with treatment effects. The time-to-event 
“survival” curve will be presented using the Kaplan-Meier method. Median time-to-event and the 95% 
confidence interval of the median times will be presented, if estimable. In these time-to-event analyses, 
subjects who do not have the event during the entire study will be censored at Day 84 (end of Week 12 
day). 
9.5.4 CHANGE FROM BASELINE TO LAST WEEK OF TREATMENT IN PGI-I SCALE  
Change from baseline in PGI-I will be analyzed via similar methods to those for the primary efficacy 
variable. 
9.5.5 CHANGE FROM THE OPEN-LABEL TITRATION PHASE BASELINE TO THE 
LAST WEEK OF TREATMENT OF THE DOUBLE-BLIND TREATMENT PHASE 
IN WPAI SCORE  
This variable will be analyzed via similar methods to those for the primary efficacy variable. 
9.5.6 CHANGE FROM THE OPEN-LABEL TITRATION PHASE BASELINE TO THE 
LAST WEEK OF TREATMENT OF THE DOUBLE-BLIND TREATMENT PHASE 
IN EUROQOL GROUP EQ-5D-5L SCORE  
This variable will be analyzed via similar methods to those for the primary efficacy variable. 
9.5.7 RESCUE MEDICATION USAGE (NUMBER OF DAYS) DURING THE DOUBLE-
BLIND TREATMENT PHASE.  
Rescue medication usage will be collected from the electronic diaries.  
 
There were technical issues with the electronic diaries for rescue medication usage. For example, subjects 
entered data multiple times (more than 30 times per day in some cases), possibly due to poor internet 
connectivity. As a result of these issues, the total rescue dosage was not reliable. Therefore, the electronic 
diary source of rescue medication usage will be used only to derive the number of days that rescue 
medication was used.  
 
The number of days that rescue medication is used will be normalized on a weekly basis in the analysis 
(i.e., number of days that rescue medication is used per week) based on the electronic diaries. 
Specifically, number of days that rescue medication is used per week will be derived as 7*(X/Y), where 
X=total number of days that rescue medication is taken during the week and Y=total number of days that 
diaries are available in that week. This variable will be analyzed via similar methods used to analyze the 
primary efficacy variable.  
9.6 
 EXPLORATORY EFFICACY OUTCOMES 
The exploratory efficacy endpoints are as follows: 
x 
Percentage of subjects with a 70% or greater decrease in API from the Open-Label Titration 
Phase baseline to Week 12 of the Double-Blind Treatment Phase 
x 
Change from baseline to Week 12 of the Double-Blind Treatment Phase in Clinical Global 
Impression of Improvement (CGI-I) scale (as assessed by the Investigator). 
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9.6.1 PROPORTION OF RESPONDERS WITH A ≥70% REDUCTION FROM THE 
OPEN-LABEL TITRATION PHASE BASELINE TO WEEK 12 OF THE DOUBLE-
BLIND TREATMENT PHASE IN API SCORE OVER TIME  
Percent reduction from the Open-Label Titration Phase baseline in NRS score to a given post-baseline 
Week will be derived as 100*(Titration baseline pain score – Post-Baseline API) / (Titration baseline pain 
score). A subject is a responder if the percent reduction is at least 70%. A subject with missing API for a 
given post-baseline week will be considered as a non-responder. 
 
This variable will be analyzed using the chi-square test. The percentages, the difference of the 
percentages, and the two-sided 95% confidence interval of the treatment difference will be presented. The 
95% confidence intervals of the treatment difference will be calculated using normal approximation. 
9.6.2 CHANGE FROM BASELINE TO WEEK 12 IN CGI-I SCALE  
Change from baseline in CGI-I will be analyzed via the similar methods to those for the primary efficacy 
variable. 
9.7 
INTERIM ANALYSES 
No interim analyses will be performed. 
9.8 
ADJUSTMENTS FOR MULTIPLICITY 
There is only one primary comparison for the study. The clinical efficacy endpoints listed below are listed 
in order of hierarchical importance: 
 
1. The primary efficacy endpoint, which is change from baseline in WAAPI at last week of treatment; 
2. Change from baseline in the weekly average of daily WPI scores at last week of treatment of the 
Double-Blind Treatment Phase, based on an NRS-11; 
3. Percentage of subjects with a 50% or greater decrease in API from the Open-Label Titration Phase 
baseline to the last week of treatment of the Double-Blind Treatment Phase; 
4. Percentage of subjects with a 30% or greater decrease in API from the Open-Label Titration Phase 
baseline to the last week of treatment of the Double-Blind Treatment Phase; 
5. Time to loss of efficacy, defined as discontinuation from the study or study drug for lack of efficacy; 
6. Change from baseline to last week of treatment of the Double-Blind Treatment Phase in PGI-I scale 
(as assessed by the subject); 
7. Change from baseline to last week of treatment of the Double-Blind Treatment Phase in WPAI 
score; 
8. Change from baseline to last week of treatment of the Double-Blind Treatment Phase in EuroQoL 
Group EQ-5D-5L score; and 
9. Rescue medication usage during the Double-Blind Treatment Phase. 
 
The null hypotheses of no treatment difference for the above endpoints will be tested at a two-sided 
significance level of 0.05 in the order specified. To protect the family-wise two-sided p-value at the 0.05 
significance level, the treatment superiority for an endpoint cannot be claimed, unless the superiority claims 
for all prior endpoints in the list, if any, have been established. 
9.9 
POWER AND SAMPLE SIZE JUSTIFICATION 
A sample size of 170 subjects per treatment group will provide over 90% power to detect a treatment 
difference at a two-sided 5% significance level. In the sample size calculation, a treatment difference of 0.7 
units and an SD of 2 (or a standardized effect of 0.35) for the primary efficacy variable were assumed. 
 
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10. SUMMARIES OF MEASURES OF SAFETY 
Safety analyses will be performed for both the Primary and Supportive Safety Populations. Safety 
evaluations will be based on the incidence, intensity, and type of adverse events (AEs), as well as on 
clinically significant changes in the subject’s physical examination, vital signs, electrocardiogram (ECG), 
clinical laboratory results, and injection site examination. Safety variables will be tabulated and presented 
by study drug received. 
 
Because there is no pre-specified safety outcome defined in terms of AEs, clinically relevant laboratory 
parameters, or vital signs in the Double-Blind Treatment Phase of the study, any formal comparisons 
between the treatment arms with respect to specific safety parameters will be post hoc. 
10.1 EXTENT OF EXPOSURE 
Summary statistics (number and percentage) of weeks of exposure to study drug (i.e., from date of initial 
injection to 4 weeks after the last injection for q4w, or 1 week for q1w) will be tabulated by treatment 
group.  
10.2 ADVERSE EVENTS 
All AE and serious adverse event (SAE) terms recorded on the CRFs will be coded by primary system 
organ class (SOC) and will be mapped to a preferred term using the MedDRA. 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 the first 
dose of CAM2038, or any ongoing event on the date of first dose that worsens in severity after the first 
dose of CAM2038. Only TEAEs with an onset date prior to date of last dose plus 30 days will be tabulated 
in summary tables. For the purpose of calculating TEAEs and inclusion in summary tables, incomplete 
onset dates will be imputed as detailed in Appendix A.  
 
AEs will be summarized by the number and percent of subjects in each primary SOC and preferred term, 
and subjects will be counted only once for each primary SOC and each preferred term. Summary tables of 
AEs by primary SOC, preferred term, and intensity will be provided. If a subject has more than one AE 
coded to the same preferred term, the subject will be counted only once for that preferred term by using the 
event with the highest intensity. Similarly, if a subject has more than one AE within a primary SOC 
category, the subject will be counted only once in that SOC category by using the event with the highest 
intensity.  
 
AEs by primary SOC, preferred term, and relationship to study drug will be provided as well. If a subject 
has more than one AE coded to the same preferred term, the subject will be counted only once for that 
preferred term by using the most related event. Similarly, if a subject has more than one AE within a primary 
SOC category, the subject will be counted only once in that primary SOC category by using the most related 
event.  
 
In addition, SAEs by primary SOC and preferred term will be provided. Deaths and SAEs will be 
summarized similarly to AEs. All adverse event tables will also include the total number of events, counting 
multiple events per subject. 
 
AEs, Injection-related AEs, and other (non-injection related) AEs will be presented by treatment group and 
overall. Summaries of these AE subsets will be presented for the following categories: 
 
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x 
Study drug related AEs 
x 
AEs by intensity 
x 
AE relationship to injection 
x 
Possibly study drug related AEs, by intensity 
x 
AEs reasonably related to injection, by intensity 
x 
SAEs 
x 
AEs that led to discontinuation 
x 
SAEs that led to discontinuation 
x 
AEs occurring in ≥5% 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. 
10.3 LABORATORY ASSESSMENTS 
Chemistry, hematology, urinalysis and coagulation profiles will be assessed (see Protocol Section 9.5.9 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. 
If a subject has repeated laboratory values for a given timepoint, the value from the first evaluation at that 
timepoint will be used for summary purposes. For the purpose of determining baseline, the last non-missing 
observation on or prior to randomization will be used.  
10.4 VITAL SIGNS 
For the purposes of this SAP, vital signs will consist of blood pressure (systolic and diastolic blood pressure, 
mm Hg), pulse rate (beats per minute), respiratory rate (breaths/minute) and oxygen saturation (%), 
collected while sitting, following a rest period of at least 3 minutes. Vital signs values and change from 
baseline in the vital signs will be summarized for each treatment group. 
10.5 PHYSICAL EXAMINATIONS 
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 examinations data for each subject will also be 
presented in a listing. 
10.6 12-LEAD ELECTROCARDIOGRAM (ECG) 
Twelve-Lead ECGs will be assessed after the subject has been resting in a recumbent/supine position for at 
least 3 minutes (see Protocol Section 9.5.11 for a complete list of parameters to be assessed). The ECG 
variables will include ventricular heart rate and the PR, QRS, QT, QTcB and QTcF intervals. The ECGs 
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will be signed and dated by a medically qualified individual; he or she will confirm review of the ECG and 
verify whether any abnormalities are clinically significant.  
 
Number and percent of subjects in each ECG finding category (normal; abnormal not clinically significant; 
and abnormal and clinically significant) will be summarized for each visit by each treatment group and 
overall. Summary statistics will be presented for the actual value and change for each ECG parameter. 
10.7 INJECTION-SITE EXAMINATION 
Injection-site reactions can occur with injection of CAM2038 or placebo. The injection site will be visually 
inspected for evidence of itching, erythema/redness (with erythema/redness rating), swelling (with swelling 
rating) and any other abnormalities.  
 
Results from the injection-site examinations will be summarized and listed.  
 
AEs that are believed to be associated with injection procedures will be summarized similarly to how other 
AEs are summarized (i.e., AEs not associated with injections). 
10.8 URINE DRUG SCREEN 
Urine drug screen will be summarized and listed. 
10.9 COWS 
The Clinical Opiate Withdrawal Scale (COWS) data will be summarized and listed. 
10.10 SOWS 
The Subjective Opiate Withdrawal Scale (SOWS) data will be summarized and listed. 
10.11 C-SSRS 
Columbia–Suicide Severity Rating Scale (C-SSRS) data will be summarized and listed. 
 
11. IDENTIFICATION AND SUMMARY OF PROTOCOL DEVIATIONS 
Major protocol deviations from entry criteria and treatment compliance will be summarized as far as they 
can be extracted from numeric or coded study data. 
 
12. DATA QUALITY ASSURANCE 
Accurate and reliable data collection will be ensured by verification and cross check of the CRFs against 
the Investigator’s records by the Study Monitor (source document verification) and by the maintenance of 
a drug-dispensing log by the Investigator. Collected data will be entered into a computer database and will 
be subject to electronic and manual quality assurance procedures. 
 
Additionally, due to the observations identified in the two sites that have been excluded from the primary 
ITT dataset (Sites 068 and 077), additional measures were taken to assure the quality of study conduct and 
data collection from other top sites; these were sites that enrolled more than 10 subjects in the study. The 
Sponsor’s Quality Department, in parallel with an independent third-party auditor, conducted quality visits 
to these sites, and the results of revealed no critical or major findings or observations that would impact the 
quality of the data. 
 
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13. REFERENCES 
None. 
 
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14. APPENDICES 
14.1 APPENDIX A — IMPUTATION ALGORITHM FOR PARTIAL AND MISSING 
DATES  
This section describes missing date imputation methods. 
 
For Adverse Events 
 
If the onset date is completely missing, the onset date is set to the date of randomization. 
If the year is present, and month and day are missing, or if the year and day are present, and the month is 
missing: 
x 
If year = year of randomization, then set month and day to month and day of randomization 
x 
If year < year of randomization, then set month and day to December 31 
x 
If year > year of randomization, then set month and day to January 1 
If month and year are present and day is missing: 
x 
If year = year of randomization and  
x 
If month = month of randomization, then set day to day of first dose 
x 
If month < month of first dose, then set day to last day of month 
x 
If month > month of first dose, then set day to first day of month 
x 
If year < year of randomization, then set day to last day of month 
x 
If year > year of randomization, then set day to first day of month 
 
For all other cases, set the onset date to the date of randomization. 
 
Concomitant Medications/Medical History 
For start date 
x 
If start date is completely missing, start date will not be imputed 
x 
If year is present and month and day are missing, or if year and day are present and month is 
missing, set month and day to January 1 
x 
If year and month are present and day is missing, set day to first day of month 
 
For end date 
x 
If end date is completely missing, end date will not be imputed 
x 
If year is present and month and day are missing, or if year and day are present and month is 
missing, set month and day to December 31 
x 
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, the medication will be classified as concomitant. 
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