Buprenorphine (CAM2038) in Subjects With a Recent History of Moderate to Severe Chronic Low Back Pain

• Sponsor: Braeburn Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02946073
• Collaborator: Medpace, Inc. (Industry), Camurus AB (Industry)
• Enrollment: 1,053
• Locations: 69
• Arms: 2
• Actual Duration (Months): 29
• Patients Per Site: 15.3
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Lower Back Pain; Chronic Pain	Drug: buprenorphine; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1053 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official 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
• Actual Study Start Date: Sep 1, 2016
• Actual Primary Completion Date: May 1, 2018
• Actual Study Completion Date: Feb 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo CAM2038 placebo injections	Other: Placebo
Experimental: CAM2038 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.	Drug: buprenorphine; Other Names: CAM2038

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Weekly Average of (Daily) Average Pain Intensity (WAAPI) and the Primary Timepoint Will be Week 12 of the Double-Blind Phase. [12 weeks- from randomization baseline to 12 weeks after randomization]

   Change from baseline in Weekly Average of (Daily) Average Pain Intensity (WAAPI) and the primary timepoint will be Week 12 of the Double-Blind Phase based on the 11-Point numerical rating scale with 0 being no pain and 10 being the worst pain.

2. Change From Baseline in Weekly Average of (Daily) Average Pain Intensity (WAAPI) of the Open Label Phase. [48 weeks -From baseline to 48 weeks after baseline (Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects).]

   Change from baseline in Weekly Average of (Daily) Average Pain Intensity (WAAPI) of the Open Label Phase based on the 11-Point numerical rating scale with 10 being the worst pain. Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects.

Secondary Outcome Measures

1. Change From Baseline in the Weekly Average of (Daily) Worst Pain Intensity Scores at Week 12 of the Double-Blind Phase Based on 11-Point Numerical Rating Scale With 10 Being the Worst Pain. [12 weeks- from randomization baseline to 12 weeks after randomization]

   Change from baseline in Weekly Average of (Daily) Worst Pain Intensity (WAWPI) and the primary timepoint will be Week 12 of the Double-Blind Phase based on the 11-Point numerical rating scale with 0 being no pain and 10 being the worst pain.

2. Number of Subjects With a 30% and 50% Reduction in WAAPI From Baseline to Week 12 of the Double-Blind Phase. [12 weeks- from randomization baseline to 12 weeks after randomization]

   Number of Responders With a 30% and 50% Reduction in WAAPI from the Open-Label Titration Period Baseline to Week 12 of the Double-Blind Treatment Period (mITT Population)

3. Summary of Rescue Medication Usage- Double-Blind Phase. [12 weeks- from randomization baseline to 12 weeks after randomization]

   Rescue medication usage (number of days used) during the Double-Blind Phase.

4. Change From Open Label Titration Baseline to Week 12 of the Double-Blind Phase in EuroQol Group 5-dimension 5-level Self-report Questionnaire Score. [12 weeks- from randomization baseline to 12 weeks after randomization]

   Change from Open Label Titration baseline to Week 12 of the Double-Blind Phase in EuroQol Group 5-dimension 5-level self-report questionnaire score. 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 subjects 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 were converted into a weighted health-state index score, according to the US population-based algorithm, with higher scores indicating better quality of life. The score ranges from 0-100 with 0 as the worst health and 100 as the best health.

5. Change From Baseline to Week 12 of the Double-Blind Phase in Work Productivity and Activity Impairment Score [23 weeks- from baseline to 12 weeks after randomization]

   Change from baseline to Week 12 of the Double-Blind Phase in Work Productivity and Activity Impairment score. 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 (higher scores indicate greater impairment): Absenteeism (work time missed)，Presenteeism (impairment at work/reduced on-the-job effectiveness), Work Productivity Loss (overall work impairment/absenteeism plus presenteeism)，and Activity Impairment. Scores range from 0-100 for each of the four types with higher scores indicating greater impairment.

6. Number of Subjects Discontinued Due to Loss of Efficacy [12 weeks- from randomization baseline to 12 weeks after randomization]

   Number of Subjects Discontinued due to loss of efficacy, defined as discontinuation of study drug for lack of efficacy.

7. Change From Baseline to Week 12 of the Double-Blind Phase in Patient Global Impression of Improvement (PGI-I) Scale [12 weeks- from baseline (randomization) to 12 weeks after randomization]

   Change from baseline to Week 12 of the Double-Blind Phase in Patient global Impression of Improvement (PGI-I) Scale. PGI-I)Scale is a single question 7-point likert scale that required the subject to assess how much his/her pain had improved or worsened relative to the start of the study at the beginning of the intervention . Ratings were: 1, much worse; 2, worse; 3, a little worse; 4, no change; 5, a little better; 6, better; or 7, much better

8. Change From Baseline in Weekly Average of (Daily) Worst Pain Intensity (WAWPI) of the Open Label Phase. [48 weeks -From baseline to 48 weeks after baseline (Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects).]

   Change from baseline in Weekly Average of (Daily) Worst Pain Intensity (WAWPI) and the primary timepoint will be Week 52 of the Open Label Phase based on the 11-Point numerical rating scale with 10 being the worst pain. Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects.

9. Subject Discontinued Due to Loss of Efficacy, Defined as Discontinuation of Study Drug for Lack of Efficacy. [48 weeks -From baseline to 48 weeks after baseline (Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects).]

   Subject Discontinued Due to Loss of Efficacy, Defined as Discontinuation of Study Drug for Lack of Efficacy Open Label Phase.

10. Summary of Rescue Medication Usage-Open Label Phase [48 weeks -From baseline to 48 weeks after baseline (Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects).]

    Rescue medication usage (number of days used) during the Open Label Phase.

11. Summary of Change From Baseline in EuroQoL Group EQ-5D-5L Scores Over Time-Open Label Phase [48 weeks -From baseline to 48 weeks after baseline (Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects).]

    Change from Open Label Titration baseline in EuroQol Group 5-dimension 5-level self-report questionnaire score in the Open Label Phase. 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 subjects 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 were converted into a weighted health-state index score, according to the US population-based algorithm, with higher scores indicating better quality of life. The score ranges from 0-100 with 0 as the worst health and 100 as the best health.

12. Summary of Change From Baseline in Clinical Global Impression of Improvement (CGI-I) Scale-Open Label [48 weeks -From baseline to 48 weeks after baseline (Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects).]

    Summary of Change from Baseline in Clinical Global Impression of Improvement (CGI-I) scale. The Clinician Global Impression of Improvement (CGI-I) Scale is a 7-point scale that required the clinician to assess how much the subject's Pain had improved or worsened relative to the start of the study. Assessments were 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

13. Summary of Change From Baseline in Patient Global Impression of Improvement (PGI-I) Scale [48 weeks -From baseline to 48 weeks after baseline (Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects).]

    Change from baseline in the Open Label Phase in Patient global Impression of Improvement (PGI-I) Scale. PGI-I Scale is a single question 7-point likert scale that required the subject to assess how much his/her pain had improved or worsened relative to the start of the study. Ratings were: 1, much worse; 2, worse; 3, a little worse; 4, no change; 5, a little better; 6, better; or 7, much better

14. Summary of Change From Baseline in Work Productivity and Activity Impairment Questionnaire (WPAI) Open Label Phase [48 weeks -From baseline to 48 weeks after baseline (Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects).]

    Change from baseline in the Open Label Phase in Work Productivity and Activity Impairment score with a range of 0-100 for 4 types of scores with higher scores indicating greater impairment. 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 (higher scores indicate greater impairment): Absenteeism (work time missed)，Presenteeism (impairment at work/reduced on-the-job effectiveness), Work Productivity Loss (overall work impairment/absenteeism plus presenteeism)，and Activity Impairment. Scores range from 0-100 for each of the four types with higher scores indicating greater impairment.

15. Number of Subjects Discontinued Due to Loss of Efficacy [48 weeks -From baseline to 48 weeks after baseline (Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects).]

    Number of Subjects Discontinued due to loss of efficacy, defined as discontinuation of study drug for lack of efficacy.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

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:

3. Severe respiratory insufficiency, respiratory depression, airway obstruction, gastrointestinal motility disorders, biliary tract disease, severe hepatic insufficiency, or planned surgery.

4. Bipolar disorder

5. 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.

6. Female subject planning to become pregnant during the study.

7. Surgical procedure(s) for CLBP within 6 months prior to Screening.

8. 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.

9. QTcF >450 ms for males and >470 ms for females, or clinically significant electrocardiogram (ECG) abnormality at Screening, at the investigator's discretion.

10. 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.

11. 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.

12. History of chemotherapy or confirmed malignancy (except basal cell carcinoma) within the past 2 years.

13. 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.

14. An active or pending workman's compensation, insurance claim, or litigation related to back pain (i.e., primary claim is back pain).

15. Clinically significant history, in the opinion of the investigator, of suicidal ideation or current evidence that the subject is actively suicidal.

16. Clinically significant history of major depressive disorder that is poorly controlled with medication, per investigator judgment.

17. Hypersensitivity or allergy to BPN, other opioids, or excipients of CAM2038.

18. Hypersensitivity or allergy to acetaminophen.

19. 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,

20. Use or planned use of natural supplements that can affect CYP3A4, such as St. John's Wort, throughout the study.

21. Has a major bleeding disorder, such as hemophilia, or treated with high levels of anticoagulants per the investigator's discretion.

22. Current or confirmed past diagnosis of Sphincter of Oddi dysfunction.

23. 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).

24. 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.

25. 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.

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.

• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Parkway Medical Center	Birmingham	Alabama	United States	35215
2	Boyett Health Services Inc	Hamilton	Alabama	United States	35570
3	National Centers for Pain Management and Research	Vestavia Hills	Alabama	United States	35243
4	Elite Clinical Studies	Phoenix	Arizona	United States	85018
5	Phoenix Clinical	Phoenix	Arizona	United States	85021
6	Noesis Pharma	Phoenix	Arizona	United States	85032
7	Arizona Research Center	Phoenix	Arizona	United States	85053
8	MD Studies, Inc.	Fountain Valley	California	United States	92708
9	Neuro-Pain Medical Center	Fresno	California	United States	93710
10	Alliance Research Centers	Laguna Hills	California	United States	92653
11	Clinical Trials Research	Lincoln	California	United States	95648
12	Catalina Research Institute, LLC	Montclair	California	United States	91763
13	Allied Clinical Research, LLC	Sacramento	California	United States	95842
14	Care Practice	San Francisco	California	United States	94708
15	Syrentis Clinical Research	Santa Ana	California	United States	92705
16	Universal Pain Management Group	Valencia	California	United States	91355
17	Tampa Pain Relief Center-Brandon	Brandon	Florida	United States	33511
18	International Research Partners	Doral	Florida	United States	33122
19	Dr. Vijapura and Associates	Jacksonville	Florida	United States	32256
20	Florida Institute of Medical Research	Jacksonville	Florida	United States	32257
21	Lake Howell Health Center	Maitland	Florida	United States	32751
22	Ocean Blue Medical Research Center, Inc.	Miami Springs	Florida	United States	33166
23	Scientific Clinical Research, Inc.	North Miami	Florida	United States	33161
24	Gold Coast Research, LLC	Plantation	Florida	United States	33317
25	FMPM Research	Saint Petersburg	Florida	United States	33709
26	Clinical Research of West Florida-Tampa	Tampa	Florida	United States	33603
27	Tampa Pain Relief Centers-Hillsborough	Tampa	Florida	United States	33603
28	Palm Beach Research Center	West Palm Beach	Florida	United States	33409
29	River Birch Research Alliance LLC	Blue Ridge	Georgia	United States	30513
30	Columbus Regional Research Institute	Knoxville	Georgia	United States	37909
31	Drug Studies America	Marietta	Georgia	United States	30060
32	Non-Surgical Orthopedics, P.C.	Marietta	Georgia	United States	30060
33	Injury Care Research, LLC	Boise	Idaho	United States	83713
34	Millennium Pain Center	Bloomington	Illinois	United States	61701
35	Clinical Investigation Specialists, Inc.-Gurnee	Gurnee	Illinois	United States	60031
36	Medisphere Medical Research Center	Evansville	Indiana	United States	47714
37	International Clinical Research Institute Inc.	Overland Park	Kansas	United States	66210
38	Phoenix Medical Research	Prairie Village	Kansas	United States	66208
39	Otrimed	Edgewood	Kentucky	United States	41017
40	River Cities Clinical Research Center	Shreveport	Louisiana	United States	71105
41	Boston Paincare	Waltham	Massachusetts	United States	02451
42	MedVadis Research Corporation	Watertown	Massachusetts	United States	02472
43	Amicis Trials	Festus	Missouri	United States	63028
44	Hassman Research Institute	Berlin	New Jersey	United States	08009
45	New York Clinical Trials, Inc	New York	New York	United States	10022
46	MedEx Healthcare Research, Inc-NY	New York	New York	United States	10036
47	Upstate Clinical Research Associates	Williamsville	New York	United States	14221
48	Rapha Institute for Clinical Research	Fayetteville	North Carolina	United States	28314
49	OnSite Clinical Solutions, LLC-Hickory	Hickory	North Carolina	United States	28602
50	Center for Clinical Research, LLC-Winston-Salem	Winston-Salem	North Carolina	United States	27103
51	Aventiv Research, Inc.	Columbus	Ohio	United States	43213
52	Dayton Outpatient Center (DOC) Clinical Research	Dayton	Ohio	United States	45432
53	Providence Health Partners-Center for Clinical Research	Dayton	Ohio	United States	45439
54	Medical Research Internationl	Oklahoma City	Oklahoma	United States	73109
55	SP Research, PLLC	Oklahoma City	Oklahoma	United States	73112
56	Frost Medical Group, LLC	Conshohocken	Pennsylvania	United States	19428
57	Suburban Research Associates	Media	Pennsylvania	United States	19063
58	Coastal Carolina Research Center	Charleston	South Carolina	United States	29406
59	Medical Research South, LLC	Charleston	South Carolina	United States	29407
60	New Phase Research & Development	Knoxville	Tennessee	United States	37909
61	FutureSearch Trials of Dallas, LP	Dallas	Texas	United States	75231
62	Renaissance Clinical Research and Hypertension Clinic	Dallas	Texas	United States	75234
63	Research Concepts GP, LLC-Houstion	Houston	Texas	United States	77004
64	Pioneer Research Solutions Inc.	Houston	Texas	United States	77099
65	The Pain Relief Center	Plano	Texas	United States	75024
66	The SMART Clinic/Physicians Research Options LLC	Draper	Utah	United States	84020
67	EPIC Medical Research	Murray	Utah	United States	84123
68	Aspen Clinical Research	Orem	Utah	United States	84058
69	Mid Columbia Research	Richland	Washington	United States	99352

Sponsors and Collaborators

• Braeburn Pharmaceuticals
• Medpace, Inc.
• Camurus AB

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Apr 12, 2018
• Statistical Analysis Plan - Aug 31, 2018

More Information

Publications

None provided.

• Responsible Party: Braeburn Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02946073
• Other Study ID Numbers: HS-16-555
• First Posted: Oct 26, 2016
• Last Update Posted: Oct 15, 2021
• Last Verified: Jan 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Back Pain; Low Back Pain; Chronic Pain; Buprenorphine

Study Results

Participant Flow

Recruitment Details

965 of those subjects entered the Double Blind phase of the study. 108 subjects signed consent as De Novo subjects, but 20 of those subjects were part of the Double Blind phase. The total number of subjects that signed consent was 1053 (965 + 88).Two sites had quality issues with the data, so those subjects were eliminated from the analysis. This made the total number of subjects who were analyzed 222 in the double blind randomized phase and 132 subjects for the open label phase.

Pre-assignment Detail

Subjects are screened prior to entry into a titration phase where they are titrated to an appropriate dose. Once they are titrated, they were randomized and entered the double blind period or open label period for de novo subjects.

Arm/Group Title	CAM2038 q1w or q4w BPN Treatment- Double Blind Phase	Placebo Subcutaneous Injections-Double Blind Phase	De Novo Subjects-Open Label Phase	Rollover Subjects-Open Label
Arm/Group Description	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. buprenorphine	CAM2038 placebo: 0.16, 0.18, 0.24, 0.27, 0.36, and 0.64 mL SC injection administered once weekly or once monthly	De Novo subjects proceeded directly from the Open-Label Titration Period to the Open-Label Safety Extension Phase without participating in the Double-Blind Treatment Period. CAM2038 q1w (buprenorphine FluidCrystal®) : SC injection depot for once weekly or monthly administration at doses of 4, 8, 12, 16, 24 and 32 mg (buprenorphine base) 0.16, 0.24, and 0.64 mL SC injection CAM2038 (buprenorphine FluidCrystal® once-weekly injection depot) CAM2038 q4w ( buprenorphine FluidCrystal®): SC injection depot for once monthly administration (356 mg/mL) at doses of 64, 96, 128 or 160 mg (buprenorphine base) 0.18, 0.27, and 0.36 mL SC injection CAM2038 (buprenorphine FluidCrystal® once-monthly injection depot)	CAM2038 q1w (buprenorphine FluidCrystal®) : SC injection depot for once weekly or monthly administration at doses of 4, 8, 12, 16, 24 and 32 mg (buprenorphine base) 0.16, 0.24, and 0.64 mL SC injection CAM2038 (buprenorphine FluidCrystal® once-weekly injection depot) CAM2038 q4w ( buprenorphine FluidCrystal®): SC injection depot for once monthly administration (356 mg/mL) at doses of 64, 96, 128 or 160 mg (buprenorphine base) 0.18, 0.27, and 0.36 mL SC injection CAM2038 (buprenorphine FluidCrystal® once-monthly injection depot)
Period Title: Titration Phase
STARTED	811	0	98	0
COMPLETED	222	0	75	0
NOT COMPLETED	589	0	23	0
Period Title: Titration Phase
STARTED	112	110	0	0
COMPLETED	88	70	0	0
NOT COMPLETED	24	40	0	0
Period Title: Titration Phase
STARTED	0	0	75	57
COMPLETED	0	0	54	44
NOT COMPLETED	0	0	21	13

Baseline Characteristics

Arm/Group Title	CAM2038 q1w or q4w BPN Treatment- Double Blind Phase	Placebo Subcutaneous Injections-Double Blind Phase	De Novo Subjects-Open Label	Rollover Subjects-Open Label	Total
Arm/Group Description	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. buprenorphine	CAM2038 placebo: 0.16, 0.18, 0.24, 0.27, 0.36, and 0.64 mL SC injection administered once weekly or once monthly (matching volumes for CAM2038 q1w and near-matching volumes for CAM2038 q4w).	CAM2038 q1w (buprenorphine FluidCrystal®) : SC injection depot for once weekly or monthly administration at doses of 4, 8, 12, 16, 24 and 32 mg (buprenorphine base) 0.16, 0.24, and 0.64 mL SC injection CAM2038 (buprenorphine FluidCrystal® once-weekly injection depot) CAM2038 q4w ( buprenorphine FluidCrystal®): SC injection depot for once monthly administration (356 mg/mL) at doses of 64, 96, 128 or 160 mg (buprenorphine base) 0.18, 0.27, and 0.36 mL SC injection CAM2038 (buprenorphine FluidCrystal® once-monthly injection depot)	CAM2038 q1w (buprenorphine FluidCrystal®) : SC injection depot for once weekly or monthly administration at doses of 4, 8, 12, 16, 24 and 32 mg (buprenorphine base) 0.16, 0.24, and 0.64 mL SC injection CAM2038 (buprenorphine FluidCrystal® once-weekly injection depot) CAM2038 q4w ( buprenorphine FluidCrystal®): SC injection depot for once monthly administration (356 mg/mL) at doses of 64, 96, 128 or 160 mg (buprenorphine base) 0.18, 0.27, and 0.36 mL SC injection CAM2038 (buprenorphine FluidCrystal® once-monthly injection depot)	Total of all reporting groups
Overall Participants	112	110	75	57	354
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.7 (12.19)	54.7 (11.36)	54.2 (11.77)
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.3 (10.27)	56.4 (11.49)	55.2 (10.82)
Sex: Female, Male (Count of Participants)
Female	66 58.9%	56 50.9%	122 162.7%
Male	46 41.1%	54 49.1%	100 133.3%
Sex: Female, Male (Count of Participants)
Female	44 39.3%	34 30.9%	78 104%
Male	31 27.7%	23 20.9%	54 72%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	11 9.8%	11 10%	22 29.3%
Not Hispanic or Latino	101 90.2%	97 88.2%	198 264%
Unknown or Not Reported	0 0%	2 1.8%	2 2.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 0.9%	4 3.6%	5 6.7%
Not Hispanic or Latino	73 65.2%	51 46.4%	124 165.3%
Unknown or Not Reported	1 0.9%	2 1.8%	3 4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.9%	0 0%	1 1.3%
Asian	0 0%	1 0.9%	1 1.3%
Native Hawaiian or Other Pacific Islander	1 0.9%	0 0%	1 1.3%
Black or African American	10 8.9%	12 10.9%	22 29.3%
White	100 89.3%	97 88.2%	197 262.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.9%	0 0%	1 1.3%
Asian	0 0%	1 0.9%	1 1.3%
Native Hawaiian or Other Pacific Islander	1 0.9%	0 0%	1 1.3%
Black or African American	6 5.4%	7 6.4%	13 17.3%
White	67 59.8%	49 44.5%	116 154.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	29.1 (4.78)	29.3 (5.27)	29.2 (5.02)
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	29.5 (5.55)	29.1 (5.29)	29.3 (5.42)
Pain Score at Start of Open-Label Titration Period (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	7.0 (1.42)	7.0 (1.39)	7.0 (1.40)
Pain Score at Start of Open-Label Titration Period (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	6.7 (1.46)	6.6 (1.73)	6.7 (1.57)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Weekly Average of (Daily) Average Pain Intensity (WAAPI) and the Primary Timepoint Will be Week 12 of the Double-Blind Phase.
Description	Change from baseline in Weekly Average of (Daily) Average Pain Intensity (WAAPI) and the primary timepoint will be Week 12 of the Double-Blind Phase based on the 11-Point numerical rating scale with 0 being no pain and 10 being the worst pain.
Time Frame	12 weeks- from randomization baseline to 12 weeks after randomization

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (mITT) Population: The mITT Population consisted of all randomized subjects, with the exception of the subjects from Sites 068 and 077 due to persistent site non-compliance

Arm/Group Title	CAM2038 (Buprenorphine FluidCrystal®) q1w and q4w	Placebo Subcutaneous Injections
Arm/Group Description	CAM2038 q1w (buprenorphine FluidCrystal®) : SC injection depot for once weekly or monthly administration at doses of 4, 8, 12 mg (buprenorphine base) 0.16, 0.24, and 0.64 mL SC injection CAM2038 (buprenorphine FluidCrystal® once-weekly injection depot) CAM2038 q4w ( buprenorphine FluidCrystal®): SC injection depot for once monthly administration (356 mg/mL) at doses of 64, 96, 128 mg (buprenorphine base) 0.18, 0.27, and 0.36 mL SC injection CAM2038 (buprenorphine FluidCrystal® once-monthly injection depot)	CAM2038 placebo: 0.16, 0.18, 0.24, 0.27, 0.36, and 0.64 mL SC injection administered once weekly or once monthly (matching volumes for CAM2038 q1w and near-matching volumes for CAM2038 q4w).
Measure Participants	112	110
Baseline	2.7 (1.26)	2.4 (1.25)
Change from Baseline to Week 12	-0.9 (1.62)	-1.9 (1.97)

2. Primary Outcome

Title	Change From Baseline in Weekly Average of (Daily) Average Pain Intensity (WAAPI) of the Open Label Phase.
Description	Change from baseline in Weekly Average of (Daily) Average Pain Intensity (WAAPI) of the Open Label Phase based on the 11-Point numerical rating scale with 10 being the worst pain. Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects.
Time Frame	48 weeks -From baseline to 48 weeks after baseline (Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects).

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (mITT) Population: The mITT Population consisted of all randomized subjects, with the exception of the subjects from Sites 068 and 077 due to persistent site non-compliance

Arm/Group Title	De Novo	CAM2038	Rollover Placebo Injections
Arm/Group Description	CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg. buprenorphine	CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg buprenorphine during both Double Blind Phase and Open Label Phase	Placebo injections during Double Blind Phase, CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg orCAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg buprenorphine during Open Label Phase
Measure Participants	54	24	31
Baseline	2.839 (1.0753)	2.256 (1.1642)	1.944 (1.1288)
Change from Baseline to Week 4	-0.434 (0.94)	-0.531 (0.93)	-1.586 (1.80)
Change from Baseline to Week 8	-0.555 (1.28)	-0.729 (0.99)	-2.165 (2.20)
Change from Baseline to Week 12	-0.752 (1.35)	-0.767 (1.20)	-2.079 (2.01)
Change from Baseline to Week 16	-0.543 (1.19)	-0.312 (0.68)	-1.229 (1.42)
Change from Baseline to Week 20	-0.690 (1.47)	-0.566 (1.05)	-1.013 (1.63)
Change from Baseline to Week 24	-0.718 (1.46)	-0.872 (1.51)	-1.220 (1.41)
Change from Baseline to Week 28	-0.905 (1.56)	-0.338 (1.06)	-1.212 (1.46)
Change from Baseline to Week 32	-0.941 (1.64)	-0.275 (1.41)	-1.111 (1.27)
Change from Baseline to Week 36	-0.920 (1.48)	-0.623 (1.36)	-1.119 (1.42)
Change from Baseline to Week 40	-0.913 (1.37)	-0.519 (1.51)	-1.113 (1.49)
Change from Baseline to Week 44	-0.767 (1.32)	-0.560 (1.37)	-1.282 (1.57)
Change from Baseline to Week 48	-0.996 (1.39)	-0.619 (1.58)	-1.215 (1.57)

3. Secondary Outcome

Title	Change From Baseline in the Weekly Average of (Daily) Worst Pain Intensity Scores at Week 12 of the Double-Blind Phase Based on 11-Point Numerical Rating Scale With 10 Being the Worst Pain.
Description	Change from baseline in Weekly Average of (Daily) Worst Pain Intensity (WAWPI) and the primary timepoint will be Week 12 of the Double-Blind Phase based on the 11-Point numerical rating scale with 0 being no pain and 10 being the worst pain.
Time Frame	12 weeks- from randomization baseline to 12 weeks after randomization

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (mITT) Population: The mITT Population consisted of all randomized subjects, with the exception of the subjects from Sites 068 and 077 due to persistent site non-compliance

Arm/Group Title	CAM2038	Placebo
Arm/Group Description	CAM2038 50 mg/mL q1w at doses of 8 mg, 12 mg, CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg. buprenorphine	CAM2038 placebo: 0.16, 0.18, 0.24, 0.27, 0.36, and 0.64 mL SC injection administered once weekly or once monthly (matching volumes for CAM2038 q1w and near-matching volumes for CAM2038 q4w).
Measure Participants	112	110
Baseline	3.8 (1.59)	3.7 (1.65)
Change from Baseline to Week 12	-1.1 (1.81)	-2.2 (2.18)

4. Secondary Outcome

Title	Number of Subjects With a 30% and 50% Reduction in WAAPI From Baseline to Week 12 of the Double-Blind Phase.
Description	Number of Responders With a 30% and 50% Reduction in WAAPI from the Open-Label Titration Period Baseline to Week 12 of the Double-Blind Treatment Period (mITT Population)
Time Frame	12 weeks- from randomization baseline to 12 weeks after randomization

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (mITT) Population: The mITT Population consisted of all randomized subjects, with the exception of the subjects from Sites 068 and 077 due to persistent site non-compliance

Arm/Group Title	CAM2038	Placebo
Arm/Group Description	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. buprenorphine	CAM2038 placebo injections Placebo
Measure Participants	112	110
>= 30% improvement	60 53.6%	47 42.7%
>= 50% improvement	44 39.3%	32 29.1%

5. Secondary Outcome

Title	Summary of Rescue Medication Usage- Double-Blind Phase.
Description	Rescue medication usage (number of days used) during the Double-Blind Phase.
Time Frame	12 weeks- from randomization baseline to 12 weeks after randomization

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (mITT) Population: The mITT Population consisted of all randomized subjects, with the exception of the subjects from Sites 068 and 077 due to persistent site non-compliance

Arm/Group Title	CAM2038	Placebo
Arm/Group Description	CAM2038 50 mg/mL q1w at doses of 8 mg, 12 mg, CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg. buprenorphine	CAM2038 placebo injections Placebo
Measure Participants	112	110
Baseline	3.4 (2.84)	3.5 (2.91)
Change from Baseline to Week 12	-1.5 (2.58)	-2.1 (2.63)

6. Secondary Outcome

Title	Change From Open Label Titration Baseline to Week 12 of the Double-Blind Phase in EuroQol Group 5-dimension 5-level Self-report Questionnaire Score.
Description	Change from Open Label Titration baseline to Week 12 of the Double-Blind Phase in EuroQol Group 5-dimension 5-level self-report questionnaire score. 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 subjects 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 were converted into a weighted health-state index score, according to the US population-based algorithm, with higher scores indicating better quality of life. The score ranges from 0-100 with 0 as the worst health and 100 as the best health.
Time Frame	12 weeks- from randomization baseline to 12 weeks after randomization

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (mITT) Population: The mITT Population consisted of all randomized subjects, with the exception of the subjects from Sites 068 and 077 due to persistent site non-compliance

Arm/Group Title	CAM2038	Placebo
Arm/Group Description	CAM2038 50 mg/mL q1w at doses of 8 mg, 12 mg CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg. buprenorphine	CAM2038 placebo injections Placebo
Measure Participants	112	110
Titration Baseline	63.7 (20.55)	61.3 (22.05)
Change from Baseline to Week 12	-9.4 (18.47)	-7.2 (23.04)

7. Secondary Outcome

Title	Change From Baseline to Week 12 of the Double-Blind Phase in Work Productivity and Activity Impairment Score
Description	Change from baseline to Week 12 of the Double-Blind Phase in Work Productivity and Activity Impairment score. 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 (higher scores indicate greater impairment): Absenteeism (work time missed)，Presenteeism (impairment at work/reduced on-the-job effectiveness), Work Productivity Loss (overall work impairment/absenteeism plus presenteeism)，and Activity Impairment. Scores range from 0-100 for each of the four types with higher scores indicating greater impairment.
Time Frame	23 weeks- from baseline to 12 weeks after randomization

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (mITT) Population: The mITT Population consisted of all randomized subjects, with the exception of the subjects from Sites 068 and 077 due to persistent site non-compliance

Arm/Group Title	CAM2038	Placebo
Arm/Group Description	CAM2038 50 mg/mL q1w at doses of 8 mg, 12 mg, CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg. buprenorphine	CAM2038 placebo injections Placebo
Measure Participants	112	110
Baseline-Activity Impairment	58.8 (23.68)	61.2 (22.74)
Change from Baseline to Week 12 after randomization-Activity impairment	18.1 (24.88)	11.7 (26.28)
Baseline-Absenteesim	5.1 (10.19)	9.9 (22.50)
Change from Baseline to Week 12 after randomization-Absenteesim	-0.8 (10.75)	-4.6 (22.88)
Baseline-Presenteeism	38.9 (22.33)	47.8 (25.20)
Change from Baseline to Week 12 after randomization-Presenteeism	5.0 (27.47)	9.0 (27.37)
Baseline-Work Productivity Loss	41.3 (23.09)	52.3 (26.77)
Change from Baseline to Week 12 after randomization- Work Productivity Loss	5.4 (23.05)	7.8 (26.40)

8. Secondary Outcome

Title	Number of Subjects Discontinued Due to Loss of Efficacy
Description	Number of Subjects Discontinued due to loss of efficacy, defined as discontinuation of study drug for lack of efficacy.
Time Frame	12 weeks- from randomization baseline to 12 weeks after randomization

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (mITT) Population: The mITT Population consisted of all randomized subjects, with the exception of the subjects from Sites 068 and 077 due to persistent site non-compliance

Arm/Group Title	CAM2038	Placebo
Arm/Group Description	CAM2038 50 mg/mL q1w at doses of 8 mg, 12 mg, CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg. buprenorphine	CAM2038 placebo injections Placebo
Measure Participants	112	110
Count of Participants [Participants]	7 6.3%	21 19.1%

9. Secondary Outcome

Title	Change From Baseline to Week 12 of the Double-Blind Phase in Patient Global Impression of Improvement (PGI-I) Scale
Description	Change from baseline to Week 12 of the Double-Blind Phase in Patient global Impression of Improvement (PGI-I) Scale. PGI-I)Scale is a single question 7-point likert scale that required the subject to assess how much his/her pain had improved or worsened relative to the start of the study at the beginning of the intervention . Ratings were: 1, much worse; 2, worse; 3, a little worse; 4, no change; 5, a little better; 6, better; or 7, much better
Time Frame	12 weeks- from baseline (randomization) to 12 weeks after randomization

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (mITT) Population: The mITT Population consisted of all randomized subjects, with the exception of the subjects from Sites 068 and 077 due to persistent site non-compliance

Arm/Group Title	CAM2038	Placebo
Arm/Group Description	CAM2038 50 mg/mL q1w at doses of 8 mg, 12 mg, CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg. buprenorphine	CAM2038 placebo injections Placebo
Measure Participants	112	110
Baseline	6.0 (0.96)	6.2 (0.74)
Change from Baseline to Week 12	0.4 (1.48)	1.5 (1.63)

10. Secondary Outcome

Title	Change From Baseline in Weekly Average of (Daily) Worst Pain Intensity (WAWPI) of the Open Label Phase.
Description	Change from baseline in Weekly Average of (Daily) Worst Pain Intensity (WAWPI) and the primary timepoint will be Week 52 of the Open Label Phase based on the 11-Point numerical rating scale with 10 being the worst pain. Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects.
Time Frame	48 weeks -From baseline to 48 weeks after baseline (Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects).

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (mITT) Population: The mITT Population consisted of all randomized subjects, with the exception of the subjects from Sites 068 and 077 due to persistent site non-compliance

Arm/Group Title	De Novo	CAM2038	Rollover Placebo Injections
Arm/Group Description	CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg. buprenorphine	CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg buprenorphine during both Double Blind Phase and Open Label Phase	Placebo injections during Double Blind Phase, CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg orCAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg buprenorphine during Open Label Phase
Measure Participants	54	21	31
Baseline	4.139 (1.55)	3.717 (3.86)	3.246 (3.29)
Change from Baseline to Week 4	-0.517 (1.34)	-0.859 (1.57)	-1.734 (1.97)
Change from Baseline to Week 8	-0.625 (1.48)	-1.066 (1.68)	-2.404 (2.47)
Change from Baseline to Week 12	-0.846 (1.53)	-1.157 (1.95)	-2.455 (2.26)
Change from Baseline to Week 16	-0.689 (1.51)	-0.487 (1.14)	-1.587 (2.03)
Change from Baseline to Week 20	-0.725 (1.59)	-0.592 (1.157)	-1.391 (2.18)
Change from Baseline to Week 24	-0.735 (1.67)	-0.902 (2.13)	-1.461 (1.97)
Change from Baseline to Week 28	-1.013 (1.55)	-0.518 (1.74)	-1.531 (2.13)
Change from Baseline to Week 32	-0.996 (1.90)	-0.322 (1.76)	-1.462 (2.06)
Change from Baseline to Week 36	-1.044 (1.71)	-0.682 (0.20)	-1.112 (1.34)
Change from Baseline to Week 40	-0.935 (1.50)	-0.658 (1.92)	-1.087 (1.48)
Change from Baseline to Week 44	-0.897 (1.56)	-0.764 (2.03)	-1.216 (1.68)
Change from Baseline to Week 48	-1.059 (1.59)	-0.896 (2.26)	-1.292 (1.78)

11. Secondary Outcome

Title	Subject Discontinued Due to Loss of Efficacy, Defined as Discontinuation of Study Drug for Lack of Efficacy.
Description	Subject Discontinued Due to Loss of Efficacy, Defined as Discontinuation of Study Drug for Lack of Efficacy Open Label Phase.
Time Frame	48 weeks -From baseline to 48 weeks after baseline (Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects).

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (mITT) Population: The mITT Population consisted of all randomized subjects, with the exception of the subjects from Sites 068 and 077 due to persistent site non-compliance

Arm/Group Title	De Novo	CAM2038	Rollover Placebo Injections
Arm/Group Description	CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg. buprenorphine	CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg buprenorphine during both Double Blind Phase and Open Label Phase	Placebo injections during Double Blind Phase, CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg orCAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg buprenorphine during Open Label Phase
Measure Participants	54	24	31
Count of Participants [Participants]	1 0.9%	0 0%	1 1.3%

12. Secondary Outcome

Title	Summary of Rescue Medication Usage-Open Label Phase
Description	Rescue medication usage (number of days used) during the Open Label Phase.
Time Frame	48 weeks -From baseline to 48 weeks after baseline (Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects).

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (mITT) Population: The mITT Population consisted of all randomized subjects, with the exception of the subjects from Sites 068 and 077 due to persistent site non-compliance

Arm/Group Title	De Novo	CAM2038	Rollover Placebo Injections
Arm/Group Description	CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg. buprenorphine	CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg buprenorphine during both Double Blind Phase and Open Label Phase	Placebo injections during Double Blind Phase, CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg orCAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg buprenorphine during Open Label Phase
Measure Participants	54	24	31
Baseline	1.172 (1.99)	0.352 (0.68)	1.330 (2.23)
Change from Baseline to Week 4	-0.744 (1.54)	-0.793 (2.47)	-1.124 (2.32)
Change from Baseline to Week 8	-0.301 (1.75)	-0.671 (2.18)	-1.672 (2.29)
Change from Baseline to Week 12	-0.472 (1.99)	-1.180 (2.48)	-1.817 (2.53)
Change from Baseline to Week 16	-0.679 (1.87)	-0.418 (2.33)	-0.990 (2.07)
Change from Baseline to Week 20	-0.562 (2.00)	-0.745 (2.02)	-0.490 (2.48)
Change from Baseline to Week 24	-0.689 (1.96)	-0.959 (2.52)	-0.933 (2.64)
Change from Baseline to Week 28	-1.045 (2.17)	-0.553 (1.64)	-0.875 (2.80)
Change from Baseline to Week 32	-0.864 (2.36)	-0.577 (2.12)	-1.280 (2.70)
Change from Baseline to Week 36	-0.989 (2.29)	-0.359 (1.63)	-1.479 (2.91)
Change from Baseline to Week 40	-0.941 (2.41)	-0.980 (2.26)	-1.339 (2.81)
Change from Baseline to Week 44	-1.050 (2.54)	-0.767 (1.90)	-1.465 (2.51)
Change from Baseline to Week 48	-1.088 (2.20)	-0.929 (2.15)	-2.302 (2.89)

13. Secondary Outcome

Title	Summary of Change From Baseline in EuroQoL Group EQ-5D-5L Scores Over Time-Open Label Phase
Description	Change from Open Label Titration baseline in EuroQol Group 5-dimension 5-level self-report questionnaire score in the Open Label Phase. 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 subjects 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 were converted into a weighted health-state index score, according to the US population-based algorithm, with higher scores indicating better quality of life. The score ranges from 0-100 with 0 as the worst health and 100 as the best health.
Time Frame	48 weeks -From baseline to 48 weeks after baseline (Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects).

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (mITT) Population: The mITT Population consisted of all randomized subjects, with the exception of the subjects from Sites 068 and 077 due to persistent site non-compliance

Arm/Group Title	De Novo	CAM2038	Rollover Placebo Injections
Arm/Group Description	CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg. buprenorphine	CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg buprenorphine during both Double Blind Phase and Open Label Phase	Placebo injections during Double Blind Phase, CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg orCAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg buprenorphine during Open Label Phase
Measure Participants	54	24	31
Baseline	76.59 (13.31)	83.38 (14.89)	79.65 (14.00)
Change from Baseline at End of Treatment Visit	5.17 (15.43)	9.95 (18.83)	6.35 (18.95)

14. Secondary Outcome

Title	Summary of Change From Baseline in Clinical Global Impression of Improvement (CGI-I) Scale-Open Label
Description	Summary of Change from Baseline in Clinical Global Impression of Improvement (CGI-I) scale. The Clinician Global Impression of Improvement (CGI-I) Scale is a 7-point scale that required the clinician to assess how much the subject's Pain had improved or worsened relative to the start of the study. Assessments were 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
Time Frame	48 weeks -From baseline to 48 weeks after baseline (Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects).

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (mITT) Population: The mITT Population consisted of all randomized subjects, with the exception of the subjects from Sites 068 and 077 due to persistent site non-compliance

Arm/Group Title	De Novo	CAM2038	Rollover Placebo Injections
Arm/Group Description	CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg. buprenorphine	CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg buprenorphine during both Double Blind Phase and Open Label Phase	Placebo injections during Double Blind Phase, CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg orCAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg buprenorphine during Open Label Phase
Measure Participants	54	24	31
Baseline	1.9 (0.79)	1.7 (0.56)	2.0 (1.13)
Change from Baseline at End of Treatment Visit	-0.4 (1.25)	-0.1 (1.08)	0.1 (1.31)

15. Secondary Outcome

Title	Summary of Change From Baseline in Patient Global Impression of Improvement (PGI-I) Scale
Description	Change from baseline in the Open Label Phase in Patient global Impression of Improvement (PGI-I) Scale. PGI-I Scale is a single question 7-point likert scale that required the subject to assess how much his/her pain had improved or worsened relative to the start of the study. Ratings were: 1, much worse; 2, worse; 3, a little worse; 4, no change; 5, a little better; 6, better; or 7, much better
Time Frame	48 weeks -From baseline to 48 weeks after baseline (Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects).

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (mITT) Population: The mITT Population consisted of all randomized subjects, with the exception of the subjects from Sites 068 and 077 due to persistent site non-compliance

Arm/Group Title	De Novo	CAM2038	Rollover Placebo Injections
Arm/Group Description	CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg. buprenorphine	CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg buprenorphine during both Double Blind Phase and Open Label Phase	Placebo injections during Double Blind Phase, CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg orCAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg buprenorphine during Open Label Phase
Measure Participants	54	24	31
Baseline	5.8 (0.84)	6.1 (1.10)	6.3 (0.84)
Change from Baseline at End of Treatment Visit	0.2 (1.16)	-0.2 (1.04)	0.5 (0.92)

16. Secondary Outcome

Title	Summary of Change From Baseline in Work Productivity and Activity Impairment Questionnaire (WPAI) Open Label Phase
Description	Change from baseline in the Open Label Phase in Work Productivity and Activity Impairment score with a range of 0-100 for 4 types of scores with higher scores indicating greater impairment. 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 (higher scores indicate greater impairment): Absenteeism (work time missed)，Presenteeism (impairment at work/reduced on-the-job effectiveness), Work Productivity Loss (overall work impairment/absenteeism plus presenteeism)，and Activity Impairment. Scores range from 0-100 for each of the four types with higher scores indicating greater impairment.
Time Frame	48 weeks -From baseline to 48 weeks after baseline (Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects).

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (mITT) Population: The mITT Population consisted of all randomized subjects, with the exception of the subjects from Sites 068 and 077 due to persistent site non-compliance

Arm/Group Title	De Novo	CAM2038	Rollover Placebo Injections
Arm/Group Description	CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg. buprenorphine	CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg buprenorphine during both Double Blind Phase and Open Label Phase	Placebo injections during Double Blind Phase, CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg orCAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg buprenorphine during Open Label Phase
Measure Participants	54	24	31
Baseline-Absenteesim	1.538 (5.55)	0 (0)	0 (0)
Change from Baseline at End of Treatment Visit-Absenteesim	0 (0)	-2.137 (5.23)	0 (0)
Baseline-Presenteeism	26.9 (18.43)	22.9 (19.76)	21.0 (11.97)
Change from Baseline at End of Treatment Visit-Presenteeism	1.0 (15.95)	1.7 (7.53)	6.7 (23.98)
Baseline-Work Productivity Loss	27.846 (19.42)	22.857 (19.76)	21.000 (11.97)
Change from Baseline at End of Treatment Visit- Work Productivity Loss	1.000 (15.95)	-0.043 (11.05)	6.667 (23.98)
Baseline-Activity Impairment	32.1 (20.55)	29.0 (23.82)	22.9 (16.52)
Change from Baseline at End of Treatment Visit-Activity Impairment	-12.1 (22.20)	-6.5 (25.60)	-18.2 (22.45)

17. Secondary Outcome

Title	Number of Subjects Discontinued Due to Loss of Efficacy
Description	Number of Subjects Discontinued due to loss of efficacy, defined as discontinuation of study drug for lack of efficacy.
Time Frame	48 weeks -From baseline to 48 weeks after baseline (Baseline is defined as the last week prior to Visit 14 (Randomization Visit) for the roll-over subjects and the last week prior to Visit 14 (Enrollment Visit) for de novo subjects).

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (mITT) Population: The mITT Population consisted of all randomized subjects, with the exception of the subjects from Sites 068 and 077 due to persistent site non-compliance

Arm/Group Title	De Novo	CAM2038	Rollover Placebo Injections
Arm/Group Description	CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg. buprenorphine	CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg buprenorphine during both Double Blind Phase and Open Label Phase	Placebo injections during Double Blind Phase, CAM2038 50 mg/mL q1w at doses of 4 mg, 8 mg, 12 mg orCAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg buprenorphine during Open Label Phase
Measure Participants	54	24	31
Count of Participants [Participants]	1 0.9%	0 0%	1 1.3%

Adverse Events

Time Frame	Double Blind Phase-up to 26 weeks Open Label Phase-up to 64 weeks
Arm/Group Title	CAM2038 q1w or q4w BPN Treatment-Titration Period of Double Blind Phase		CAM2038 q1w or q4w BPN Treatment- Double Blind Period of Double Blind Phase		Placebo Subcutaneous Injections-Double Blind Period of Double Blind Phase		De Novo Subjects-Open Label, Titration Period Only		Rollover Subjects-Open Label, Titration Period Only		De Novo Subjects-Open Label, Enrollment Period Only		Rollover Subjects-Open Label, Enrollment Period Only
Arm/Group Description	CAM2038 q1w (buprenorphine FluidCrystal®) : SC injection depot for once weekly or monthly administration at doses of 4, 8, 12, 16, 24 and 32 mg (buprenorphine base) 0.16, 0.24, and 0.64 mL SC injection CAM2038 (buprenorphine FluidCrystal® once-weekly injection depot)		CAM2038 50 mg/mL q1w at doses of 4, mg 8 mg, 12 mg, CAM2038 356 mg/mL q4w at doses of 64 mg, 96 mg, or 128 mg. buprenorphine		CAM2038 placebo: 0.16, 0.18, 0.24, 0.27, 0.36, and 0.64 mL SC injection administered once weekly or once monthly (matching volumes for CAM2038 q1w and near-matching volumes for CAM2038 q4w).		CAM2038 q1w (buprenorphine FluidCrystal®) : SC injection depot for once weekly or monthly administration at doses of 4, 8, 12, 16, 24 and 32 mg (buprenorphine base) 0.16, 0.24, and 0.64 mL SC injection CAM2038 (buprenorphine FluidCrystal® once-weekly injection depot)		CAM2038 q1w (buprenorphine FluidCrystal®) : SC injection depot for once weekly or monthly administration at doses of 4, 8, 12, 16, 24 and 32 mg (buprenorphine base) 0.16, 0.24, and 0.64 mL SC injection		CAM2038 q1w (buprenorphine FluidCrystal®) : SC injection depot for once weekly or monthly administration at doses of 4, 8, 12 mg (buprenorphine base) 0.16, 0.24, and 0.64 mL SC injection CAM2038 (buprenorphine FluidCrystal® once-weekly injection depot) CAM2038 q4w ( buprenorphine FluidCrystal®): SC injection depot for once monthly administration (356 mg/mL) at doses of 64, 96, 128 mg (buprenorphine base) 0.18, 0.27, and 0.36 mL SC injection CAM2038 (buprenorphine FluidCrystal® once-monthly injection depot)		CAM2038 q1w (buprenorphine FluidCrystal®) : SC injection depot for once weekly or monthly administration at doses of 4, 8, 12 mg (buprenorphine base) 0.16, 0.24, and 0.64 mL SC injection CAM2038 (buprenorphine FluidCrystal® once-weekly injection depot) CAM2038 q4w ( buprenorphine FluidCrystal®): SC injection depot for once monthly administration (356 mg/mL) at doses of 64, 96, 128 mg (buprenorphine base) 0.18, 0.27, and 0.36 mL SC injection CAM2038 (buprenorphine FluidCrystal® once-monthly injection depot)
All Cause Mortality
	CAM2038 q1w or q4w BPN Treatment-Titration Period of Double Blind Phase		CAM2038 q1w or q4w BPN Treatment- Double Blind Period of Double Blind Phase		Placebo Subcutaneous Injections-Double Blind Period of Double Blind Phase		De Novo Subjects-Open Label, Titration Period Only		Rollover Subjects-Open Label, Titration Period Only		De Novo Subjects-Open Label, Enrollment Period Only		Rollover Subjects-Open Label, Enrollment Period Only
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/468 (0.2%)		0/112 (0%)		1/110 (0.9%)		0/75 (0%)		0/46 (0%)		0/54 (0%)		0/55 (0%)
Serious Adverse Events
	CAM2038 q1w or q4w BPN Treatment-Titration Period of Double Blind Phase		CAM2038 q1w or q4w BPN Treatment- Double Blind Period of Double Blind Phase		Placebo Subcutaneous Injections-Double Blind Period of Double Blind Phase		De Novo Subjects-Open Label, Titration Period Only		Rollover Subjects-Open Label, Titration Period Only		De Novo Subjects-Open Label, Enrollment Period Only		Rollover Subjects-Open Label, Enrollment Period Only
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/468 (2.1%)		3/112 (2.7%)		3/110 (2.7%)		1/75 (1.3%)		1/46 (2.2%)		7/54 (13%)		7/55 (12.7%)
Blood and lymphatic system disorders
Anaemia	0/468 (0%)	0	0/112 (0%)	0	1/110 (0.9%)	1	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Cardiac disorders
Acute myocardial infarction	0/468 (0%)	0	0/112 (0%)	0	0/110 (0%)	0	1/75 (1.3%)	1	0/46 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Bradycardia	0/468 (0%)	0	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Gastrointestinal disorders
Inguinal hernia	0/468 (0%)	0	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Intestinal obstruction	0/468 (0%)	0	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Lower gastrointestinal haemorrhage	0/468 (0%)	0	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Small intestinal obstruction	0/468 (0%)	0	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Vomiting	1/468 (0.2%)	1	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Nausea	1/468 (0.2%)	1	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Dysphagia	1/468 (0.2%)	1	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
General disorders
Non-cardiac chest pain	1/468 (0.2%)	1	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Asthenia	1/468 (0.2%)	1	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Multi-organ failure	1/468 (0.2%)	1	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Hepatobiliary disorders
Cholecystitis	0/468 (0%)	0	1/112 (0.9%)	1	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Acute hepatic failure	1/468 (0.2%)	1	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Infections and infestations
Appendicitis	0/468 (0%)	0	0/112 (0%)	0	1/110 (0.9%)	1	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Cellulitis	1/468 (0.2%)	1	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Injury, poisoning and procedural complications
Accidental overdose	0/468 (0%)	0	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Femur fracture	0/468 (0%)	0	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Wrist fracture	0/468 (0%)	0	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	1/468 (0.2%)	1	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastatic squamous cell carcinoma	0/468 (0%)	0	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Triple negative breast cancer	0/468 (0%)	0	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Metastases to liver	0/468 (0%)	0	0/112 (0%)	0	1/110 (0.9%)	1	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Pancreatic carcinoma	0/468 (0%)	0	0/112 (0%)	0	1/110 (0.9%)	1	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Nervous system disorders
Dizzyness	0/468 (0%)	0	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Seizure	0/468 (0%)	0	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Cauda equina syndrome	0/468 (0%)	0	1/112 (0.9%)	1	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Hemiparesis	1/468 (0.2%)	1	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Psychiatric disorders
Mental status changes	0/468 (0%)	0	1/112 (0.9%)	1	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Schizoaffective disorder	1/468 (0.2%)	1	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/468 (0%)	0	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Nephrolithiasis	0/468 (0%)	0	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulonary disease	0/468 (0%)	0	0/112 (0%)	0	0/110 (0%)	0	1/75 (1.3%)	1	0/46 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Sleep apnoea syndrome	0/468 (0%)	0	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	1/46 (2.2%)	1	0/54 (0%)	0	0/55 (0%)	0
Pleuritic pain	1/468 (0.2%)	1	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	0/54 (0%)	0	0/55 (0%)	0
Other (Not Including Serious) Adverse Events
	CAM2038 q1w or q4w BPN Treatment-Titration Period of Double Blind Phase		CAM2038 q1w or q4w BPN Treatment- Double Blind Period of Double Blind Phase		Placebo Subcutaneous Injections-Double Blind Period of Double Blind Phase		De Novo Subjects-Open Label, Titration Period Only		Rollover Subjects-Open Label, Titration Period Only		De Novo Subjects-Open Label, Enrollment Period Only		Rollover Subjects-Open Label, Enrollment Period Only
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	300/468 (64.1%)		36/112 (32.1%)		32/110 (29.1%)		41/75 (54.7%)		15/46 (32.6%)		41/54 (75.9%)		46/55 (83.6%)
Gastrointestinal disorders
Constipation	25/468 (5.3%)	25	2/112 (1.8%)	2	1/110 (0.9%)	1	4/75 (5.3%)	4	0/46 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Nausea	87/468 (18.6%)	87	2/112 (1.8%)	2	1/110 (0.9%)	1	9/75 (12%)	9	7/46 (15.2%)	7	4/54 (7.4%)	4	2/55 (3.6%)	2
Vomiting	64/468 (13.7%)	64	3/112 (2.7%)	3	1/110 (0.9%)	1	7/75 (9.3%)	7	4/46 (8.7%)	4	3/54 (5.6%)	3	3/55 (5.5%)	3
General disorders
Injection Site Erythema	32/468 (6.8%)	32	2/112 (1.8%)	2	3/110 (2.7%)	3	6/75 (8%)	6	0/46 (0%)	0	1/54 (1.9%)	1	3/55 (5.5%)	3
Injection site pain	29/468 (6.2%)	29	1/112 (0.9%)	1	3/110 (2.7%)	3	4/75 (5.3%)	4	0/46 (0%)	0	2/54 (3.7%)	2	1/55 (1.8%)	1
Injection site pruritus	40/468 (8.5%)	40	0/112 (0%)	0	0/110 (0%)	0	6/75 (8%)	6	2/46 (4.3%)	2	2/54 (3.7%)	2	3/55 (5.5%)	3
Injection Site Swelling	25/468 (5.3%)	25	1/112 (0.9%)	1	3/110 (2.7%)	3	4/75 (5.3%)	4	0/46 (0%)	0	3/54 (5.6%)	3	0/55 (0%)	0
Oedema peripheral	6/468 (1.3%)	6	3/112 (2.7%)	3	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	1/54 (1.9%)	1	3/55 (5.5%)	3
Infections and infestations
Upper respiratory tract injection	6/468 (1.3%)	6	2/112 (1.8%)	2	4/110 (3.6%)	4	6/75 (8%)	6	1/46 (2.2%)	1	1/54 (1.9%)	1	3/55 (5.5%)	3
Influenza	5/468 (1.1%)	5	1/112 (0.9%)	1	1/110 (0.9%)	1	1/75 (1.3%)	1	1/46 (2.2%)	1	1/54 (1.9%)	1	4/55 (7.3%)	4
Nasopharyngitis	7/468 (1.5%)	7	0/112 (0%)	0	1/110 (0.9%)	1	1/75 (1.3%)	1	0/46 (0%)	0	1/54 (1.9%)	1	3/55 (5.5%)	3
Urinary Tract Infection	8/468 (1.7%)	8	5/112 (4.5%)	5	7/110 (6.4%)	7	0/75 (0%)	0	1/46 (2.2%)	1	4/54 (7.4%)	4	5/55 (9.1%)	5
Injury, poisoning and procedural complications
Fall	16/468 (3.4%)	16	5/112 (4.5%)	5	1/110 (0.9%)	1	3/75 (4%)	3	1/46 (2.2%)	1	2/54 (3.7%)	2	3/55 (5.5%)	3
Investigations
Aspartate aminotransferase increased	1/468 (0.2%)	1	1/112 (0.9%)	1	1/110 (0.9%)	1	1/75 (1.3%)	1	0/46 (0%)	0	3/54 (5.6%)	3	0/55 (0%)	0
Blood glucose increased	2/468 (0.4%)	2	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	6/54 (11.1%)	6	0/55 (0%)	0
Gamma-glutamyltransferase increased	5/468 (1.1%)	5	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	3/54 (5.6%)	3	2/55 (3.6%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	15/468 (3.2%)	15	1/112 (0.9%)	1	1/110 (0.9%)	1	2/75 (2.7%)	2	0/46 (0%)	0	1/54 (1.9%)	1	6/55 (10.9%)	6
Back Pain	9/468 (1.9%)	9	7/112 (6.3%)	7	2/110 (1.8%)	2	1/75 (1.3%)	1	1/46 (2.2%)	1	1/54 (1.9%)	1	3/55 (5.5%)	3
Nervous system disorders
Dizziness	38/468 (8.1%)	38	0/112 (0%)	0	1/110 (0.9%)	1	2/75 (2.7%)	2	2/46 (4.3%)	2	1/54 (1.9%)	1	0/55 (0%)	0
Headache	28/468 (6%)	28	1/112 (0.9%)	1	1/110 (0.9%)	1	0/75 (0%)	0	2/46 (4.3%)	2	2/54 (3.7%)	2	3/55 (5.5%)	3
Renal and urinary disorders
Proteinuria	1/468 (0.2%)	1	0/112 (0%)	0	0/110 (0%)	0	0/75 (0%)	0	0/46 (0%)	0	3/54 (5.6%)	3	0/55 (0%)	0

Limitations/Caveats

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.