Clinical trial NCT02946073: Buprenorphine (CAM2038) in Subjects With a Recent History of Moderate to Severe Chronic Low Back Pain
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Lower Back Pain
Chronic Pain
Lead sponsor: Braeburn Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: Medpace, Inc.
name: Camurus AB
First posted: 2016-10-26
Enrollment: 1053
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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:

   1. Severe respiratory insufficiency, respiratory depression, airway obstruction, gastrointestinal motility disorders, biliary tract disease, severe hepatic insufficiency, or planned surgery.
   2. 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.
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.

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

Primary outcomes:
measure: 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.
timeFrame: 12 weeks- from randomization baseline to 12 weeks after randomization
measure: Change From Baseline in Weekly Average of (Daily) Average Pain Intensity (WAAPI) of the Open Label Phase.
timeFrame: 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).
Secondary outcomes:
measure: 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.
timeFrame: 12 weeks- from randomization baseline to 12 weeks after randomization
measure: Number of Subjects With a 30% and 50% Reduction in WAAPI From Baseline to Week 12 of the Double-Blind Phase.
timeFrame: 12 weeks- from randomization baseline to 12 weeks after randomization
measure: Summary of Rescue Medication Usage- Double-Blind Phase.
timeFrame: 12 weeks- from randomization baseline to 12 weeks after randomization
measure: 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.
timeFrame: 12 weeks- from randomization baseline to 12 weeks after randomization
measure: Change From Baseline to Week 12 of the Double-Blind Phase in Work Productivity and Activity Impairment Score
timeFrame: 23 weeks- from baseline to 12 weeks after randomization
measure: Number of Subjects Discontinued Due to Loss of Efficacy
timeFrame: 12 weeks- from randomization baseline to 12 weeks after randomization
measure: Change From Baseline to Week 12 of the Double-Blind Phase in Patient Global Impression of Improvement (PGI-I) Scale
timeFrame: 12 weeks- from baseline (randomization) to 12 weeks after randomization
measure: Change From Baseline in Weekly Average of (Daily) Worst Pain Intensity (WAWPI) of the Open Label Phase.
timeFrame: 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).
measure: Subject Discontinued Due to Loss of Efficacy, Defined as Discontinuation of Study Drug for Lack of Efficacy.
timeFrame: 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).
measure: Summary of Rescue Medication Usage-Open Label Phase
timeFrame: 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).
measure: Summary of Change From Baseline in EuroQoL Group EQ-5D-5L Scores Over Time-Open Label Phase
timeFrame: 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).
measure: Summary of Change From Baseline in Clinical Global Impression of Improvement (CGI-I) Scale-Open Label
timeFrame: 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).
measure: Summary of Change From Baseline in Patient Global Impression of Improvement (PGI-I) Scale
timeFrame: 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).
measure: Summary of Change From Baseline in Work Productivity and Activity Impairment Questionnaire (WPAI) Open Label Phase
timeFrame: 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).
measure: Number of Subjects Discontinued Due to Loss of Efficacy
timeFrame: 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).
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Parkway Medical Center
state: Alabama
city: Hamilton
country: United States
facility: Boyett Health Services Inc
state: Alabama
city: Vestavia Hills
country: United States
facility: National Centers for Pain Management and Research
state: Alabama
city: Phoenix
country: United States
facility: Elite Clinical Studies
state: Arizona
city: Phoenix
country: United States
facility: Phoenix Clinical
state: Arizona
city: Phoenix
country: United States
facility: Noesis Pharma
state: Arizona
city: Phoenix
country: United States
facility: Arizona Research Center
state: Arizona
city: Fountain Valley
country: United States
facility: MD Studies, Inc.
state: California
city: Fresno
country: United States
facility: Neuro-Pain Medical Center
state: California
city: Laguna Hills
country: United States
facility: Alliance Research Centers
state: California
city: Lincoln
country: United States
facility: Clinical Trials Research
state: California
city: Montclair
country: United States
facility: Catalina Research Institute, LLC
state: California
city: Sacramento
country: United States
facility: Allied Clinical Research, LLC
state: California
city: San Francisco
country: United States
facility: Care Practice
state: California
city: Santa Ana
country: United States
facility: Syrentis Clinical Research
state: California
city: Valencia
country: United States
facility: Universal Pain Management Group
state: California
city: Brandon
country: United States
facility: Tampa Pain Relief Center-Brandon
state: Florida
city: Doral
country: United States
facility: International Research Partners
state: Florida
city: Jacksonville
country: United States
facility: Dr. Vijapura and Associates
state: Florida
city: Jacksonville
country: United States
facility: Florida Institute of Medical Research
state: Florida
city: Maitland
country: United States
facility: Lake Howell Health Center
state: Florida
city: Miami Springs
country: United States
facility: Ocean Blue Medical Research Center, Inc.
state: Florida
city: North Miami
country: United States
facility: Scientific Clinical Research, Inc.
state: Florida
city: Plantation
country: United States
facility: Gold Coast Research, LLC
state: Florida
city: Saint Petersburg
country: United States
facility: FMPM Research
state: Florida
city: Tampa
country: United States
facility: Clinical Research of West Florida-Tampa
state: Florida
city: Tampa
country: United States
facility: Tampa Pain Relief Centers-Hillsborough
state: Florida
city: West Palm Beach
country: United States
facility: Palm Beach Research Center
state: Florida
city: Blue Ridge
country: United States
facility: River Birch Research Alliance LLC
state: Georgia
city: Knoxville
country: United States
facility: Columbus Regional Research Institute
state: Georgia
city: Marietta
country: United States
facility: Drug Studies America
state: Georgia
city: Marietta
country: United States
facility: Non-Surgical Orthopedics, P.C.
state: Georgia
city: Boise
country: United States
facility: Injury Care Research, LLC
state: Idaho
city: Bloomington
country: United States
facility: Millennium Pain Center
state: Illinois
city: Gurnee
country: United States
facility: Clinical Investigation Specialists, Inc.-Gurnee
state: Illinois
city: Evansville
country: United States
facility: Medisphere Medical Research Center
state: Indiana
city: Overland Park
country: United States
facility: International Clinical Research Institute Inc.
state: Kansas
city: Prairie Village
country: United States
facility: Phoenix Medical Research
state: Kansas
city: Edgewood
country: United States
facility: Otrimed
state: Kentucky
city: Shreveport
country: United States
facility: River Cities Clinical Research Center
state: Louisiana
city: Waltham
country: United States
facility: Boston Paincare
state: Massachusetts
city: Watertown
country: United States
facility: MedVadis Research Corporation
state: Massachusetts
city: Festus
country: United States
facility: Amicis Trials
state: Missouri
city: Berlin
country: United States
facility: Hassman Research Institute
state: New Jersey
city: New York
country: United States
facility: New York Clinical Trials, Inc
state: New York
city: New York
country: United States
facility: MedEx Healthcare Research, Inc-NY
state: New York
city: Williamsville
country: United States
facility: Upstate Clinical Research Associates
state: New York
city: Fayetteville
country: United States
facility: Rapha Institute for Clinical Research
state: North Carolina
city: Hickory
country: United States
facility: OnSite Clinical Solutions, LLC-Hickory
state: North Carolina
city: Winston-Salem
country: United States
facility: Center for Clinical Research, LLC-Winston-Salem
state: North Carolina
city: Columbus
country: United States
facility: Aventiv Research, Inc.
state: Ohio
city: Dayton
country: United States
facility: Dayton Outpatient Center (DOC) Clinical Research
state: Ohio
city: Dayton
country: United States
facility: Providence Health Partners-Center for Clinical Research
state: Ohio
city: Oklahoma City
country: United States
facility: Medical Research Internationl
state: Oklahoma
city: Oklahoma City
country: United States
facility: SP Research, PLLC
state: Oklahoma
city: Conshohocken
country: United States
facility: Frost Medical Group, LLC
state: Pennsylvania
city: Media
country: United States
facility: Suburban Research Associates
state: Pennsylvania
city: Charleston
country: United States
facility: Coastal Carolina Research Center
state: South Carolina
city: Charleston
country: United States
facility: Medical Research South, LLC
state: South Carolina
city: Knoxville
country: United States
facility: New Phase Research & Development
state: Tennessee
city: Dallas
country: United States
facility: FutureSearch Trials of Dallas, LP
state: Texas
city: Dallas
country: United States
facility: Renaissance Clinical Research and Hypertension Clinic
state: Texas
city: Houston
country: United States
facility: Research Concepts GP, LLC-Houstion
state: Texas
city: Houston
country: United States
facility: Pioneer Research Solutions Inc.
state: Texas
city: Plano
country: United States
facility: The Pain Relief Center
state: Texas
city: Draper
country: United States
facility: The SMART Clinic/Physicians Research Options LLC
state: Utah
city: Murray
country: United States
facility: EPIC Medical Research
state: Utah
city: Orem
country: United States
facility: Aspen Clinical Research
state: Utah
city: Richland
country: United States
facility: Mid Columbia Research
state: Washington
Study officials:
References: