Buprenorphine (CAM2038) in Subjects With a Recent History of Moderate to Severe Chronic Low Back Pain
Condition: Chronic Lower Back Pain; Chronic Pain
MeSH terms: Back Pain; Low Back Pain; Chronic Pain
Intervention: buprenorphine; Placebo
Intervention MeSH terms: Buprenorphine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 1053.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No

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