A Study of Adult Outpatients With Opioid Dependence Transitioned From a Daily SL Buprenorphine to Probuphine® Subdermal Implants

Study Overview
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Brief Summary
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The primary objective of the study is to demonstrate maintenance of treatment efficacy when transferring adult outpatients with opioid dependence, who are clinically stabilized on 8 mg or less of sublingual (SL) buprenorphine (BPN), to 4 Probuphine implants compared to SL BPN. The secondary objective of the study is to confirm safety of 4 Probuphine implants in adult outpatients with opioid dependence who are clinically stabilized on 8 mg or less of SL BPN.

Detailed Description
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This is a randomized, double-blind, double-dummy, active-controlled multi-center study to evaluate the efficacy of transition to four 80 mg Probuphine implants in adult outpatients with opioid dependence, who are clinically stabilized on 8 mg or less of SL BPN. The study will include 3 Phases; Screening, Maintenance and Follow-up. Medical and eligibility screening should occur within 2 weeks of the first Maintenance Phase visit. The Screening Visit will include standard medical screening procedures, complete medical/psychosocial history, urine toxicology and detailed substance use and treatment history. All subjects who have provided written informed consent and have met the other study entry criteria will be eligible for randomization. Following confirmation of eligibility, subjects will be randomized to one of two treatment groups in a 1:1 ratio: Treatment Group A: Daily SL BPN tablets (≤8 mg/daily) + four placebo implants Treatment Group B: Four 80 mg Probuphine implants + daily SL placebo tablets Implants will be surgically inserted on Day 1 (Baseline and Initiation of Study Drugs Visit). On Post-Implant Visit, additional follow-up safety and implant assessment procedures will be conducted. Subjects will return for monthly study visits on Weeks 4, 8, 12, 16, 20, and 24 (End of Treatment Visit). In addition to the monthly scheduled visits, subjects will provide 4 random urine toxicology samples throughout the 24-week treatment period. A total of 10 urine toxicology samples will be collected; 6 at scheduled visits (1 per month) and 4 at random urine toxicology visits throughout the 24-week treatment period. At the scheduled visits, other assessments of efficacy and safety will be collected. Implants will be removed at the End of Treatment Visit on Week 24. Following Week 24, subjects will be re-transitioned back to usual care (pre-trial), as needed. During Week 25, telephone contact will be made with all subjects. and Week 26 will include an on-site visit to the clinic for final follow-up assessments (Follow-up Visit).

Official Title
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A Randomized, Double-Blind, Double-Dummy, Active-Controlled Multicenter Study of Adult Outpatients With Opioid Dependence Transitioned From a Daily Maintenance Dose of 8 mg or Less of Sublingual Buprenorphine or Buprenorphine/Naloxone to Four Probuphine® Subdermal Implants

Conditions
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Opioid Dependence

Intervention / Treatment
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* Drug: sublingual buprenorphine tablets
* Drug: Buprenorphine implant
* Drug: placebo implants
* Drug: sublingual placebo tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must provide written informed consent prior to the conduct of any study-related procedures. Male or female, 18-65 years of age, inclusive. Primary diagnosis of opioid dependence (DSM-IV-TR). Subject is considered clinically stable by their treating healthcare provider and confirmed by the following: Subject must be on SL BPN treatment for at least 6 months. Subject must have been on a SL BPN dose of 8 mg or less daily for at least the last 90 days prior to Screening. No positive urine toxicology results for illicit opioids in the last 90 days. Free from significant withdrawal symptoms (score of ≤ 5 on the Clinical Opiate Withdrawal Scale [COWS]), as measured at the Screening Visit. Female subjects of childbearing potential must be willing to use a reliable method of contraception during the entire study (Screening Visit to Follow-Up Visit). Exclusion Criteria: Current diagnosis of Acquired Immune Deficiency Syndrome (AIDS). Current diagnosis of chronic pain syndrome requiring chronic opioid treatment, or conditions associated with acute episodic flares that require opioid treatment. Pregnant or lactating or planning to become pregnant during the study. Hypersensitivity or allergy to ethylene vinyl acetate (EVA)-containing substances or naloxone. Recent scarring or tattoos on their upper arms, or a history of keloid scarring. Requires current use of agents metabolized through CYP 3A4 such as azole antifungals (e.g., ketoconazole), macrolide antibiotics (e.g., erythromycin), or protease inhibitors (e.g., ritonavir, indinavir, and saquinavir). History of coagulopathy within the past 90 days, and/or current anti-coagulant therapy such as warfarin. Current DSM-IV-TR diagnosis for substance dependence on any other psychoactive substances other than opioids or nicotine (e.g., alcohol, cocaine). Significant symptoms or other factors which in the opinion of the Investigator would preclude compliance with the protocol, subject safety, adequate cooperation in the study, or obtaining informed consent. Current medical conditions such as severe respiratory insufficiency that may prevent the subject from safely participating in study. Any pending legal action that could prohibit participation or compliance in the study. Exposure to any investigational drug within the 8 weeks prior to Screening. Aspartate aminotransferase levels ≥3 X the upper limit of normal, alanine aminotransferase levels ≥ 3 X the upper limit of normal, total bilirubin ≥ 1.5 X the upper limit of normal, or creatinine ≥ 1.5 X upper limit of normal on the Screening laboratory assessments. Clinically significant low platelet count on the Screening laboratory assessments, according to the Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: buprenorphine implants + placebo tablets<br>Four 80 mg Probuphine implants + daily SL placebo tablets | Drug: Buprenorphine implant<br> <br> Drug: sublingual placebo tablets<br> <br> |
| Active Comparator: buprenorphine tablets + placebo implants<br>Daily SL BPN tablets (≤8 mg/daily) + four placebo implants | Drug: sublingual buprenorphine tablets<br> <br> Drug: placebo implants<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Primary Efficacy Endpoint is a Responder Rate Analysis, Where a Responder is Defined as a Patient With no More Than 2 of 6 Months With Any Evidence of Illicit Opioid Use. | The primary efficacy endpoint is a responder analysis. A subject will be designated as a responder (meaning they have maintained stability) if they have no more than 2 of 6 months with any evidence of illicit opioid use. Evidence of illicit opioid use is defined as a positive opioid urine toxicology result or self-reported illicit opioid use. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Subjects With no Urine Illicit Opioid Use by Month; | The secondary outcome is the percent of subjects with no urine illicit opioid use by month. | 24 weeks | 
| Number of Participants With Evidence of Urine Illicit Opioid Use by Month | Secondary efficacy endpoint measures number of participants with evidence of urine illicit opioid use by month. | 24 weeks | 
| Percent of Subjects With no Self-reported Illicit Drug Use by Month | Subjects in the ITT population with no self-reported use of any illicit drugs (opioid or non-opioid) by month of evaluation | 24 weeks | 
| Measures of Craving: Desire to Use Visual Analogue Scale (VAS) | The secondary outcome of measures of craving: desire to use is a change from Day 1 (baseline) in the unipolar visual analogue scale (VAS), which is a 0-100 mm scale, where 0 mm is no desire, and 100 mm is strongest possible desire. | 24 weeks | 
| Measures of Withdrawal: Clinical Opiate Withdrawal Scale (COWS) | The secondary outcome measures the change in baseline in the Clinical opiate withdrawal scale (COWS), which is a scale consisting of 11 common opiate withdrawal signs or symptoms, rated on a numeric scale with higher scores associated with greater withdrawal symptoms. A total score was calculated as the sum of the responses to the 11 signs/symptoms for a total range of 0-48. Withdrawal severity was classified, based on the total score, as follows: 0-4=none/normal, 5-12=mild, 13-24=moderate, 25-36=moderately severe, more than 36=severe withdrawal. | 24 weeks | 
| Measures of Withdrawal: Subjective Opioid Withdrawal Scale (SOWS) (ITT Population) | The secondary outcome measures the change in baseline in the subjective opioid withdrawal scale (SOWS), which is a scale which is a subject self-assessment of withdrawal symptoms. The scale consists of 16 questions that rate the intensity of withdrawal from 0 (not at all) to 4 (extremely) with a cumulative score ranging from 0-64 (0 =not at all, 64=extremely) | 24 weeks | 
| Measures of Craving: Need to Use Visual Analogue Scale (VAS) | The secondary outcome of measures of craving: Need to use is a change from Day 1 (baseline) in the unipolar visual analogue scale (VAS), which is a 0-100 mm scale, where 0 mm is no need, and 100 mm is strongest possible need. | 24 weeks |