Study to Assess Efficacy and Safety of BNX Sublingual Tablets for the Induction of Treatment of Opioid Dependence

Study Overview
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Brief Summary
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The purpose of the study was to assess the efficacy of induction treatment with buprenorphine/naloxone (BNX) sublingual tablet s compared with induction treatment with buprenorphine only. The hypothesis is that starting directly on OX219 works equally well (e.g. not significantly worse) as starting on buprenorphine only and switching to OX219 on Day 3.

Detailed Description
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This was a prospective, randomized, multicenter, blinded, parallel-group, active-controlled, non-inferiority study conducted at 13 sites within the US. Eligible patients participated in 8 treatment visits on Days 1, 2, 3, 4, 8, 15, 22, and 29. Effectiveness of treatment was assessed as follows: Retention in treatment at Day 3 Clinician and patient assessments of opioid withdrawal symptoms Assessment opioid cravings

Official Title
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A Randomized, Blinded, Active-controlled Non-inferiority Study of the Efficacy and Safety of OX219 for the Induction of Treatment of Opioid Dependence

Conditions
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Opioid-Related Disorders, Opiate Dependence

Intervention / Treatment
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* Drug: Buprenorphine/naloxone sublingual tablets
* Drug: Buprenorphine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to read, comprehend, and sign the informed consent form and willingly provide written informed consent Prepared to engage in opioid replacement therapy and to abstain from opioid utilization other than the study drug, and from other illicit drugs Male or female, 18 to 65 years of age (inclusive) Met clinical criteria for opioid dependence in past 12 months based on DSM-IV-TR Provided buprenorphine-negative urine drug screen prior to randomization Provided negative urine pregnancy test Females of childbearing potential were required to be using a reliable method of contraception (e.g., hormonal, condom with spermicide, intrauterine device [IUD]) after the screening visit and for the duration of the study Participants receiving opioids for pain must receive clearance from their prescribing physician to be withdrawn from their prescribed opioids Generally good health as determined by the investigator Participants should demonstrate at least mild withdrawal symptoms (defined as a COWS score >9 at Day 1 predose) Exclusion Criteria: Females who are pregnant or lactating, or planning to be pregnant during study Any previous prescribed treatment with buprenorphine monotherapy (e.g., generic buprenorphine sublingual tablets) Prescribed treatment with buprenorphine or naloxone within 90 days prior to start of treatment Methadone patients with any daily dose over 30 mg during the past week and who received the last dose of methadone less than 30 hours prior to start of treatment Participants who are unwilling or unable to comply with the requirements of the protocol Participants who are participating in any other clinical study in which medication(s) are being delivered or who have used an investigational drug or device within the last 30 days Participants with any known allergy or sensitivity or intolerance to buprenorphine, naloxone, or any related drug Participants who are on the staff, affiliated with, or a family member of the staff personnel directly involved with this study Participants with serious untreated Axis I DSM-IV-TR psychiatric comorbidity Tongue piercing or other piercings in the mouth, including lips and cheek Participants with current or history of clinically significant medical disorder or condition Participants who are human immunodeficiency virus (HIV)-seropositive with a CD4+ count <200 or active acquired immune deficiency syndrome (AIDS) Participants who have any Class III or IV congestive heart failure, symptomatic myocardial ischemia, a history of long QT syndrome. Participants who are currently taking Class 1A antiarrhythmic medications or Class III antiarrhythmic medications Participants who have uncontrolled hypertension or clinically significant ECG abnormalities Participants who have a pulse oximetry ≤93% at screening, due to any medical reason. Individuals with AST or ALT levels ≥3 X the upper limit of normal or total bilirubin or creatinine ≥1.5 X ULN, on the screening laboratory assessments Participants with known significant liver disease. Participants who take any medication, nutraceutical, herbal product with known CYP3A4 inhibition or induction properties within 14 days of screening. Participants who are at suicidal risk

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BNX Sublingual Tablets Induction<br>Day 1-2 (Blinded Induction): BNX sublingual tablets Day 3-28 (Open-label Maintenance): BNX sublingual tablets | Drug: Buprenorphine/naloxone sublingual tablets<br>* Advanced-formulation buprenorphine/naloxone sublingual tablets<br>* Other names: OX219;|
| Active Comparator: Buprenorphine Induction<br>Day 1-2 (Blinded Induction): Generic buprenorphine sublingual tablets Day 3-28 (Open-label Maintenance): BNX sublingual tablets | Drug: Buprenorphine/naloxone sublingual tablets<br>* Advanced-formulation buprenorphine/naloxone sublingual tablets<br>* Other names: OX219;Drug: Buprenorphine<br>* Buprenorphine sublingual tablets<br>* Other names: Generic buprenorphine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Retention in Treatment in the Per Protocol Population | Retention in treatment at Day 3 in the per protocol population (n=256) was defined as the number of patients in each induction arm completing the induction phase and who received study medication on Day 3. Treatment with BNX sublingual tablets was considered non-inferior to generic buprenorphine if the lower limit of the 95% confidence interval for the difference between BNX and generic buprenorphine was ≥-10% in the number of patients retained in treatment on Day 3. | Day 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve (AUC) in Clinical Opiate Withdrawal Scale (COWS) Total Score on Days 1 to 3 Inclusive | Least squares mean AUC in COWS total score on Days 1 to 3; COWS scores range from 0-48, with a lower score being more favorable | Pre-dose on Days 1-3 and 0.5, 1, 1.5, 3, and 6 hours post-dose on Day 1 | 
| AUC in Subjective Opiate Withdrawal Scale (SOWS) Total Score on Days 1 to 3 Inclusive | Least squares mean AUC day 1 pre-dose through Day 3 in SOWS; SOWS scores range from 0-64, with a lower score being more favorable | Pre-dose on Days 1-3 and 0.5, 1, 1.5, 3, and 6 hours post-dose on Day 1 | 
| AUC in Visual Analog Scale (VAS) Score for Craving on Days 1 to 3 Inclusive | Least squares mean AUC measurement in VAS score for cravings on Days 1 to 3; the VAS craving scores range from 0 (no cravings) to 100 (most intense craving I have ever had) | Pre-dose on Days 1-3 and 0.5, 1, 1.5, 3, and 6 hours post-dose on Day 1 | 
| Mean Change From Baseline in COWS Total Score After Day 3 (Maintenance Phase) | Mean change from baseline in COWS total scores during the maintenance phase (Days 4, 8, 15, 22, and 29); COWS scores range from 0-48, with a lower score being more favorable | Predose on Days 4, 8, 15, 22, and 29 | 
| Mean Change From Baseline in SOWS Total Score After Day 3 (Maintenance Phase) | Mean change from baseline in SOWS total scores during the maintenance phase (Days 4, 8, 15, 22, and 29); SOWS scores range from 0-64, with a lower score being more favorable | Pre-dose on Days 4, 8, 15, 22, and 29 | 
| Mean Change From Baseline in the VAS Score for Cravings After Day 3 (Maintenance Phase) | Mean change from baseline in VAS scores for cravings during the maintenance phase (Days 4, 8, 15, 22, and 29); the VAS craving scores range from 0 (no cravings) to 100 (most intense craving I have ever had) | Pre-dose on Days 4, 8, 15, 22, and 29 | 
| Retention in Treatment in the Full Analysis Population | Retention in treatment at Day 3 in the full analysis population (N=310) was defined as the number of patients in each induction arm completing the induction phase and who received study medication on Day 3. Treatment with BNX sublingual tablets was considered non-inferior to generic buprenorphine if the lower limit of the 95% confidence interval for the difference between BNX and generic buprenorphine was ≥-10% in the number of patients retained in treatment on Day 3. | Day 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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opioid dependence, buprenorphine/naloxone, sublingual