Efficacy of BNX Sublingual Tablets Versus BNX Sublingual Film for Treatment of Opioid-Dependent Adults

Phase 3

Completed

• Conditions: Opioid Dependence, on Agonist Therapy
• Interventions: Drug: BNX sublingual tablets; Drug: BNX sublingual film; Drug: Buprenorphine

• Registration Number: NCT01908842
• Lead Sponsor: Orexo AB

Brief Summary

The purpose of this study was to assess retention in treatment after induction with buprenorphine/naloxone (BNX) sublingual tablets compared with generic buprenorphine and after stabilization with BNX sublingual tablets compared with BNX film. Secondary objectives included assessment of treatment effects on opioid withdrawal symptoms, opioid cravings, and safety.

Detailed Description

This prospective, randomized, multicenter, parallel-group, non-inferiority study was conducted at 43 centers in the United States from August 2013 to April 2014. A non-inferior design was used because both products contain the same active components, and it was considered unethical to include a placebo arm. The study comprised an induction phase of 2 days and a stabilization phase of 20 days, with study visits scheduled on Days 1, 2, 3, 4, 8, 15, and 22. Eligible opioid-dependent patients were randomly assigned within 14 days of screening to induction with either the BNX sublingual tablets or generic buprenorphine tablets for 2 days. On Day 3, patients initially allocated to buprenorphine were switched to BNX film, whereas those allocated to BNX sublingual tablets continued on the same treatment. On Day 15, patients receiving BNX film were switched to BNX sublingual tablets, and those on BNX sublingual tablets were switched to BNX film. At the final study visit on Day 22, patients were offered the option of continuing in an open-label follow-up study of BNX sublingual tablets.

Study Timeline

• Study First Submitted: 2013-07-19
• Study First Submitted QC: 2013-07-25
• Study First Posted: 2013-07-26
• Study Start: 2013-08
• Primary Completion: 2014-04
• Study Completion: 2014-04
• Results First Submitted: 2015-04-08
• Results First Submitted QC: 2015-05-05
• Results First Posted: 2015-05-22
• Status Verified: 2017-04
• Last Update Submitted: 2017-04-03
• Last Update Posted: 2017-05-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 759

Inclusion Criteria

1. Male/female 18-65 years old
2. Able to read, comprehend & sign the informed consent form
3. Meet opioid dependence criteria in DSM-IV-TR the past 12 months
4. Have a buprenorphine-negative UDS &/or urine dipstick
5. Prepared to abstain from opioids other than the study drug & from other addictive drugs
6. Negative urine pregnancy test
7. Females of childbearing potential who use a reliable method of contraception. Females of non-childbearing potential; surgically sterile or post-menopausal as defined by being at least 50 years of age & having an absence of menses for at least 2 years
8. Clearance from the prescribing MD to be withdrawn from their prescribed opioids for subjects receiving opioids for pain
9. Lack of clinically significant abnormalities in health assessments performed at screening. Unclear cases should be approved by the medical monitor
10. At least mild withdrawal symptoms (COWS ≥9)

Exclusion Criteria

1. Pregnant, lactating or planning to be pregnant during study
2. Unwilling/unable to comply with the requirements of the protocol (e.g., pending incarceration) are in a situation/condition that may interfere with participation in the study
3. Prescribed treatment with generic buprenorphine monotherapy within 90 days prior start of treatment
4. Daily dose of methadone over 30 mg during the past week or who received the last dose of methadone less than 30 hours prior to treatment
5. Participating in other clinical studies in which medications is delivered or who have used an investigational drug/device within the last 30 days
6. Allergy, sensitivity or intolerance to BUP, NAL or any related drug; history of drug hypersensitivity or intolerance which, in the opinion of the investigator, would compromise the safety of the subject/study
7. Staff, affiliated with, or family member of the staff directly involved with this study
8. Serious untreated Axis I DSM-IV-TR psychiatric comorbidity (actively suicidal or homicidal, have untreated schizophrenia)
9. Tongue/oral deformities that may affect the absorption of the drug products
10. Current/history of clinically significant medical disorder or condition which would jeopardize the safety or impact the validity of the results. Unclear cases should be discussed with & approved by the medical monitor
11. HIV-seropositive with a CD4+ count <200, active AIDS defining infection in the last 120 days
12. Have Class III/IV congestive heart failure, symptomatic myocardial ischemia or history of long QT syndrome (or an immediate family member with this condition)
13. Currently taking Class 1A antiarrhythmic medications (e.g., quinidine, procainamide, & disopyramide) or Class III antiarrhythmic medications (e.g., sotalol, amiodarone, & dofetilide)
14. Have uncontrolled hypertension, pulse oximetry ≤92%or clinically significant abnormality on 12-lead ECG, including a corrected QT (QTc) interval >450 ms
15. Severe liver disease

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Buprenorphine; then OL BNX film, then BNX tablets	BNX sublingual film	Days 1-2: Generic buprenorphine sublingual tablets (blinded); Days 3 to 14: Buprenorphine/naloxone sublingual film (open-label); Days 15-21: BNX sublingual tablets (open-label); Day 22: Offered option in continuing in open-label follow-up study of BNX sublingual tablets
Buprenorphine; then OL BNX film, then BNX tablets	BNX sublingual tablets	Days 1-2: Generic buprenorphine sublingual tablets (blinded); Days 3 to 14: Buprenorphine/naloxone sublingual film (open-label); Days 15-21: BNX sublingual tablets (open-label); Day 22: Offered option in continuing in open-label follow-up study of BNX sublingual tablets
BNX tablets, then OL BNX tablets, then BNX film	BNX sublingual film	Days 1-2: BNX sublingual tablets (blinded); Days 3 to 14: BNX sublingual tablets (open-label); Days 15-21: Buprenorphine/naloxone sublingual film (open-label); Day 22: Offered option in continuing in open-label follow-up study of BNX sublingual tablets
BNX tablets, then OL BNX tablets, then BNX film	BNX sublingual tablets	Days 1-2: BNX sublingual tablets (blinded); Days 3 to 14: BNX sublingual tablets (open-label); Days 15-21: Buprenorphine/naloxone sublingual film (open-label); Day 22: Offered option in continuing in open-label follow-up study of BNX sublingual tablets
Buprenorphine; then OL BNX film, then BNX tablets	Buprenorphine	Days 1-2: Generic buprenorphine sublingual tablets (blinded); Days 3 to 14: Buprenorphine/naloxone sublingual film (open-label); Days 15-21: BNX sublingual tablets (open-label); Day 22: Offered option in continuing in open-label follow-up study of BNX sublingual tablets

Primary Outcome Measures

Name	Time	Method
Primary Endpoints of Retention in Treatment at Days 3 and 15	Day 3 and Day 15	Retention rates (number of patients retained) for the primary efficacy endpoints of retention in treatment at Days 3 and 15, which was defined as the number of patients who received treatment on Days 3 and 15.

Secondary Outcome Measures

Name	Time	Method
Clinical Opiate Withdrawal Scale (COWS) Scores: Induction	Days 1 and 2	Absolute ± mean standard deviation values for COWS total scores at baseline; 0.5 h, 1.5 h, 3 h, and 6 h post dose on Day 1, and Day 2; COWS scores range from 0-48, with a lower score being more favorable
COWS Total Scores: Stabilization/Maintenance	Days 3 through 22	Absolute ± mean standard deviation values for COWS total scores at Days 3, 4, 8, 15, and 22; COWS scores range from 0-48, with a lower score being more favorable
Subjective Opiate Withdrawal Scale (SOWS) Scores: Induction	Days 1 and 2	Absolute ± mean standard deviation values for SOWS total scores at baseline, 0.5 h, 1.5 h, 3 h, and 6 h post dose on Day 1, and Day 2; SOWS score ranges from 0-64, with a lower score being more favorable
Visual Analog Scale (VAS) Cravings: Induction	Days 1 and 2	Absolute mean ± standard deviation values for VAS cravings at baseline, 0.5 h, 1.5 h, 3 h, and 6 post dose on Day 1, and Day 2; the VAS craving scores range from 0 ("no cravings") to 100 ("most intense craving I have ever had")
VAS Craving Scores: Stabilization/Maintenance	Days 3 through 22	Absolute mean ± standard deviation values for VAS cravings scores on Days 3, 4, 8, 15, and 22; the VAS craving scores range from 0 ("no cravings") to 100 ("most intense craving I have ever had")
SOWS Total Scores: Stabilization/Maintenance	Days 3 through 22	Absolute ± mean standard deviation values for SOWS total scores on Days 2, 3, 4, 8, 15, and 22; SOWS scores ranged from 0-64, with a lower score being more favorable