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

Phase 3

Completed

Conditions: Opioid-Related Disorders
Opiate Dependence

Interventions: Drug: Buprenorphine/naloxone sublingual tablets
Drug: Buprenorphine

Registration Number: NCT01848054

Lead Sponsor: Orexo AB

Brief Summary: 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: 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

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 313

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Participants receiving opioids for pain must receive clearance from their prescribing physician to be withdrawn from their prescribed opioids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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Buprenorphine Induction	Buprenorphine/naloxone sublingual tablets	Day 1-2 (Blinded Induction): Generic buprenorphine sublingual tablets Day 3-28 (Open-label Maintenance): BNX sublingual tablets
BNX Sublingual Tablets Induction	Buprenorphine/naloxone sublingual tablets	Day 1-2 (Blinded Induction): BNX sublingual tablets Day 3-28 (Open-label Maintenance): BNX sublingual tablets
Buprenorphine Induction	Buprenorphine	Day 1-2 (Blinded Induction): Generic buprenorphine sublingual tablets Day 3-28 (Open-label Maintenance): BNX sublingual tablets

Primary Outcome Measures

Name	Time	Method
Retention in Treatment in the Per Protocol Population	Day 3	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.

Secondary Outcome Measures

Name	Time	Method
AUC in Subjective Opiate Withdrawal Scale (SOWS) Total Score on Days 1 to 3 Inclusive	Pre-dose on Days 1-3 and 0.5, 1, 1.5, 3, and 6 hours post-dose on Day 1	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
Area Under the Curve (AUC) in Clinical Opiate Withdrawal Scale (COWS) Total Score on Days 1 to 3 Inclusive	Pre-dose on Days 1-3 and 0.5, 1, 1.5, 3, and 6 hours post-dose on Day 1	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
Retention in Treatment in the Full Analysis Population	Day 3	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.
AUC in Visual Analog Scale (VAS) Score for Craving on Days 1 to 3 Inclusive	Pre-dose on Days 1-3 and 0.5, 1, 1.5, 3, and 6 hours post-dose on Day 1	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")
Mean Change From Baseline in COWS Total Score After Day 3 (Maintenance Phase)	Predose on Days 4, 8, 15, 22, and 29	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
Mean Change From Baseline in SOWS Total Score After Day 3 (Maintenance Phase)	Pre-dose on Days 4, 8, 15, 22, and 29	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
Mean Change From Baseline in the VAS Score for Cravings After Day 3 (Maintenance Phase)	Pre-dose on Days 4, 8, 15, 22, and 29	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")