Opiate Dependence, Opioid-Related Disorders
Conditions
Keywords
opioid dependence, buprenorphine/naloxone, sublingual
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
Interventions
Advanced-formulation buprenorphine/naloxone sublingual tablets
DRUGBuprenorphine
Buprenorphine sublingual tablets
Sponsors
Worldwide Clinical Trials
Orexo AB
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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of the study * Participants receiving opioids for pain must receive clearance from their prescribing physician to be withdrawn from their prescribed opioids * Generally good health as determined by the investigator * Participants should demonstrate at least mild withdrawal symptoms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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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 |
| 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) |
| 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. |
| 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 |
Countries
United States
Participant flow
Pre-assignment details
A total of 313 patients were enrolled. Three patients who were randomized did not receive study drug, making the participant flow 310.
Participants by arm
| Arm | Count |
|---|---|
| BNX Sublingual Tablets Induction Days 1-2: Induction on BNX sublingual tablets (blinded); Days 3-28: Maintenance treatment with BNX sublingual tablets (open-label) | 155 |
| Buprenorphine Induction Days 1-2: Induction on buprenorphine sublingual tablets (blinded); Days 3-28: Maintenance treatment with BNX sublingual tablets (open-label) | 155 |
| Total | 310 |
Baseline characteristics
| Characteristic | Buprenorphine Induction | Total | BNX Sublingual Tablets Induction |
|---|---|---|---|
| Age, Continuous | 38.0 years STANDARD_DEVIATION 10.9 | 38.4 years STANDARD_DEVIATION 10.7 | 38.9 years STANDARD_DEVIATION 10.6 |
| Body mass index (BMI) | 25.3 kg/m^2 STANDARD_DEVIATION 5 | 25.7 kg/m^2 STANDARD_DEVIATION 5.9 | 26.2 kg/m^2 STANDARD_DEVIATION 6.7 |
| Duration of opioid dependence | 11.6 years STANDARD_DEVIATION 9.2 | 12.4 years STANDARD_DEVIATION 9.3 | 13.3 years STANDARD_DEVIATION 9.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 19 Participants | 38 Participants | 19 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 135 Participants | 269 Participants | 134 Participants |
| Sex: Female, Male Female | 52 Participants | 107 Participants | 55 Participants |
| Sex: Female, Male Male | 103 Participants | 203 Participants | 100 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 37 / 155 | 43 / 155 |
| serious Total, serious adverse events | 1 / 155 | 2 / 155 |
Outcome results
Primary
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.
Time frame: Day 3
Population: Per protocol population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BNX Sublingual Tablets Induction | Retention in Treatment in the Per Protocol Population | 113 participants |
| Buprenorphine Induction | Retention in Treatment in the Per Protocol Population | 122 participants |
p-value: <0.05t-test, 2 sided
Secondary
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
Time frame: Pre-dose on Days 1-3 and 0.5, 1, 1.5, 3, and 6 hours post-dose on Day 1
Population: Full analysis population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BNX Sublingual Tablets Induction | Area Under the Curve (AUC) in Clinical Opiate Withdrawal Scale (COWS) Total Score on Days 1 to 3 Inclusive | 7.21 score x hour | Standard Deviation 4.3 |
| Buprenorphine Induction | Area Under the Curve (AUC) in Clinical Opiate Withdrawal Scale (COWS) Total Score on Days 1 to 3 Inclusive | 6.88 score x hour | Standard Deviation 4 |
Secondary
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
Time frame: Pre-dose on Days 1-3 and 0.5, 1, 1.5, 3, and 6 hours post-dose on Day 1
Population: Full analysis population; patients with missing data were excluded from the analysis and are reflected in the number of participants analyzed
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BNX Sublingual Tablets Induction | AUC in Subjective Opiate Withdrawal Scale (SOWS) Total Score on Days 1 to 3 Inclusive | 17.7 score x hour | Standard Deviation 13.5 |
| Buprenorphine Induction | AUC in Subjective Opiate Withdrawal Scale (SOWS) Total Score on Days 1 to 3 Inclusive | 17.4 score x hour | Standard Deviation 12.8 |
Secondary
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)
Time frame: Pre-dose on Days 1-3 and 0.5, 1, 1.5, 3, and 6 hours post-dose on Day 1
Population: Full analysis population; patients with missing data were excluded from the analysis and are reflected in the number of participants analyzed
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BNX Sublingual Tablets Induction | AUC in Visual Analog Scale (VAS) Score for Craving on Days 1 to 3 Inclusive | 40.0 score x hour | Standard Deviation 25.3 |
| Buprenorphine Induction | AUC in Visual Analog Scale (VAS) Score for Craving on Days 1 to 3 Inclusive | 39.5 score x hour | Standard Deviation 24.7 |
Secondary
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
Time frame: Predose on Days 4, 8, 15, 22, and 29
Population: Full analysis population; patients with missing data were excluded from the analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BNX Sublingual Tablets Induction | Mean Change From Baseline in COWS Total Score After Day 3 (Maintenance Phase) | Day 8 | -11.2 units on a scale | Standard Deviation 4.9 |
| BNX Sublingual Tablets Induction | Mean Change From Baseline in COWS Total Score After Day 3 (Maintenance Phase) | Day 22 | -12.5 units on a scale | Standard Deviation 4.7 |
| BNX Sublingual Tablets Induction | Mean Change From Baseline in COWS Total Score After Day 3 (Maintenance Phase) | Day 15 | -11.9 units on a scale | Standard Deviation 4.9 |
| BNX Sublingual Tablets Induction | Mean Change From Baseline in COWS Total Score After Day 3 (Maintenance Phase) | Day 29/premature discontinuation | -12.5 units on a scale | Standard Deviation 5.2 |
| BNX Sublingual Tablets Induction | Mean Change From Baseline in COWS Total Score After Day 3 (Maintenance Phase) | Day 4 | -9.4 units on a scale | Standard Deviation 5.8 |
| Buprenorphine Induction | Mean Change From Baseline in COWS Total Score After Day 3 (Maintenance Phase) | Day 29/premature discontinuation | -11.4 units on a scale | Standard Deviation 5.4 |
| Buprenorphine Induction | Mean Change From Baseline in COWS Total Score After Day 3 (Maintenance Phase) | Day 4 | -8.5 units on a scale | Standard Deviation 5.7 |
| Buprenorphine Induction | Mean Change From Baseline in COWS Total Score After Day 3 (Maintenance Phase) | Day 8 | -10.1 units on a scale | Standard Deviation 5.3 |
| Buprenorphine Induction | Mean Change From Baseline in COWS Total Score After Day 3 (Maintenance Phase) | Day 15 | -11.1 units on a scale | Standard Deviation 5.2 |
| Buprenorphine Induction | Mean Change From Baseline in COWS Total Score After Day 3 (Maintenance Phase) | Day 22 | -11.6 units on a scale | Standard Deviation 5 |
Secondary
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
Time frame: Pre-dose on Days 4, 8, 15, 22, and 29
Population: Full analysis population; patients with missing data were excluded from the analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BNX Sublingual Tablets Induction | Mean Change From Baseline in SOWS Total Score After Day 3 (Maintenance Phase) | Day 8 | -27.0 units on a scale | Standard Deviation 15.8 |
| BNX Sublingual Tablets Induction | Mean Change From Baseline in SOWS Total Score After Day 3 (Maintenance Phase) | Day 22 | -30.8 units on a scale | Standard Deviation 15.6 |
| BNX Sublingual Tablets Induction | Mean Change From Baseline in SOWS Total Score After Day 3 (Maintenance Phase) | Day 15 | -29.2 units on a scale | Standard Deviation 15.5 |
| BNX Sublingual Tablets Induction | Mean Change From Baseline in SOWS Total Score After Day 3 (Maintenance Phase) | Day 29/premature discontinuation | -30.4 units on a scale | Standard Deviation 16 |
| BNX Sublingual Tablets Induction | Mean Change From Baseline in SOWS Total Score After Day 3 (Maintenance Phase) | Day 4 | -24.7 units on a scale | Standard Deviation 16 |
| Buprenorphine Induction | Mean Change From Baseline in SOWS Total Score After Day 3 (Maintenance Phase) | Day 29/premature discontinuation | -24.3 units on a scale | Standard Deviation 14.2 |
| Buprenorphine Induction | Mean Change From Baseline in SOWS Total Score After Day 3 (Maintenance Phase) | Day 4 | -18.9 units on a scale | Standard Deviation 13.8 |
| Buprenorphine Induction | Mean Change From Baseline in SOWS Total Score After Day 3 (Maintenance Phase) | Day 8 | -21.3 units on a scale | Standard Deviation 13.6 |
| Buprenorphine Induction | Mean Change From Baseline in SOWS Total Score After Day 3 (Maintenance Phase) | Day 15 | -23.3 units on a scale | Standard Deviation 13.7 |
| Buprenorphine Induction | Mean Change From Baseline in SOWS Total Score After Day 3 (Maintenance Phase) | Day 22 | -24.1 units on a scale | Standard Deviation 13.8 |
Secondary
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)
Time frame: Pre-dose on Days 4, 8, 15, 22, and 29
Population: Full analysis population; patients with missing data were excluded from the analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BNX Sublingual Tablets Induction | Mean Change From Baseline in the VAS Score for Cravings After Day 3 (Maintenance Phase) | Day 8 | -46.1 units on a scale | Standard Deviation 29.5 |
| BNX Sublingual Tablets Induction | Mean Change From Baseline in the VAS Score for Cravings After Day 3 (Maintenance Phase) | Day 22 | -53.3 units on a scale | Standard Deviation 29.5 |
| BNX Sublingual Tablets Induction | Mean Change From Baseline in the VAS Score for Cravings After Day 3 (Maintenance Phase) | Day 15 | -48.5 units on a scale | Standard Deviation 30.3 |
| BNX Sublingual Tablets Induction | Mean Change From Baseline in the VAS Score for Cravings After Day 3 (Maintenance Phase) | Day 29 | -52.7 units on a scale | Standard Deviation 29.1 |
| BNX Sublingual Tablets Induction | Mean Change From Baseline in the VAS Score for Cravings After Day 3 (Maintenance Phase) | Day 4 | -40.1 units on a scale | Standard Deviation 28.6 |
| Buprenorphine Induction | Mean Change From Baseline in the VAS Score for Cravings After Day 3 (Maintenance Phase) | Day 29 | -45.1 units on a scale | Standard Deviation 29.8 |
| Buprenorphine Induction | Mean Change From Baseline in the VAS Score for Cravings After Day 3 (Maintenance Phase) | Day 4 | -34.2 units on a scale | Standard Deviation 29.4 |
| Buprenorphine Induction | Mean Change From Baseline in the VAS Score for Cravings After Day 3 (Maintenance Phase) | Day 8 | -39.9 units on a scale | Standard Deviation 27.7 |
| Buprenorphine Induction | Mean Change From Baseline in the VAS Score for Cravings After Day 3 (Maintenance Phase) | Day 15 | -44.3 units on a scale | Standard Deviation 26.1 |
| Buprenorphine Induction | Mean Change From Baseline in the VAS Score for Cravings After Day 3 (Maintenance Phase) | Day 22 | -47.2 units on a scale | Standard Deviation 25.3 |
Secondary
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.
Time frame: Day 3
Population: Full analysis population; patients with missing data were excluded from the analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BNX Sublingual Tablets Induction | Retention in Treatment in the Full Analysis Population | 132 participants |
| Buprenorphine Induction | Retention in Treatment in the Full Analysis Population | 147 participants |
p-value: <0.05t-test, 2 sided