Opiate Dependence
Conditions
Keywords
Addiction, Opiate dependence, Inpatient detoxification, opioid dependence, heroin dependence
Brief summary
This is a Phase 3 multi-center trial designed to evaluate the clinical efficacy and safety of VIVITROL® (Medisorb® naltrexone 380 mg) versus placebo when administered to adults upon discharge from inpatient treatment for opioid dependence. The study was conducted in 2 parts, Part A and Part B. The clinical portion of both parts has completed. Results for Part B are not yet available.
Detailed description
Part A was a double-blind, randomized, placebo-controlled assessment of the efficacy and safety of 24 weeks of monthly treatment with VIVITROL compared to placebo in opioid-dependent adults. Subjects who completed Part A could choose to continue to Part B, which was an open-label extension to assess longer-term safety, durability of effect, health economics, and quality of life (QOL) in the continuing study population for up to 1 year. At the conclusion of both parts, each completing subject will have received a total of up to 19 injections of study drug over approximately 1.5 years. Dosing was performed by the principal investigator or designated study staff member. All subjects received standardized, manual-based psychosocial support at each scheduled visit. Opioid use was tracked through urine drug testing and subjects' self reports. Other evaluations for efficacy and safety, health economics, and quality of life were routinely conducted throughout the study.
Interventions
DRUGVIVITROL® 380 mg
Administered via intramuscular (IM) injection once every 4 weeks for 24 weeks during Part A, followed by once every 4 weeks for 52 weeks in Part B.
DRUGPlacebo
Administered via IM injection once every 4 weeks for 24 weeks during Part A, followed by VIVITROL® 380 mg via IM injection once every 4 weeks for 52 weeks in Part B.
Sponsors
Alkermes, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Primary Inclusion Criteria: * Written, informed consent * 18 years of age or older * Current diagnosis of opioid dependence, based on Diagnostic and Statistical Manual of Mental Health Disorders, 4th Ed. (DSM-IV-TR) criteria * Voluntarily seeking treatment for opioid dependence * Completing or recently completed up to 30 days of inpatient treatment for opioid detoxification, and off all opioids (including buprenorphine and methadone) for at least 7 days * Noncustodial, stable residence and phone, plus 1 contact with verifiable address and phone * Significant other (eg, spouse, relative) willing to supervise compliance with the study visit schedule and procedures * Agree to use contraception for study duration if of childbearing potential Primary
Exclusion criteria
* Pregnancy or lactation * Clinically significant medical condition or observed abnormalities (eg: physical exam, electrocardiogram (ECG), lab and/or urinalysis findings) * Positive naloxone challenge test at randomization (Day 0) * Evidence of hepatic failure including: ascites, bilirubin \>10% above upper limit of normal (ULN) and/or esophageal variceal disease * Past or present history of an acquired immunodeficiency syndrome (AIDS)-indicator disease in HIV-infected subjects * Active hepatitis and/or aspartate aminotransferase (AST), alanine aminotransferase(ALT) \>3xULN * Current major depression with suicidal ideation, psychosis, bipolar disorder, or any psychiatric disorder that would compromise ability to complete the study * Recent history (within 6 months prior to screening) of suicidal ideation or attempt * Dependence within prior year based on DSM-IV-TR, to any drugs other than prescription opioids or heroin, caffeine, marijuana, or nicotine * Active alcohol dependence within prior 6 months * Current alcohol use disorder that would, in the Investigator's opinion, preclude successful completion of the study * Positive urine drug test for cocaine, benzodiazepines, or amphetamines at screening * Use of oral naltrexone for 7 consecutive days within 60 days prior to screening * Known intolerance and/or hypersensitivity to naltrexone, carboxymethylcellulose, or polylactide-co-glycolide (PLG)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage (%) of Opioid-free Weeks Per Subject in Double-blind Period (Part A) | 20 weeks | Included are data from the last 20 weeks of the 24-week double-blind treatment period (Part A). Response profiles for each Arm are based on subjects' individual rates of weekly opioid-free data, including negative urine test results, attendance at study visits, and self-reports of opioid use/non-use. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Percentage of Self-reported Opioid-free Days From Baseline to Week 24 | 24 Weeks | Opioid use was measured using subjects' entries on a validated Timeline FollowBack (TLFB) calendar in which they recorded their use/non-use of opioids each day. |
| Days to Discontinuation During Part A | 168 days (24 weeks) | Defined as the duration of study participation and calculated as the number of days from Dose 1 to the day of study discontinuation. |
| Craving Score: Change From Baseline | Baseline to 6 months (24 weeks) | Measured using subjects' response on a validated Visual Analog Scale at prespecified weekly visits throughout Part A, with comparison of baseline to end of Part A. The scale ranged from 0 (No craving) to 100 (highest possible craving). |
| Incidence of Subjects Who Relapsed to Physiologic Opioid Dependence During the 24-week Treatment Period (Part A) | 24 Weeks | Assessment of relapse to physiologic opioid dependence was based on individual subjects' results on the naloxone challenge test. A positive naloxone challenge test result was considered as a relapse to physiologic opioid dependence. |
Countries
Russia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| VIVITROL® 380 mg Single intramuscular (IM) injection administered every 4 weeks | 126 |
| Placebo Single intramuscular (IM) injection administered every 4 weeks | 124 |
| Total | 250 |
Baseline characteristics
| Characteristic | Placebo | VIVITROL® 380 mg | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 124 Participants | 126 Participants | 250 Participants |
| Age, Continuous | 29.7 years STANDARD_DEVIATION 3.6 | 29.4 years STANDARD_DEVIATION 4.8 | 29.6 years STANDARD_DEVIATION 4.2 |
| Gender Female | 17 Participants | 13 Participants | 30 Participants |
| Gender Male | 107 Participants | 113 Participants | 220 Participants |
| Region of Enrollment Russian Federation | 124 participants | 126 participants | 250 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 63 / 126 | 40 / 124 |
| serious Total, serious adverse events | 3 / 126 | 4 / 124 |
Outcome results
Primary
Percentage (%) of Opioid-free Weeks Per Subject in Double-blind Period (Part A)
Included are data from the last 20 weeks of the 24-week double-blind treatment period (Part A). Response profiles for each Arm are based on subjects' individual rates of weekly opioid-free data, including negative urine test results, attendance at study visits, and self-reports of opioid use/non-use.
Time frame: 20 weeks
Population: Analyses include all randomized subjects who received at least 1 dose of study drug (Intent-to-treat \[ITT\] population).
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| VIVITROL® 380 mg | Percentage (%) of Opioid-free Weeks Per Subject in Double-blind Period (Part A) | 90.0 Percentage of opioid-free weeks | Inter-Quartile Range 40.1 |
| Placebo | Percentage (%) of Opioid-free Weeks Per Subject in Double-blind Period (Part A) | 35.0 Percentage of opioid-free weeks | Inter-Quartile Range 43.3 |
Comparison: Null hypothesis = the distribution function of opioid-free weeks is the same for both treatment groups.p-value: 0.0002Van der Waerden
Secondary
Change in Percentage of Self-reported Opioid-free Days From Baseline to Week 24
Opioid use was measured using subjects' entries on a validated Timeline FollowBack (TLFB) calendar in which they recorded their use/non-use of opioids each day.
Time frame: 24 Weeks
Population: Analyses include all randomized subjects who received at least 1 dose of study drug (ITT population). Change from baseline was calculated per subject as the percent of subjects' self-reported opioid-free days in Part A minus the percent of opioid-free days prior to the subjects' hospitalization for pre-study detoxification.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| VIVITROL® 380 mg | Change in Percentage of Self-reported Opioid-free Days From Baseline to Week 24 | 75.83 Percentage of opioid-free days |
| Placebo | Change in Percentage of Self-reported Opioid-free Days From Baseline to Week 24 | 46.43 Percentage of opioid-free days |
Comparison: Null hypothesis: Treatment difference=0. Missing data from subjects due to early discontinuation during Part A were imputed using the baseline rate; thus data for subjects who discontinued early were imputed as having no change from baseline.p-value: 0.0031van der Waerden
Secondary
Craving Score: Change From Baseline
Measured using subjects' response on a validated Visual Analog Scale at prespecified weekly visits throughout Part A, with comparison of baseline to end of Part A. The scale ranged from 0 (No craving) to 100 (highest possible craving).
Time frame: Baseline to 6 months (24 weeks)
Population: Analyses include all randomized subjects who received at least 1 dose of study drug (ITT population).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| VIVITROL® 380 mg | Craving Score: Change From Baseline | -10.087 Units on a scale |
| Placebo | Craving Score: Change From Baseline | 0.654 Units on a scale |
Comparison: P-value was calculated using the Chi-square test for the null hypothesis: mean treatment difference = 0.~Calculations were based on the Generalized Estimating Equation (GEE) model (normal distribution, identity link and AR(1) correlation structure) for repeated data on change from baseline with treatment and visit as main effects, and baseline as a covariate. Missing data were imputed using the Last Observation Carried Forward (LOCF) method.p-value: <0.0001Chi-squared
Secondary
Days to Discontinuation During Part A
Defined as the duration of study participation and calculated as the number of days from Dose 1 to the day of study discontinuation.
Time frame: 168 days (24 weeks)
Population: Analyses include all randomized subjects who received at least 1 dose of study drug (ITT population).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| VIVITROL® 380 mg | Days to Discontinuation During Part A | NA Days to study discontinuation |
| Placebo | Days to Discontinuation During Part A | 96.0 Days to study discontinuation |
Comparison: P-value was calculated using the log-rank test for the null hypothesis: the distribution of days to discontinuation does not differ by treatment.p-value: 0.0042Kaplan Meier
Secondary
Incidence of Subjects Who Relapsed to Physiologic Opioid Dependence During the 24-week Treatment Period (Part A)
Assessment of relapse to physiologic opioid dependence was based on individual subjects' results on the naloxone challenge test. A positive naloxone challenge test result was considered as a relapse to physiologic opioid dependence.
Time frame: 24 Weeks
Population: Analyses include all randomized subjects who received at least 1 dose of study drug (ITT population).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VIVITROL® 380 mg | Incidence of Subjects Who Relapsed to Physiologic Opioid Dependence During the 24-week Treatment Period (Part A) | 46.8 Percentage of participants who relapsed |
| Placebo | Incidence of Subjects Who Relapsed to Physiologic Opioid Dependence During the 24-week Treatment Period (Part A) | 62.1 Percentage of participants who relapsed |
Comparison: Chi-square test was used to calculate the p-value for treatment. Null hypothesis = no association between relapse to dependence and study treatment.~Subjects who discontinued prematurely from the study were imputed as having a positive naloxone challenge test result.p-value: 0.015495% CI: [0.6, 0.95]Chi-squared