Alcoholism
Conditions
Keywords
Alcoholism
Brief summary
This was a Phase 3, multicenter, randomized, double-blind, placebo-controlled study conducted in subjects diagnosed with alcohol dependence as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. (DSM-IV). Subjects were randomized (2:2:1:1) to receive intramuscular (IM) injections of Medisorb® naltrexone 190 mg, Medisorb naltrexone 380 mg, placebo for Medisorb naltrexone 190 mg, or placebo for Medisorb naltrexone 380 mg (VIVITROL®). Study drug was administered every 4 weeks for a total of 6 injections.
Detailed description
All subjects received standardized biopsychosocial support therapy (BRENDA Approach \[Volpicelli, JR \[2001\]; Guilford Press: New York\]) at each visit. Subjects who completed this study (ie, received 6 injections of study drug and completed all study visits) and continued to meet eligibility criteria were given the option to enroll in extension study ALK21-003EXT (NCT01218971). A second extension, Study ALK21-010 (NCT00156923), was conducted subsequent to ALK21-003EXT.
Interventions
DRUGPlacebo matching Medisorb naltrexone 380 mg
IM injection once every 4 weeks for a total of 6 administrations.
DRUGPlacebo matching Medisorb naltrexone 190 mg
IM injection once every 4 weeks for a total of 6 administrations.
Intramuscular (IM) injection once every 4 weeks for a total of 6 administrations.
IM injection once every 4 weeks for a total of 6 administrations.
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: * Diagnosis of alcohol dependence based on Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. (DSM-IV) criteria * Male or non-pregnant, non-lactating female * Able to provide TimeLine Follow-Back (TLFB) alcohol consumption information for 90-day period before detoxification and/or screening * At least 2 episodes of heavy alcohol drinking per week during the 30 days before detoxification and/or screening * Negative urine toxicological screen for opiates on day of randomization * Noncustodial, stable residence and phone plus 1 contact with verifiable address and phone Primary
Exclusion criteria
* Evidence of hepatic failure including: ascites, prolonged prothrombin time (PT) (international normalized ratio \[INR\] ≥1.7), bilirubin \>10% above upper limit of normal (ULN) and/or esophageal variceal disease * Active hepatitis and/or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) higher than 3xULN * History of pancreatitis * Major depression with suicidal ideation, psychosis, bipolar disorder, or psychiatric disorders that would compromise subject's ability to complete the study * Current dependence (within past year) per DSM-IV criteria to benzodiazepines, opioids or cocaine * Use of benzodiazepines and/or Ambien® (zolpidem tartrate) within 7 days prior to first dose of study medication * Greater than 7 days inpatient treatment for substance use disorders within 30 days of randomization * Use of any opioids and/or methadone within 14 days of screening, or likely requiring opioid therapy during study period * Use of oral naltrexone or disulfiram within 14 days of screening * Known intolerance and/or hypersensitivity to naltrexone, carboxymethylcellulose, or polylactide-co-glycolide (PLG)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Heavy Drinking Days Over the Treatment Period | Baseline through Week 24 (168 days) | Drinking rates were assessed from participants' self-reports using the validated Timeline Follow-Back (TLFB) method. Using a TLFB calendar, participants reported the number of days they had consumed alcohol along with the amount they consumed on each day. A heavy drinking day was defined as ≥5 drinks/day for men and ≥4 drinks/day for women. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Reporting at Least 1 Treatment-emergent Adverse Event (TEAE) | 24 weeks (Baseline to Week 24) | A TEAE is any adverse event, whether or not considered drug-related, that develops or worsens in severity after study drug administration begins (ie, from the first administration through the end of the follow-up period). |
Participant flow
Recruitment details
Potential subjects were screened up to 14 days before administration of study drug (Study Day 0).
Pre-assignment details
A dynamic randomization was implemented to optimize balancing treatment assignment for 4 prespecified factors: gender, subject's baseline goal of abstinence (ie, yes/no), presence of abstinence prior to randomization, and study site.
Participants by arm
| Arm | Count |
|---|---|
| Medisorb Naltrexone 190 mg | 210 |
| Medisorb Naltrexone 380 mg | 205 |
| Placebo Groups (Pooled) Results for the two groups that received placebo were pooled together for reporting purposes. | 209 |
| Total | 624 |
Baseline characteristics
| Characteristic | Medisorb Naltrexone 380 mg | Placebo Groups (Pooled) | Medisorb Naltrexone 190 mg | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 10 Participants | 7 Participants | 22 Participants |
| Age, Categorical Between 18 and 65 years | 200 Participants | 199 Participants | 203 Participants | 602 Participants |
| Age, Continuous | 45.0 years STANDARD_DEVIATION 10.1 | 44.7 years STANDARD_DEVIATION 10.8 | 44.6 years STANDARD_DEVIATION 10.8 | 44.7 years STANDARD_DEVIATION 10.6 |
| Region of Enrollment United States | 205 participants | 209 participants | 210 participants | 624 participants |
| Sex: Female, Male Female | 67 Participants | 66 Participants | 68 Participants | 201 Participants |
| Sex: Female, Male Male | 138 Participants | 143 Participants | 142 Participants | 423 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 190 / 210 | 187 / 205 | 181 / 209 |
| serious Total, serious adverse events | 10 / 210 | 11 / 205 | 15 / 209 |
Outcome results
Primary
Percentage of Heavy Drinking Days Over the Treatment Period
Drinking rates were assessed from participants' self-reports using the validated Timeline Follow-Back (TLFB) method. Using a TLFB calendar, participants reported the number of days they had consumed alcohol along with the amount they consumed on each day. A heavy drinking day was defined as ≥5 drinks/day for men and ≥4 drinks/day for women.
Time frame: Baseline through Week 24 (168 days)
Population: The last post-baseline observation carried forward (LOCF) of each participant in the intent-to-treat population (all randomized participants who received at least 1 injection of study drug) were utilized for the primary efficacy analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Medisorb Naltrexone 190 mg | Percentage of Heavy Drinking Days Over the Treatment Period | 14.75 Percentage of days |
| Medisorb Naltrexone 380 mg | Percentage of Heavy Drinking Days Over the Treatment Period | 10.23 Percentage of days |
| Placebo Groups (Pooled) | Percentage of Heavy Drinking Days Over the Treatment Period | 19.77 Percentage of days |
Comparison: The event rate (percentage) is represented by the number of heavy drinking days divided by number of days at risk. For each day, the active groups' results were contrasted with placebo to form the event rate ratio. Thus, a hazard ratio of 0.75 for the 380 mg group indicates a 25% reduction in heavy drinking compared with that of placebo.~The method of analysis estimates the average ratio over time and accounts for discontinuation. Point/interval estimates for pairwise ratios were derived.p-value: 0.024595% CI: [0.6, 0.94]Andersen-Gill recurrent-event Cox
p-value: 0.074495% CI: [0.677, 1.018]Andersen-Gill recurrent-event Cox model
Secondary
Number of Participants Reporting at Least 1 Treatment-emergent Adverse Event (TEAE)
A TEAE is any adverse event, whether or not considered drug-related, that develops or worsens in severity after study drug administration begins (ie, from the first administration through the end of the follow-up period).
Time frame: 24 weeks (Baseline to Week 24)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Medisorb Naltrexone 190 mg | Number of Participants Reporting at Least 1 Treatment-emergent Adverse Event (TEAE) | 190 Participants |
| Medisorb Naltrexone 380 mg | Number of Participants Reporting at Least 1 Treatment-emergent Adverse Event (TEAE) | 187 Participants |
| Placebo Groups (Pooled) | Number of Participants Reporting at Least 1 Treatment-emergent Adverse Event (TEAE) | 181 Participants |