Alcohol Dependence
Conditions
Keywords
alcoholism, addiction, alcohol detoxification
Brief summary
This was a study of the effects of VIVITROL® on alcohol cue-induced craving and the associated brain activation patterns in alcohol-dependent adults who had recently completed alcohol detoxification and were seeking further treatment for their alcohol dependence. The study was powered to to detect whether VIVITROL attenuates or blocks the BOLD signal increases in response to alcohol-related cues. In the double-blind portion, subjects received a single administration of study drug (VIVITROL 380 mg or placebo). Subjects who completed the double-blind portion could opt to continue to the open-label portion and receive 2 additional months of treatment with VIVITROL 380 mg.
Detailed description
The double-blind phase consisted of 6 visits over a 5- to 6-week period and included 2 telephone contacts and 2 functional magnetic resonance imaging (fMRI) scans. The optional open-label extension included 2 visits approximately 1 month apart. Subjects who completed both phases participated in a total of 8 scheduled visits (including 2 fMRI scans and 2 telephone contacts) over a period of up to 14 weeks. At screening, eligible, consenting subjects were given an Actiwatch®-Score device. They were instructed to record their alcohol craving using this device throughout the double-blind phase. The Actiwatch was programmed to beep every 3 hours ±20 minutes, thereby signaling the subjects to enter their craving or desire to use alcohol, at that exact moment, on a scale of 0 to 10 (with 0 being no craving at all and 10 being extreme craving). In addition, subjects entered any drug and/or alcohol use at the time of occurrence. The Actiwatch was not utilized in the open-label portion of the study.
Interventions
DRUGVIVITROL 380 mg
Administered via intramuscular (IM) injection once during the double-blind phase and for 2 additional injections, 4 weeks apart, during the optional open-label extension.
DRUGPlacebo
Placebo matching VIVITROL 380 mg was administered by IM injection once during the double-blind phase, only.
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 65 Years
Healthy volunteers
No
Inclusion criteria
Primary Inclusion Criteria: * Current diagnosis of alcohol dependence, meeting at least 3 criteria from the Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. (DSM-IV) * Recently completed alcohol detoxification and seeking treatment for alcohol dependence * Women of childbearing potential must agree to use an approved method of contraception for study duration Primary
Exclusion criteria
* Pregnancy or lactation * Evidence of hepatic failure including: ascites, bilirubin \>10% above upper limit of normal (ULN) and/or esophageal variceal disease * Current dependence (within the past year) to benzodiazepines or cocaine, or current or history of opioid dependence according to DSM-IV criteria * Use of any opioids and/or methadone within 14 days prior to the screening visit, or likely to require opioid therapy during the study period * Previous enrollment in a VIVITROL clinical trial or previous VIVITROL experience * Known intolerance and/or hypersensitivity to naltrexone, carboxymethylcellulose, or polylactide-co-glycolide (PLG) * Parole, probation, or pending legal proceedings having the potential for incarceration during the study period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Blood Oxygen-level-dependent (BOLD) Signal Activation Values Detected in the Reward Circuitry of the Brain in Alcohol-dependent Subjects After Presentation of Alcohol-related Cues. | 14 days (Baseline to Day 14) | As was standard among fMRI studies conducted at the study site at the time, a change in BOLD signal in the range of 5% to 6% in anterior cingulate as measured using a 3T magnet,is considered highly significant in block-designed experiments. |
| Change From Baseline in BOLD Signal Activation Values for the Inferior Frontal Gyrus | 14 days (Baseline to Day 14) | — |
| Change From Baseline in BOLD Signal Activation Values in the Reward Circuitry | 14 days (Baseline to Day 14) | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Obsessive-Compulsive Drinking Scale (OCDS) Score in Alcohol-dependent Subjects | 28 days (Baseline to Day 28) | There are 14 items on the Obsessive Compulsive Drinking Scale (OCDS). The scale is scored from 0 to 40 (units). A score of 0 units indicates no obsession-compulsion with respect to alcohol (best score). A score of 40 units indicates maximum obsession-compulsion with respect to alcohol (worst score). A negative Change from Baseline value indicates an improvement. For scoring methods, see: Anton RF, Moak DH, Latham P (1995), The Obsessive Compulsive Drinking Scale: A self-rated instrument for the quantification of thoughts about alcohol and drinking behavior. Alcohol Clin Exp Res 19:92-9. |
| Change From Baseline in Daily Craving Score in Alcohol-dependent Subjects (Actiwatch Data) | 28 days (Baseline to Day 28) | The Actiwatch-Score device (MiniMitter Co.) was used to collect data on daily alcohol craving. The Actiwatch device is a wrist-worn, battery-operated monitor programmed to beep every 3 hours ±20 minutes, to signal the subjects to enter their alcohol craving or desire to use alcohol at that exact moment on a scale of 0 to 10 units: 0 indicates no craving at all (best score) and 10 indicates extreme craving (worst score). A negative result for Change in Baseline at Day 28 indicates an improvement in daily craving as of 1 month after study drug administration. |
Countries
United States
Participant flow
Recruitment details
Subjects were enrolled at a single clinical study center. The first subject was enrolled in July 2007. The last subject was enrolled in May 2009.
Pre-assignment details
Screening evaluations were conducted during a 1-week period. All screening evaluations were to be completed at least 2 days before randomization and dosing.
Participants by arm
| Arm | Count |
|---|---|
| VIVITROL 380 mg VIVITROL 380 mg (naltrexone for extended-release injectable suspension) - single administration via intramuscular (IM) injection on Day 1 | 16 |
| Placebo Placebo matching VIVITROL 380 mg - single administration via intramuscular injection on Day 1 | 15 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind Period | Lost to Follow-up | 1 | 0 |
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 | 15 Participants | 16 Participants | 31 Participants |
| Age, Continuous | 44.8 years STANDARD_DEVIATION 9.5 | 48.3 years STANDARD_DEVIATION 8.8 | 46.6 years STANDARD_DEVIATION 9.2 |
| Region of Enrollment United States | 15 participants | 16 participants | 31 participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Male | 10 Participants | 11 Participants | 21 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 | 6 / 16 | 10 / 15 | 7 / 22 |
| serious Total, serious adverse events | 0 / 16 | 0 / 15 | 0 / 22 |
Outcome results
Primary
Change From Baseline in Blood Oxygen-level-dependent (BOLD) Signal Activation Values Detected in the Reward Circuitry of the Brain in Alcohol-dependent Subjects After Presentation of Alcohol-related Cues.
As was standard among fMRI studies conducted at the study site at the time, a change in BOLD signal in the range of 5% to 6% in anterior cingulate as measured using a 3T magnet,is considered highly significant in block-designed experiments.
Time frame: 14 days (Baseline to Day 14)
Population: Analyses include all randomized, dosed subjects who had functional magnetic resolution imaging (fMRI) on Day 14. No data were imputed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VIVITROL 380 mg | Change From Baseline in Blood Oxygen-level-dependent (BOLD) Signal Activation Values Detected in the Reward Circuitry of the Brain in Alcohol-dependent Subjects After Presentation of Alcohol-related Cues. | 0.041 Percentage (%) of Change | Standard Deviation 0.036 |
| Placebo | Change From Baseline in Blood Oxygen-level-dependent (BOLD) Signal Activation Values Detected in the Reward Circuitry of the Brain in Alcohol-dependent Subjects After Presentation of Alcohol-related Cues. | -0.044 Percentage (%) of Change | Standard Deviation 0.049 |
Comparison: Null hypothesis: mean treatment difference=0.p-value: <0.00002t-test, 1 sided
Primary
Change From Baseline in BOLD Signal Activation Values for the Inferior Frontal Gyrus
Time frame: 14 days (Baseline to Day 14)
Population: Analyses include all randomized, dosed subjects who had functional magnetic resolution imaging (fMRI) on Day 14. No data were imputed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VIVITROL 380 mg | Change From Baseline in BOLD Signal Activation Values for the Inferior Frontal Gyrus | 0.001 Percentage (%) of Change | Standard Deviation 0.055 |
| Placebo | Change From Baseline in BOLD Signal Activation Values for the Inferior Frontal Gyrus | -0.067 Percentage (%) of Change | Standard Deviation 0.078 |
Comparison: Null hypothesis: mean treatment difference=0p-value: <0.013t-test, 1 sided
Primary
Change From Baseline in BOLD Signal Activation Values in the Reward Circuitry
Time frame: 14 days (Baseline to Day 14)
Population: Analyses include all randomized, dosed subjects who had functional magnetic resolution imaging (fMRI) on Day 14. No data were imputed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VIVITROL 380 mg | Change From Baseline in BOLD Signal Activation Values in the Reward Circuitry | -0.018 Percentage (%) of Change | Standard Deviation 0.105 |
| Placebo | Change From Baseline in BOLD Signal Activation Values in the Reward Circuitry | -0.060 Percentage (%) of Change | Standard Deviation 0.074 |
Comparison: Null hypothesis: mean treatment difference=0p-value: 0.245t-test, 1 sided
Secondary
Change From Baseline in Daily Craving Score in Alcohol-dependent Subjects (Actiwatch Data)
The Actiwatch-Score device (MiniMitter Co.) was used to collect data on daily alcohol craving. The Actiwatch device is a wrist-worn, battery-operated monitor programmed to beep every 3 hours ±20 minutes, to signal the subjects to enter their alcohol craving or desire to use alcohol at that exact moment on a scale of 0 to 10 units: 0 indicates no craving at all (best score) and 10 indicates extreme craving (worst score). A negative result for Change in Baseline at Day 28 indicates an improvement in daily craving as of 1 month after study drug administration.
Time frame: 28 days (Baseline to Day 28)
Population: All randomized subjects who received at least 1 dose of study drug and had a craving score assessment at Day 28 were included in this analysis. No last-observation-carried-forward (LOCF) approach was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VIVITROL 380 mg | Change From Baseline in Daily Craving Score in Alcohol-dependent Subjects (Actiwatch Data) | -0.846 Change in Daily Craving Score | Standard Deviation 0.881 |
| Placebo | Change From Baseline in Daily Craving Score in Alcohol-dependent Subjects (Actiwatch Data) | -0.789 Change in Daily Craving Score | Standard Deviation 0.986 |
Secondary
Change From Baseline in Obsessive-Compulsive Drinking Scale (OCDS) Score in Alcohol-dependent Subjects
There are 14 items on the Obsessive Compulsive Drinking Scale (OCDS). The scale is scored from 0 to 40 (units). A score of 0 units indicates no obsession-compulsion with respect to alcohol (best score). A score of 40 units indicates maximum obsession-compulsion with respect to alcohol (worst score). A negative Change from Baseline value indicates an improvement. For scoring methods, see: Anton RF, Moak DH, Latham P (1995), The Obsessive Compulsive Drinking Scale: A self-rated instrument for the quantification of thoughts about alcohol and drinking behavior. Alcohol Clin Exp Res 19:92-9.
Time frame: 28 days (Baseline to Day 28)
Population: All randomized subjects who received at least 1 dose of study drug and had an Obsessive-Compulsive Drinking Scale (OCDS) assessment at Day 28 were included in this analysis. No last-observation-carried-forward (LOCF) approach was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VIVITROL 380 mg | Change From Baseline in Obsessive-Compulsive Drinking Scale (OCDS) Score in Alcohol-dependent Subjects | -8.5 Change in OCDS score | Standard Deviation 5.7 |
| Placebo | Change From Baseline in Obsessive-Compulsive Drinking Scale (OCDS) Score in Alcohol-dependent Subjects | -7.3 Change in OCDS score | Standard Deviation 6.4 |