Alcohol Dependence
Conditions
Keywords
Alcohol-Related Disorders, Alcoholism, Mental Disorders, Central Nervous System Agents
Brief summary
The purpose of the study is to evaluate the efficacy, safety and tolerability of nalmefene in the treatment of alcohol dependence.
Detailed description
Alcohol dependence is a maladaptive pattern of alcohol use, leading to clinically significant impairment or distress, as manifested by at least three of a number of criteria such as tolerance, withdrawal symptoms, frequent use of alcohol in larger amounts or over longer periods than was intended, and others. Excessive intake of alcohol reduces the life span by a decade, and alcohol drinking is strongly related to mortality from liver cirrhosis, chronic pancreatitis, certain cancers, hypertension, accidents and violence. This study is planned to evaluate the efficacy and safety of as-needed use of nalmefene 18.06 mg versus placebo in decreasing monthly Heavy Drinking Days (HDDs) and decreasing the total consumption during a period of 6 months in adult patients with alcohol dependence.
Interventions
DRUGPlacebo
as-needed use, tablets, orally, 6 months
DRUGNalmefene
18.06 mg, as-needed use, tablets, orally, 6 months. 18.06 mg nalmefene equals 20 mg nalmefene hydrochloride.
Sponsors
H. Lundbeck A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
In- and outpatients who: * had a primary diagnosis of alcohol dependence according to Diagnostic and Statistical Manual of Mental Disorders - Text revision (DSM-IV-TR) criteria * had had ≥6 HDDs in the 4 weeks preceding the Screening Visit * had had an average alcohol consumption at WHO medium risk level or above in the 4 weeks preceding the Screening Visit
Exclusion criteria
The patient: * had a DSM-IV Axis I disorder other than alcohol dependence or nicotine dependence * had an antisocial personality disorder * had risk of suicide evaluated by the suicidality module of the Mini-International Neuropsychiatric Interview (MINI) * had a history of delirium tremens or alcohol withdrawal seizures * reported current or recent (within 3 months preceding screening) treatment with disulfiram, acamprosate, topiramate, naltrexone or carbimide, or with any opioid antagonists * reported current or recent treatment with antipsychotics or antidepressants * was pregnant or breast-feeding Other protocol-defined inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Monthly Number of Heavy Drinking Days (HDDs) | Baseline and Month 6 | Number of HDDs over a month (28 days), where one HDD was defined as a day with alcohol consumption ≥60 grams (g) for men and ≥40 g for women. |
| Change From Baseline in the Monthly Total Alcohol Consumption (TAC) | Baseline and Month 6 | TAC was defined as mean daily alcohol consumption in g/day over a month (28 days). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Clinical Status Using the CGI-I | Week 24 | The Clinical Global Impression - Global Improvement (CGI-I) provides the clinician's impression of the patient's improvement (or worsening). The clinician assesses the patient's condition relative to a baseline on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). |
| Drinking Risk Level (RSDRL) Response | Month 6 | RSDRL response was defined as a downward shift from baseline in Drinking Risk Level (DRL); for patients at very high risk at Baseline: a shift to medium risk or below, and for patients at high or medium risk at Baseline: a shift to low risk or below. |
| Liver Function Test Alanine Aminotransferase (ALAT) | Week 24 | ALAT values |
| Liver Function Test Gamma-glutamyl Transferase (GGT) | Week 24 | GGT values |
| Change From Baseline in Clinical Status Using CGI-S | Baseline and Week 24 | The Clinical Global Impression - Severity of Illness (CGI-S) provides the clinician's impression of the patient's current state of mental illness. The clinician uses his or her clinical experience of this patient population to rate the severity of the patient's current mental illness on a 7-point scale ranging from 1 (Normal - not at all ill) to 7 (among the most extremely ill patients). |
Countries
Austria, Finland, Germany, Sweden
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo as-needed use, tablets, orally, 6 months | 298 |
| Nalmefene 18.06 mg as-needed use, tablets, orally, 6 months | 306 |
| Total | 604 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| All Randomised Patients | Did not receive placebo/nalmefene | 2 | 4 |
| All Treated Patients | Adverse Event | 20 | 62 |
| All Treated Patients | Lack of Efficacy | 22 | 18 |
| All Treated Patients | Lost to Follow-up | 10 | 16 |
| All Treated Patients | Non-compliance | 0 | 14 |
| All Treated Patients | Other Reason | 7 | 4 |
| All Treated Patients | Protocol Violation | 9 | 16 |
| All Treated Patients | Withdrawal by Subject | 28 | 34 |
Baseline characteristics
| Characteristic | Placebo | Nalmefene 18.06 mg | Total |
|---|---|---|---|
| Age Continuous | 52.1 years STANDARD_DEVIATION 9.1 | 51.0 years STANDARD_DEVIATION 10.1 | 51.6 years STANDARD_DEVIATION 9.6 |
| Alanine Aminotransferase (ALAT) | 34.13 IU/L STANDARD_DEVIATION 21.77 | 33.15 IU/L STANDARD_DEVIATION 18.09 | 33.63 IU/L STANDARD_DEVIATION 19.98 |
| Clinical Global Impression - Severity of Illness (CGI-S) | 3.96 units on a scale STANDARD_DEVIATION 1.52 | 4.02 units on a scale STANDARD_DEVIATION 1.48 | 3.99 units on a scale STANDARD_DEVIATION 1.5 |
| Drinking Risk Level (DRL) High | 119 participants | 114 participants | 233 participants |
| Drinking Risk Level (DRL) Low | 2 participants | 1 participants | 3 participants |
| Drinking Risk Level (DRL) Medium | 60 participants | 68 participants | 128 participants |
| Drinking Risk Level (DRL) Unknown | 0 participants | 1 participants | 1 participants |
| Drinking Risk Level (DRL) Very High | 117 participants | 122 participants | 239 participants |
| Gamma-glutamyl Transferase (GGT) | 83.55 international units per liter (IU/L) STANDARD_DEVIATION 90.83 | 80.29 international units per liter (IU/L) STANDARD_DEVIATION 103.51 | 81.90 international units per liter (IU/L) STANDARD_DEVIATION 97.39 |
| Previously Treated for Alcohol Dependence NO | 209 participants | 215 participants | 424 participants |
| Previously Treated for Alcohol Dependence YES | 89 participants | 91 participants | 180 participants |
| Previously Treated for Alcohol Withdrawal Symptoms NO | 245 participants | 246 participants | 491 participants |
| Previously Treated for Alcohol Withdrawal Symptoms YES | 53 participants | 60 participants | 113 participants |
| Sex: Female, Male Female | 96 Participants | 102 Participants | 198 Participants |
| Sex: Female, Male Male | 202 Participants | 204 Participants | 406 Participants |
| Total Alcohol Consumption (TAC) g Alcohol/Day | 84.11 g STANDARD_DEVIATION 41.49 | 84.79 g STANDARD_DEVIATION 42.07 | 84.45 g STANDARD_DEVIATION 41.75 |
| Total Monthly Heavy Drinking Days (HDD) | 19.53 days STANDARD_DEVIATION 6.96 | 19.51 days STANDARD_DEVIATION 7.29 | 19.52 days STANDARD_DEVIATION 7.12 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 113 / 296 | 191 / 302 |
| serious Total, serious adverse events | 18 / 296 | 17 / 302 |
Outcome results
Primary
Change From Baseline in the Monthly Number of Heavy Drinking Days (HDDs)
Number of HDDs over a month (28 days), where one HDD was defined as a day with alcohol consumption ≥60 grams (g) for men and ≥40 g for women.
Time frame: Baseline and Month 6
Population: Full-analysis set (FAS) - all patients in the all-patients-treated set (APTS) who had at least one valid post-baseline assessment in the main treatment period of both co-primary efficacy variables (HDD and TAC) and had an average alcohol consumption at medium Drinking Risk Level (DRL) or above according to WHO criteria at Baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Monthly Number of Heavy Drinking Days (HDDs) | -8.91 days | Standard Error 0.56 |
| Nalmefene 18.06 mg | Change From Baseline in the Monthly Number of Heavy Drinking Days (HDDs) | -11.24 days | Standard Error 0.6 |
Comparison: The primary hypothesis concerned the treatment effect at Month 6. The null hypothesis of no difference in treatment effect was tested against the alternative hypothesis that there was a difference in treatment effect.~MMRM model with the Baseline score as a covariate; site, sex, time in months (Month 1-6); and treatment as fixed effects. The Baseline score-by-time and treatment-by-time interactions were also included in the model. An unstructured covariance matrix was used.p-value: 0.00295% CI: [-3.81, -0.85]Adjusted change from Baseline to Month 6
Primary
Change From Baseline in the Monthly Total Alcohol Consumption (TAC)
TAC was defined as mean daily alcohol consumption in g/day over a month (28 days).
Time frame: Baseline and Month 6
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Monthly Total Alcohol Consumption (TAC) | -39.70 g | Standard Error 2.25 |
| Nalmefene 18.06 mg | Change From Baseline in the Monthly Total Alcohol Consumption (TAC) | -50.66 g | Standard Error 2.41 |
Comparison: The primary hypothesis concerned the treatment effect at Month 6. The null hypothesis of no difference in treatment effect was tested against the alternative hypothesis that there was a difference in treatment effect.~MMRM model with the Baseline score as a covariate; site, sex, time in months (Month 1-6); and treatment as fixed effects. The Baseline score-by-time and treatment-by-time interactions were also included in the model. An unstructured covariance matrix was used.p-value: <0.00195% CI: [-16.81, -5.11]Adjusted change from Baseline to Month 6
Secondary
Change From Baseline in Clinical Status Using CGI-S
The Clinical Global Impression - Severity of Illness (CGI-S) provides the clinician's impression of the patient's current state of mental illness. The clinician uses his or her clinical experience of this patient population to rate the severity of the patient's current mental illness on a 7-point scale ranging from 1 (Normal - not at all ill) to 7 (among the most extremely ill patients).
Time frame: Baseline and Week 24
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Clinical Status Using CGI-S | -0.90 units on a scale | Standard Error 0.08 |
| Nalmefene 18.06 mg | Change From Baseline in Clinical Status Using CGI-S | -1.27 units on a scale | Standard Error 0.08 |
Comparison: MMRM model with the Baseline score as a covariate, and site, sex, time in weeks, and treatment as fixed effects. The Baseline score-by-time and treatment-by-time interactions were also included in the model; an unstructured covariance matrix was used.p-value: <0.00195% CI: [-0.57, -0.16]Adjusted change from Baseline to Week 24
Secondary
Change in Clinical Status Using the CGI-I
The Clinical Global Impression - Global Improvement (CGI-I) provides the clinician's impression of the patient's improvement (or worsening). The clinician assesses the patient's condition relative to a baseline on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse).
Time frame: Week 24
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Clinical Status Using the CGI-I | 2.65 units on a scale | Standard Error 0.07 |
| Nalmefene 18.06 mg | Change in Clinical Status Using the CGI-I | 2.30 units on a scale | Standard Error 0.08 |
Comparison: MMRM model with the Baseline CGI-S score as a covariate, and site, sex, time in weeks, and treatment as fixed effects. The Baseline CGI-S score-by-time and treatment-by-time interactions were also included in the model. An unstructured covariance matrix was used.p-value: <0.00195% CI: [-0.53, -0.15]Adjusted change from Baseline to Week 24
Secondary
Drinking Risk Level (RSDRL) Response
RSDRL response was defined as a downward shift from baseline in Drinking Risk Level (DRL); for patients at very high risk at Baseline: a shift to medium risk or below, and for patients at high or medium risk at Baseline: a shift to low risk or below.
Time frame: Month 6
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Drinking Risk Level (RSDRL) Response | 44.3 percentage of participants |
| Nalmefene 18.06 mg | Drinking Risk Level (RSDRL) Response | 36.9 percentage of participants |
Comparison: The analysis of RSDRL used a logistic regression (LREG) model, with country, sex, Baseline DRL, and treatment as fixed effects, and missing values imputed as non-response.p-value: 0.03995% CI: [0.5, 0.98]Adjusted Odds Ratio (OR) response
Secondary
Liver Function Test Alanine Aminotransferase (ALAT)
ALAT values
Time frame: Week 24
Population: FAS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Liver Function Test Alanine Aminotransferase (ALAT) | 28.1 IU/L | Geometric Coefficient of Variation 44.7 |
| Nalmefene 18.06 mg | Liver Function Test Alanine Aminotransferase (ALAT) | 25.4 IU/L | Geometric Coefficient of Variation 42.6 |
Comparison: Log-transformed ALAT values were analysed using an MMRM model with the log-transformed Baseline value as a covariate, and site, sex, time in weeks, and treatment as fixed effects. Log-transformed Baseline value-by-time and treatment-by-time interactions were included in the model. An unstructured covariance matrix was used.p-value: 0.01195% CI: [0.84, 0.98]Adjusted values
Secondary
Liver Function Test Gamma-glutamyl Transferase (GGT)
GGT values
Time frame: Week 24
Population: FAS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Liver Function Test Gamma-glutamyl Transferase (GGT) | 45.7 IU/L | Geometric Coefficient of Variation 56.2 |
| Nalmefene 18.06 mg | Liver Function Test Gamma-glutamyl Transferase (GGT) | 40.3 IU/L | Geometric Coefficient of Variation 52.5 |
Comparison: Log-transformed GGT values were analysed using an MMRM model with the log-transformed Baseline value as a covariate, and site, sex, time in weeks, and treatment as fixed effects. Log-transformed Baseline value-by-time interaction and treatment-by-time interaction were included in the model. An unstructured covariance matrix was used.p-value: 0.00995% CI: [0.8, 0.97]Adjusted values