Alcohol Dependence
Conditions
Keywords
Pharmacologic Actions, Alcohol-Related Disorders, Alcoholism, Mental Disorders, Central Nervous System Agents
Brief summary
The purpose of the study is long-term safety, tolerability and efficacy of nalmefene in patients with 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 long-term safety and tolerability as well as to evaluate the efficacy of as needed use of 18.06 mg nalmefene in patients with alcohol dependence.
Interventions
DRUGPlacebo
as-needed use, tablets, orally, 52 weeks
DRUGNalmefene
18.06 mg as-needed use, tablets, orally, 52 weeks. 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 Heavy Drinking Days (HDDs) in the 4 weeks preceding the Screening Visit
Exclusion criteria
The patient: * had a severe psychiatric disorder or 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 * was pregnant or breast-feeding Other protocol-defined inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Adverse Events (AEs) | Serious Adverse Events: 52 weeks and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 52 weeks. | Overview of AEs |
| Percentage of Patients Who Withdrew Due to Intolerance to Treatment | Baseline to Week 52 | — |
| 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 |
|---|---|---|
| Liver Function Test Alanine Aminotransferase (ALAT) | Week 24 | ALAT values |
| 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. |
| Change From Baseline in the Monthly Total Alcohol Consumption (TAC) | Baseline and Month 13 | TAC was defined as mean daily alcohol consumption in g/day over a month (28 days). |
| Change From Baseline in the Monthly Number of Heavy Drinking Days (HDDs) | Baseline and Month 13 | Number of HDDs over a month (28 days), where one HDD was defined as a day with alcohol consumption ≥60 g for men and ≥40 g for women. |
| 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). |
| 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). |
| Liver Function Test Gamma-glutamyl Transferase (GGT) | Week 24 | GGT values |
Countries
Czechia, Estonia, Hungary, Latvia, Lithuania, Poland, Russia, Slovakia, Ukraine, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo as-needed use, tablets, orally, 52 weeks | 166 |
| Nalmefene 18.06 mg as-needed use, tablets, orally, 52 weeks | 509 |
| Total | 675 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| All Randomised Patients | Did not receive placebo/nalmefene | 2 | 8 |
| All Treated Patients | Adverse Event | 2 | 43 |
| All Treated Patients | Lack of Efficacy | 2 | 3 |
| All Treated Patients | Lost to Follow-up | 3 | 12 |
| All Treated Patients | Non-compliance | 1 | 8 |
| All Treated Patients | Other Reason | 4 | 14 |
| All Treated Patients | Protocol Violation | 5 | 17 |
| All Treated Patients | Withdrawal by Subject | 35 | 94 |
Baseline characteristics
| Characteristic | Placebo | Nalmefene 18.06 mg | Total |
|---|---|---|---|
| Age Continuous | 44.3 years STANDARD_DEVIATION 12 | 44.3 years STANDARD_DEVIATION 11.2 | 44.3 years STANDARD_DEVIATION 11.4 |
| Alanine Aminotransferase (ALAT) | 31.46 IU/L STANDARD_DEVIATION 20.2 | 33.87 IU/L STANDARD_DEVIATION 22.61 | 33.28 IU/L STANDARD_DEVIATION 22.05 |
| Clinical Global Impression - Severity of Illness (CGI-S) | 3.88 units on a scale STANDARD_DEVIATION 1.03 | 3.95 units on a scale STANDARD_DEVIATION 1.12 | 3.94 units on a scale STANDARD_DEVIATION 1.09 |
| Drinking Risk Level (DRL) HIGH | 59 participants | 148 participants | 207 participants |
| Drinking Risk Level (DRL) LOW | 26 participants | 79 participants | 105 participants |
| Drinking Risk Level (DRL) MEDIUM | 49 participants | 167 participants | 216 participants |
| Drinking Risk Level (DRL) UNKNOWN | 0 participants | 1 participants | 1 participants |
| Drinking Risk Level (DRL) VERY HIGH | 32 participants | 114 participants | 146 participants |
| Gamma-glutamyl Transferase (GGT) | 71.03 international units per liter (IU/L) STANDARD_DEVIATION 116.25 | 68.82 international units per liter (IU/L) STANDARD_DEVIATION 109.87 | 69.36 international units per liter (IU/L) STANDARD_DEVIATION 111.39 |
| Previously Treated for Alcohol Dependence NO | 105 participants | 338 participants | 443 participants |
| Previously Treated for Alcohol Dependence YES | 61 participants | 171 participants | 232 participants |
| Previously Treated for Alcohol Withdrawal Symptoms NO | 118 participants | 372 participants | 490 participants |
| Previously Treated for Alcohol Withdrawal Symptoms YES | 48 participants | 137 participants | 185 participants |
| Sex: Female, Male Female | 39 Participants | 116 Participants | 155 Participants |
| Sex: Female, Male Male | 127 Participants | 393 Participants | 520 Participants |
| Total Alcohol Consumption (TAC) g Alcohol/Day | 68.00 g STANDARD_DEVIATION 40.62 | 68.64 g STANDARD_DEVIATION 39.98 | 68.49 g STANDARD_DEVIATION 40.11 |
| Total Monthly Heavy Drinking Days (HDD) | 13.69 days STANDARD_DEVIATION 6.03 | 14.08 days STANDARD_DEVIATION 6.22 | 13.98 days STANDARD_DEVIATION 6.17 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 57 / 164 | 273 / 501 |
| serious Total, serious adverse events | 8 / 164 | 35 / 501 |
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 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) | -8.92 days | Standard Error 0.56 |
| Nalmefene 18.06 mg | Change From Baseline in the Monthly Number of Heavy Drinking Days (HDDs) | -9.80 days | Standard Error 0.35 |
Comparison: The primary hypothesis concerned the treatment effect at Month 6. 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 1-13); 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: 0.1695% CI: [-2.1, 0.35]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) | -45.58 g | Standard Error 2.61 |
| Nalmefene 18.06 mg | Change From Baseline in the Monthly Total Alcohol Consumption (TAC) | -49.05 g | Standard Error 1.64 |
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 1-13); 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: 0.23295% CI: [-9.17, 2.23]Adjusted change from Baseline to Month 6
Primary
Number of Patients With Adverse Events (AEs)
Overview of AEs
Time frame: Serious Adverse Events: 52 weeks and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 52 weeks.
Population: All-patients-treated set (APTS) - all patients in the APRS excluding those with no recorded investigational medicinal product (IMP) intake and all IMP returned
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Patients With Adverse Events (AEs) | Patients with AEs | 103 participants |
| Placebo | Number of Patients With Adverse Events (AEs) | Patients with Serious AEs (SAEs) | 8 participants |
| Placebo | Number of Patients With Adverse Events (AEs) | Patients with AEs Leading to Withdrawal | 5 participants |
| Nalmefene 18.06 mg | Number of Patients With Adverse Events (AEs) | Patients with AEs | 377 participants |
| Nalmefene 18.06 mg | Number of Patients With Adverse Events (AEs) | Patients with Serious AEs (SAEs) | 35 participants |
| Nalmefene 18.06 mg | Number of Patients With Adverse Events (AEs) | Patients with AEs Leading to Withdrawal | 57 participants |
Primary
Percentage of Patients Who Withdrew Due to Intolerance to Treatment
Time frame: Baseline to Week 52
Population: All-patients-treated Set (APTS)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients Who Withdrew Due to Intolerance to Treatment | 1.2 percentage of participants |
| Nalmefene 18.06 mg | Percentage of Patients Who Withdrew Due to Intolerance to Treatment | 8.6 percentage of participants |
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 | -0.75 units on a scale | Standard Error 0.08 |
| Nalmefene 18.06 mg | Change From Baseline in Clinical Status Using CGI-S | -0.94 units on a scale | Standard Error 0.05 |
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: 0.04695% CI: [-0.37, 0]Adjusted change from Baseline to Week 24
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 52
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Clinical Status Using CGI-S | -1.08 units on a scale | Standard Error 0.1 |
| Nalmefene 18.06 mg | Change From Baseline in Clinical Status Using CGI-S | -1.30 units on a scale | Standard Error 0.06 |
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: 0.05695% CI: [-0.44, 0.01]Adjusted change from Baseline to Week 52
Secondary
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 g for men and ≥40 g for women.
Time frame: Baseline and Month 13
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Monthly Number of Heavy Drinking Days (HDDs) | -8.96 days | Standard Error 0.58 |
| Nalmefene 18.06 mg | Change From Baseline in the Monthly Number of Heavy Drinking Days (HDDs) | -10.53 days | Standard Error 0.37 |
Comparison: MMRM model with the Baseline score as a covariate; site, sex, time in months (Month 1-13); 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: 0.01795% CI: [-2.85, -0.29]Adjusted change from Baseline - Month 13
Secondary
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 13
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Monthly Total Alcohol Consumption (TAC) | -46.33 g | Standard Error 2.73 |
| Nalmefene 18.06 mg | Change From Baseline in the Monthly Total Alcohol Consumption (TAC) | -52.80 g | Standard Error 1.76 |
Comparison: MMRM model with the Baseline score as a covariate; site, sex, time in months (Month 1-13); 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: 0.03695% CI: [-12.53, -0.42]Adjusted change from Baseline - Month 13
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 | 2.68 units on a scale | Standard Error 0.1 |
| Nalmefene 18.06 mg | Change in Clinical Status Using the CGI-I | 2.54 units on a scale | Standard Error 0.06 |
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: 0.21795% CI: [-0.36, 0.08]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 52
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Clinical Status Using the CGI-I | 2.52 units on a scale | Standard Error 0.1 |
| Nalmefene 18.06 mg | Change in Clinical Status Using the CGI-I | 2.26 units on a scale | Standard Error 0.06 |
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: 0.02995% CI: [-0.5, -0.03]Adjusted change from Baseline to Week 52
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 | 63.5 percentage of participants |
| Nalmefene 18.06 mg | Drinking Risk Level (RSDRL) Response | 62.2 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 were imputed using individual-patient predicted values of TAC derived from the MMRM model.p-value: 0.68995% CI: [0.59, 1.41]Adjusted Odds Ratio (OR) response
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 13
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Drinking Risk Level (RSDRL) Response | 54.0 percentage of participants |
| Nalmefene 18.06 mg | Drinking Risk Level (RSDRL) Response | 54.5 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 were imputed using individual-patient predicted values of TAC derived from the MMRM model.p-value: 0.97695% CI: [0.67, 1.52]Adjusted Odds Ratio (OR) response
Secondary
Liver Function Test Alanine Aminotransferase (ALAT)
ALAT values
Time frame: Week 52
Population: FAS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Liver Function Test Alanine Aminotransferase (ALAT) | 27.8 IU/L | Geometric Coefficient of Variation 55.6 |
| Nalmefene 18.06 mg | Liver Function Test Alanine Aminotransferase (ALAT) | 24.6 IU/L | Geometric Coefficient of Variation 58.5 |
Comparison: Log-transformed GGT values were analysed using an MMRM model with the logtransformed 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: 0.03795% CI: [0.79, 0.99]Adjusted values
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) | 25.8 IU/L | Geometric Coefficient of Variation 52.4 |
| Nalmefene 18.06 mg | Liver Function Test Alanine Aminotransferase (ALAT) | 25.6 IU/L | Geometric Coefficient of Variation 56.7 |
Comparison: Log-transformed ALAT values were analysed using an MMRM model with the logtransformed 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: 0.91695% CI: [0.9, 1.1]Adjusted values
Secondary
Liver Function Test Gamma-glutamyl Transferase (GGT)
GGT values
Time frame: Week 52
Population: FAS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Liver Function Test Gamma-glutamyl Transferase (GGT) | 41.3 IU/L | Geometric Coefficient of Variation 76.2 |
| Nalmefene 18.06 mg | Liver Function Test Gamma-glutamyl Transferase (GGT) | 32.0 IU/L | Geometric Coefficient of Variation 80.6 |
Comparison: Log-transformed GGT values were analysed using an MMRM model with the logtransformed 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: 0.00195% CI: [0.67, 0.9]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) | 34.5 IU/L | Geometric Coefficient of Variation 63.5 |
| Nalmefene 18.06 mg | Liver Function Test Gamma-glutamyl Transferase (GGT) | 32.2 IU/L | Geometric Coefficient of Variation 71.1 |
Comparison: Log-transformed GGT values were analysed using an MMRM model with the logtransformed 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: 0.27395% CI: [0.83, 1.05]Adjusted values