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Efficacy of Nalmefene in Patients With Alcohol Dependence (ESENSE2)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00812461
Recruitment Status : Completed
First Posted : December 22, 2008
Results First Posted : July 9, 2013
Last Update Posted : July 22, 2013
Sponsor:
Information provided by (Responsible Party):
H. Lundbeck A/S

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Alcohol Dependence
Interventions Drug: Placebo
Drug: Nalmefene
Enrollment 678
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Placebo Nalmefene 18.06 mg
Hide Arm/Group Description as-needed use, tablets, orally, 6 months as-needed use, tablets, orally, 6 months
Period Title: All Randomised Patients
Started 360 358
Completed 337 341
Not Completed 23 17
Reason Not Completed
Did not receive placebo/nalmefene             23             17
Period Title: All Treated Patients
Started 337 341
Completed 205 [1] 194 [1]
Not Completed 132 147
Reason Not Completed
Adverse Event             8             15
Lack of Efficacy             13             7
Non-compliance             6             9
Protocol Violation             36             27
Withdrawal by Subject             45             54
Lost to Follow-up             11             14
Other Reason             13             21
[1]
Patients who had the final visit of the study protocol
Arm/Group Title Placebo Nalmefene 18.06 mg Total
Hide Arm/Group Description as-needed use, tablets, orally, 6 months as-needed use, tablets, orally, 6 months Total of all reporting groups
Overall Number of Baseline Participants 360 358 718
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 360 participants 358 participants 718 participants
44.4  (10.7) 45.1  (10.7) 44.8  (10.7)
[1]
Measure Description: All-patients-randomised set (APRS).
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 360 participants 358 participants 718 participants
Female
104
  28.9%
92
  25.7%
196
  27.3%
Male
256
  71.1%
266
  74.3%
522
  72.7%
[1]
Measure Description: APRS.
Previously Treated for Alcohol Dependence   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 360 participants 358 participants 718 participants
NO 213 215 428
YES 147 142 289
UNKNOWN 0 1 1
[1]
Measure Description: APRS
Previously Treated for Alcohol Withdrawal Symptoms]   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 360 participants 358 participants 718 participants
NO 292 300 592
YES 68 57 125
UNKNOWN 0 1 1
[1]
Measure Description: APRS.
Total Monthly Heavy Drinking Days (HDD)   [1] 
Mean (Standard Deviation)
Unit of measure:  Days
Number Analyzed 360 participants 358 participants 718 participants
18.37  (7.03) 19.71  (6.96) 19.04  (7.03)
[1]
Measure Description:

APRS.

Based on Timeline Followback (TLFB) data from the month preceding the screening visit.

Total Alcohol Consumption (TAC) g Alcohol/Day   [1] 
Mean (Standard Deviation)
Unit of measure:  g
Number Analyzed 360 participants 358 participants 718 participants
88.76  (48.15) 92.22  (46.87) 90.49  (47.52)
[1]
Measure Description:

APRS.

Based on TLFB data from the month preceding the screening visit.

Drinking Risk Level (DRL)   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 360 participants 358 participants 718 participants
Low 6 5 11
Medium 82 68 150
High 134 129 263
Very High 138 156 294
[1]
Measure Description: APRS.
Clinical Global Impression - Severity of Illness (CGI-S)   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 360 participants 358 participants 718 participants
3.99  (1.42) 4.05  (1.45) 4.02  (1.44)
[1]
Measure Description:

APRS.

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).

Gamma-glutamyl Transferase (GGT)   [1] 
Mean (Standard Deviation)
Unit of measure:  International units per liter (IU/L)
Number Analyzed 360 participants 358 participants 718 participants
97.39  (165.12) 91.98  (153.01) 94.69  (159.09)
[1]
Measure Description: APRS.
Alanine Aminotransferase (ALAT)   [1] 
Mean (Standard Deviation)
Unit of measure:  IU/L
Number Analyzed 360 participants 358 participants 718 participants
34.32  (26.06) 34.20  (22.70) 34.26  (24.42)
[1]
Measure Description: APRS.
1.Primary Outcome
Title Change From Baseline in the Monthly Number of Heavy Drinking Days (HDDs)
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Placebo Nalmefene 18.06 mg
Hide Arm/Group Description:
as-needed use, tablets, orally, 6 months
as-needed use, tablets, orally, 6 months
Overall Number of Participants Analyzed 229 212
Mean (Standard Error)
Unit of Measure: days
-10.58  (0.52) -12.30  (0.54)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nalmefene 18.06 mg
Comments

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.

Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.012
Comments [Not Specified]
Method Adjusted change from Baseline to Month 6
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.72
Confidence Interval (2-Sided) 95%
-3.07 to -0.38
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.68
Estimation Comments The Number of Participants Analyzed is participants with efficacy measurement available at this endpoint, that is, 229 participants in the placebo group and 212 participants in the nalmefene group.
2.Primary Outcome
Title Change From Baseline in the Monthly Total Alcohol Consumption (TAC)
Hide Description TAC was defined as mean daily alcohol consumption in g/day over a month (28 days).
Time Frame Baseline and Month 6
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Nalmefene 18.06 mg
Hide Arm/Group Description:
as-needed use, tablets, orally, 6 months
as-needed use, tablets, orally, 6 months
Overall Number of Participants Analyzed 229 212
Mean (Standard Error)
Unit of Measure: g
-54.06  (2.23) -59.01  (2.29)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nalmefene 18.06 mg
Comments

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.

Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.088
Comments [Not Specified]
Method Adjusted change from Baseline to Month 6
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -4.95
Confidence Interval (2-Sided) 95%
-10.63 to 0.73
Parameter Dispersion
Type: Standard Error of the mean
Value: 2.89
Estimation Comments The Number of Participants Analyzed is participants with efficacy measurement available at this endpoint, that is, 229 participants in the placebo group and 212 participants in the nalmefene group.
3.Secondary Outcome
Title Drinking Risk Level (RSDRL) Response
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Nalmefene 18.06 mg
Hide Arm/Group Description:
as-needed use, tablets, orally, 6 months
as-needed use, tablets, orally, 6 months
Overall Number of Participants Analyzed 326 329
Measure Type: Number
Unit of Measure: percentage of participants
47.9 45.6
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nalmefene 18.06 mg
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.630
Comments [Not Specified]
Method Adjusted Odds Ratio (OR) response
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.92
Confidence Interval (2-Sided) 95%
0.67 to 1.27
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Change From Baseline in Clinical Status Using CGI-S
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Nalmefene 18.06 mg
Hide Arm/Group Description:
as-needed use, tablets, orally, 6 months
as-needed use, tablets, orally, 6 months
Overall Number of Participants Analyzed 225 203
Mean (Standard Error)
Unit of Measure: units on a scale
-1.04  (0.08) -1.27  (0.08)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nalmefene 18.06 mg
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.029
Comments [Not Specified]
Method Adjusted change from Baseline to Week 24
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.23
Confidence Interval (2-Sided) 95%
-0.44 to -0.02
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.11
Estimation Comments The Number of Participants Analyzed is participants with efficacy measurement available at this endpoint, that is, 225 participants in the placebo group and 203 participants in the nalmefene group.
5.Secondary Outcome
Title Change in Clinical Status Using the CGI-I
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Nalmefene 18.06 mg
Hide Arm/Group Description:
as-needed use, tablets, orally, 6 months
as-needed use, tablets, orally, 6 months
Overall Number of Participants Analyzed 225 203
Mean (Standard Error)
Unit of Measure: units on a scale
2.68  (0.08) 2.51  (0.08)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nalmefene 18.06 mg
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.111
Comments [Not Specified]
Method Adjusted change from Baseline to Week 24
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.17
Confidence Interval (2-Sided) 95%
-0.38 to 0.04
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.11
Estimation Comments The Number of Participants Analyzed is participants with efficacy measurement available at this endpoint, that is, 225 participants in the placebo group and 203 participants in the nalmefene group.
6.Secondary Outcome
Title Liver Function Test Gamma-glutamyl Transferase (GGT)
Hide Description GGT values
Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Nalmefene 18.06 mg
Hide Arm/Group Description:
as-needed use, tablets, orally, 6 months
as-needed use, tablets, orally, 6 months
Overall Number of Participants Analyzed 224 207
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: IU/L
44.9
(75.7%)
43.3
(75.2%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nalmefene 18.06 mg
Comments 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. Logtransformed Baseline value-by-time interaction and treatment-by-time interaction were included in the model. An unstructured covariance matrix was used.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.529
Comments [Not Specified]
Method [Adjusted values
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio to placebo
Estimated Value 0.96
Confidence Interval (2-Sided) 95%
0.86 to 1.08
Estimation Comments The Number of Participants Analyzed is participants with efficacy measurement available at this endpoint, that is, 224 participants in the placebo group and 207 participants in the nalmefene group.
7.Secondary Outcome
Title Liver Function Test Alanine Aminotransferase (ALAT)
Hide Description ALAT values
Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Nalmefene 18.06 mg
Hide Arm/Group Description:
as-needed use, tablets, orally, 6 months
as-needed use, tablets, orally, 6 months
Overall Number of Participants Analyzed 222 205
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: IU/L
27.2
(56.3%)
25.0
(55.7%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nalmefene 18.06 mg
Comments 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. Logtransformed Baseline value-by-time and treatment-by-time interactions were included in the model. An unstructured covariance matrix was used.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.049
Comments [Not Specified]
Method [Adjusted values
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio to placebo
Estimated Value 0.92
Confidence Interval (2-Sided) 95%
0.84 to 1.00
Estimation Comments The Number of Participants Analyzed is participants with efficacy measurement available at this endpoint, that is, 222 participants in the placebo group and 205 participants in the nalmefene group.
Time Frame Serious Adverse Events: 24 weeks, a 4-week run-out period, 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: 24 weeks and a 4-week run-out period.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Nalmefene 18.06 mg
Hide Arm/Group Description as-needed use, tablets, orally, 6 months as-needed use, tablets, orally, 6 months
All-Cause Mortality
Placebo Nalmefene 18.06 mg
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Nalmefene 18.06 mg
Affected / at Risk (%) Affected / at Risk (%)
Total   14/337 (4.15%)   7/341 (2.05%) 
Cardiac disorders     
Myocardial infarction * 1  0/337 (0.00%)  1/341 (0.29%) 
Gastrointestinal disorders     
Pancreatitis acute * 1  1/337 (0.30%)  0/341 (0.00%) 
Rectal haemorrhage * 1  1/337 (0.30%)  0/341 (0.00%) 
General disorders     
Sudden death * 1  0/337 (0.00%)  1/341 (0.29%) 
Infections and infestations     
Pneumonia * 1  1/337 (0.30%)  0/341 (0.00%) 
Pyothorax * 1  1/337 (0.30%)  0/341 (0.00%) 
Subcutaneous abscess * 1  1/337 (0.30%)  0/341 (0.00%) 
Injury, poisoning and procedural complications     
Accidental overdose * 1  1/337 (0.30%)  0/341 (0.00%) 
Alcohol poisoning * 1  1/337 (0.30%)  0/341 (0.00%) 
Drug toxicity * 1  1/337 (0.30%)  0/341 (0.00%) 
Fall * 1  0/337 (0.00%)  1/341 (0.29%) 
Fibula fracture * 1  1/337 (0.30%)  0/341 (0.00%) 
Head injury * 1  0/337 (0.00%)  1/341 (0.29%) 
Intentional overdose * 1  3/337 (0.89%)  0/341 (0.00%) 
Tendon rupture * 1  0/337 (0.00%)  1/341 (0.29%) 
Tibia fracture * 1  1/337 (0.30%)  0/341 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Bile duct cancer * 1  1/337 (0.30%)  0/341 (0.00%) 
Nervous system disorders     
Dizziness * 1  1/337 (0.30%)  0/341 (0.00%) 
Epilepsy * 1  1/337 (0.30%)  0/341 (0.00%) 
Subarachnoid haemorrhage * 1  0/337 (0.00%)  1/341 (0.29%) 
Psychiatric disorders     
Alcoholism * 1  0/337 (0.00%)  2/341 (0.59%) 
Suicidal behaviour * 1  1/337 (0.30%)  0/341 (0.00%) 
Vascular disorders     
Arteritis * 1  1/337 (0.30%)  0/341 (0.00%) 
Hypotension * 1  1/337 (0.30%)  0/341 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, Meddra 13.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Nalmefene 18.06 mg
Affected / at Risk (%) Affected / at Risk (%)
Total   102/337 (30.27%)   157/341 (46.04%) 
Gastrointestinal disorders     
Diarrhoea * 1  18/337 (5.34%)  8/341 (2.35%) 
Nausea * 1  20/337 (5.93%)  59/341 (17.30%) 
Vomiting * 1  8/337 (2.37%)  19/341 (5.57%) 
Infections and infestations     
Nasopharyngitis * 1  20/337 (5.93%)  22/341 (6.45%) 
Nervous system disorders     
Dizziness * 1  14/337 (4.15%)  52/341 (15.25%) 
Headache * 1  26/337 (7.72%)  43/341 (12.61%) 
Psychiatric disorders     
Anxiety * 1  17/337 (5.04%)  11/341 (3.23%) 
Insomnia * 1  23/337 (6.82%)  49/341 (14.37%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, Meddra 13.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The main publication has to be published before any sub publication. The investigators shall obtain Lundbeck's written approval before publishing any publication relating to nalmefene, the Study, the Protocol and/or the results recorded during the Study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: H. Lundbeck A/S
Organization: H. Lundbeck A/S
Phone: +45 3630 1311
EMail: LundbeckClinicalTrials@lundbeck.com
Layout table for additonal information
Responsible Party: H. Lundbeck A/S
ClinicalTrials.gov Identifier: NCT00812461     History of Changes
Other Study ID Numbers: 12023A
2007-002563-27 ( EudraCT Number )
First Submitted: December 19, 2008
First Posted: December 22, 2008
Results First Submitted: March 12, 2013
Results First Posted: July 9, 2013
Last Update Posted: July 22, 2013