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    Clinical Trial Results:
    Exploratory, interventional, open-label, fixed-dose study with Selincro® as-needed use, in alcohol dependent patients with liver impairment

    Summary
    EudraCT number
    		 2014-000413-31
    Trial protocol
    		 DE  
    Global end of trial date
    03 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Dec 2016
    First version publication date
    11 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    15871A
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02197598
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    H. Lundbeck A/S
    Sponsor organisation address
    Ottiliavej 9, Valby, Denmark, 2500
    Public contact
    LundbeckClinicalTrials@lundbeck.com, H. Lundbeck A/S, +45 36301311, LundbeckClinicalTrials@lundbeck.com
    Scientific contact
    LundbeckClinicalTrials@lundbeck.com, H. Lundbeck A/S, +45 36301311, LundbeckClinicalTrials@lundbeck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Exploratory objectives to be assessed in patients with alcohol dependence and liver impairment treated with 18 mg Selincro® (nalmefene), as-needed, over 12 weeks: - To explore the reduction of alcohol consumption - To explore the change in liver stiffness - To explore the change in Controlled Attenuation Parameter (CAP) - To explore the change in liver enzymes - To explore the shift in fibrosis stage - To explore the associations between reduction of alcohol consumption, liver stiffness, CAP and liver enzymes To explore the change in patients with alcohol dependence and liver impairment treated with 18 mg Selincro® (nalmefene), as-needed, on: - Clinical Global Impression - Quality of life Safety objective: To evaluate safety and tolerability of 18 mg Selincro® (nalmefene), as-needed, in patients with alcohol dependence and liver impairment
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (2013) and ICH Good Clinical Practice (1996)
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Sep 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 45
    Worldwide total number of subjects
    45
    EEA total number of subjects
    45
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    34
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects who met each of the inclusion and none of the exclusion criteria were eligible to participate in the study

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Nalmefene
    Arm description
    		 One tablet orally for 12 weeks on days when the patient perceives a risk of drinking alcohol, preferably 1-2 hours prior to the anticipated risk of drinking
    Arm type
    		 Experimental

    Investigational medicinal product name
    nalmefene
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    18mg, as needed; tablets, orally

    Number of subjects in period 1
    		Nalmefene
    Started
    45
    Completed
    39
    Not completed
    6
         Consent withdrawn by subject
    2
         Adverse event, non-fatal
    2
         Lost to follow-up
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 -

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 45 45
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 34 34
        From 65-84 years
    		 11 11
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.5 ± 8 -
    Gender categorical
    Units: Subjects
        Female
    		 20 20
        Male
    		 25 25
    Race
    Units: Subjects
        White
    		 45 45

    End points

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    End points reporting groups
    Reporting group title
    Nalmefene
    Reporting group description
    		 One tablet orally for 12 weeks on days when the patient perceives a risk of drinking alcohol, preferably 1-2 hours prior to the anticipated risk of drinking

    Subject analysis set title
    Baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Nalmefene, baseline

    Subject analysis set title
    Week 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Nalmefene week 1

    Subject analysis set title
    Week 2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    nalmefene week 2

    Subject analysis set title
    Month 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Nalmefene week 4

    Subject analysis set title
    Month 2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    nalmefene week 8

    Subject analysis set title
    Month 3
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Nalmefene week 12

    Subject analysis set title
    Screening
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Screening

    Subject analysis set title
    Better Fibrosis Stage at week 12
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Better Fibrosis Stage at week 12

    Subject analysis set title
    Worse Fibrosis Stage at week 12
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Worse fibrosis stage at week 12

    Primary: Change from baseline in the number of heavy drinking days per month (HDDs)

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    End point title
    		 Change from baseline in the number of heavy drinking days per month (HDDs)
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to month 1 and 2, and 3
    End point values
    		 Baseline Month 1 Month 2 Month 3
    Number of subjects analysed
    44
    44
    40
    39
    Units: days/month
        arithmetic mean (standard error)
    26.14 ± 0.42
    13.74 ± 1.44
    13.08 ± 1.61
    12.92 ± 1.72
    Statistical analysis title
    		 Adjusted Change from Baseline to Month 1
    Statistical analysis description
    Change from baseline in number of HDDs analysed using a mixed model for repeated measurements using all available data until withdrawal from study, with sex, site, and time in months as fixed factors, and the baseline value as a covariate. The baseline value-by time interaction was also included in the model. An unstructured covariance structure was used to model the within-patient errors. Least squares means for the change from baseline in number of HDDs was presented with two-sided 95% CIs
    Comparison groups
    Month 1 v Baseline
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -12.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.5
         upper limit
    		 -9.8
    Statistical analysis title
    		 Adjusted Change from Baseline to Month 2
    Statistical analysis description
    Change from baseline in number of HDDs analysed using a mixed model for repeated measurements using all available data until withdrawal from study, with sex, site, and time in months as fixed factors, and the baseline value as a covariate. The baseline value-by time interaction was also included in the model. An unstructured covariance structure was used to model the within-patient errors. Least squares means for the change from baseline in number of HDDs was presented with two-sided 95% CIs
    Comparison groups
    Baseline v Month 2
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -13.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.2
         upper limit
    		 -10.1
    Statistical analysis title
    		 Adjusted Change from Baseline to Month 3
    Statistical analysis description
    Change from baseline in number of HDDs analysed using a mixed model for repeated measurements using all available data until withdrawal from study, with sex, site, and time in months as fixed factors, and the baseline value as a covariate. The baseline value-by time interaction was also included in the model. An unstructured covariance structure was used to model the within-patient errors. Least squares means for the change from baseline in number of HDDs was presented with two-sided 95% CIs
    Comparison groups
    Baseline v Month 3
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -13.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.8
         upper limit
    		 -10.2

    Primary: Change from baseline in weekly number of HDDs

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    End point title
    		 Change from baseline in weekly number of HDDs [1]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to weeks 1 and 2
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Summerised using descriptive statistics
    End point values
    		 Week 1 Week 2
    Number of subjects analysed
    45
    43
    Units: days/week
        arithmetic mean (standard error)
    -2.76 ± 0.37
    -3.21 ± 0.41
    No statistical analyses for this end point

    Primary: Change from Baseline in Monthly Total Alcohol Consumption (TAC)

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    End point title
    		 Change from Baseline in Monthly Total Alcohol Consumption (TAC)
    End point description
    End point type
    Primary
    End point timeframe
    baseline, months 1, 2 and 3
    End point values
    		 Baseline Month 1 Month 2 Month 3
    Number of subjects analysed
    45
    44
    40
    39
    Units: g/day
        arithmetic mean (standard error)
    98.33 ± 6.2
    56.73 ± 6.23
    57.28 ± 6.65
    54.95 ± 6.75
    Statistical analysis title
    		 Adjusted Change from Baseline to Month 1
    Statistical analysis description
    Change from baseline in TAC analysed using a mixed model for repeated measurements (MMRM) using all available data until withdrawal from study, with sex, site, and time in months as fixed factors, and the baseline value as a covariate. The baseline value-by time interaction was also included in the model. An unstructured covariance structure was used to model the within-patient errors. Least squares means for the change from baseline in TAC was presented with two-sided 95% CI
    Comparison groups
    Baseline v Month 1
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -42.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -53.4
         upper limit
    		 -31.4
    Statistical analysis title
    		 Adjusted Change from Baseline to Month 3
    Statistical analysis description
    Change from baseline in TAC analysed using a mixed model for repeated measurements (MMRM) using all available data until withdrawal from study, with sex, site, and time in months as fixed factors, and the baseline value as a covariate. The baseline value-by time interaction was also included in the model. An unstructured covariance structure was used to model the within-patient errors. Least squares means for the change from baseline in TAC was presented with two-sided 95% CI
    Comparison groups
    Baseline v Month 3
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -45.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -58.6
         upper limit
    		 -33
    Statistical analysis title
    		 Adjusted Change from Baseline to Month 2
    Statistical analysis description
    Change from baseline in TAC analysed using a mixed model for repeated measurements (MMRM) using all available data until withdrawal from study, with sex, site, and time in months as fixed factors, and the baseline value as a covariate. The baseline value-by time interaction was also included in the model. An unstructured covariance structure was used to model the within-patient errors. Least squares means for the change from baseline in TAC was presented with two-sided 95% CI
    Comparison groups
    Baseline v Month 2
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -42.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -54.2
         upper limit
    		 -31.5

    Primary: Change from Baseline in Weekly TAC

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    End point title
    		 Change from Baseline in Weekly TAC [2]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline, Week 1 and 2
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Summerised using descriptive statistics
    End point values
    		 Week 1 Week 2
    Number of subjects analysed
    45
    43
    Units: g/day
        arithmetic mean (standard error)
    -39.2 ± 6.2
    -44.56 ± 6.29
    No statistical analyses for this end point

    Primary: Response Shift Drinking Risk Level (RSDRL)

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    End point title
    		 Response Shift Drinking Risk Level (RSDRL) [3]
    End point description
    Defined as a downward shift from baseline in drinking risk level (DRL); for patients with a very high DRL at baseline, a shift to medium DRL or lower; for patients with a high DRL at baseline, a shift to low DRL or below
    End point type
    Primary
    End point timeframe
    Baseline to month 3
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Summerised using descriptive statistics
    End point values
    		 Nalmefene
    Number of subjects analysed
    39
    Units: percentage (%)
        number (confidence interval 95%)
    38.5 (24.9 to 54.1)
    No statistical analyses for this end point

    Primary: Response Low Drinking Risk Level (RLDRL)

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    End point title
    		 Response Low Drinking Risk Level (RLDRL) [4]
    End point description
    Defined as a downward shift from baseline to Month 3 in DRL; for patients at very high risk at baseline: a shift to medium risk or lower, and for patients at high risk at baseline: a shift to low risk or lower)
    End point type
    Primary
    End point timeframe
    Baseline and month 3
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Summerised using descriptive statistics
    End point values
    		 Nalmefene
    Number of subjects analysed
    39
    Units: percentage
        number (confidence interval 95%)
    33.3 (20.6 to 49)
    No statistical analyses for this end point

    Primary: Response defined as ≥50% reduction in TAC

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    End point title
    		 Response defined as ≥50% reduction in TAC [5]
    End point description
    End point type
    Primary
    End point timeframe
    baseline to month 3
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Summerised using descriptive statistics
    End point values
    		 Nalmefene
    Number of subjects analysed
    39
    Units: percentage
        number (confidence interval 95%)
    48.7 (33.9 to 63.8)
    No statistical analyses for this end point

    Primary: Response defined as ≥70% reduction in TAC

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    End point title
    		 Response defined as ≥70% reduction in TAC [6]
    End point description
    End point type
    Primary
    End point timeframe
    baseline to Month 3
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Summerised using descriptive statistics
    End point values
    		 Nalmefene
    Number of subjects analysed
    39
    Units: percentage
        number (confidence interval 95%)
    23.1 (12.6 to 38.3)
    No statistical analyses for this end point

    Primary: Response defined as 0 to 4 HDDs (days/month)

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    End point title
    		 Response defined as 0 to 4 HDDs (days/month) [7]
    End point description
    End point type
    Primary
    End point timeframe
    Month 3
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Summerised using descriptive statistics
    End point values
    		 Nalmefene
    Number of subjects analysed
    39
    Units: percentage
        number (confidence interval 95%)
    30.8 (18.6 to 46.4)
    No statistical analyses for this end point

    Primary: Liver stiffness

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    End point title
    		 Liver stiffness
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to weeks 1,2 4 and 12
    End point values
    		 Baseline Week 1 Week 2 Month 1 Month 3 Screening
    Number of subjects analysed
    44
    42
    40
    42
    39
    45
    Units: kPa
        geometric mean (standard deviation)
    6.17 ± 2.02
    6.43 ± 2.07
    6.47 ± 2.04
    6.37 ± 1.96
    6.3 ± 2.2
    7.04 ± 2.18
    Statistical analysis title
    		 Liver Stiffness: Screening vs baseline
    Statistical analysis description
    The log-transformed value of liver stiffness was analysed using an MMRM model with sex, site, and time in weeks as fixed factors, and the log-transformed baseline score as a covariate. The log-transformed baseline value-by-time interaction was also included in the model. An unstructured covariance structure was used to model the within-patient errors. The adjusted mean was back-transformed using the exponential function and presented as geometric mean
    Comparison groups
    Screening v Baseline
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.37
         upper limit
    		 7.34
    Statistical analysis title
    		 Liver Stiffness: Screening vs week 1
    Statistical analysis description
    The log-transformed value of liver stiffness was analysed using an MMRM model with sex, site, and time in weeks as fixed factors, and the log-transformed baseline score as a covariate. The log-transformed baseline value-by-time interaction was also included in the model. An unstructured covariance structure was used to model the within-patient errors. The adjusted mean was back-transformed using the exponential function and presented as geometric mean
    Comparison groups
    Screening v Week 1
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.41
         upper limit
    		 7.08
    Statistical analysis title
    		 Liver Stiffness: Screening vs week 2
    Statistical analysis description
    The log-transformed value of liver stiffness was analysed using an MMRM model with sex, site, and time in weeks as fixed factors, and the log-transformed baseline score as a covariate. The log-transformed baseline value-by-time interaction was also included in the model. An unstructured covariance structure was used to model the within-patient errors. The adjusted mean was back-transformed using the exponential function and presented as geometric mean
    Comparison groups
    Screening v Week 2
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.57
         upper limit
    		 7.54
    Statistical analysis title
    		 Liver Stiffness: Screening vs week 4
    Statistical analysis description
    The log-transformed value of liver stiffness was analysed using an MMRM model with sex, site, and time in weeks as fixed factors, and the log-transformed baseline score as a covariate. The log-transformed baseline value-by-time interaction was also included in the model. An unstructured covariance structure was used to model the within-patient errors. The adjusted mean was back-transformed using the exponential function and presented as geometric mean
    Comparison groups
    Screening v Month 1
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.51
         upper limit
    		 7.16
    Statistical analysis title
    		 Liver Stiffness: Screening vs week 12
    Statistical analysis description
    The log-transformed value of liver stiffness was analysed using an MMRM model with sex, site, and time in weeks as fixed factors, and the log-transformed baseline score as a covariate. The log-transformed baseline value-by-time interaction was also included in the model. An unstructured covariance structure was used to model the within-patient errors. The adjusted mean was back-transformed using the exponential function and presented as geometric mean
    Comparison groups
    Screening v Month 3
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.02
         upper limit
    		 7.18

    Primary: Category shift in fibrosis stage

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    End point title
    		 Category shift in fibrosis stage [8]
    End point description
    In general, the fibrosis stage remained unchanged in the majority of the patients at Month 3. A total of 8 patients shifted to a lower (better) fibrosis stage at Month 3: 4 patients shifted from stage F1-2 to F0, 3 patients shifted from stage F3 to F1-2 or F0, and 1 patient shifted from stage F4 to F0. A total of 5 patients shifted to a higher (worse) fibrosis stage at Month 3: 2 patients shifted from stage F0 to F1-2, 2 patients shifted from stage F1-2 to F3, and 1 patient shifted from stage F3 to F4.
    End point type
    Primary
    End point timeframe
    Baseline to weeks 1,2 4, and 12
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Summerised using descriptive statistics
    End point values
    		 Better Fibrosis Stage at week 12 Worse Fibrosis Stage at week 12
    Number of subjects analysed
    39
    39
    Units: Number of subjects
    8
    5
    No statistical analyses for this end point

    Primary: The therapeutic effect on the change in controlled attenuation parameter (CAP)

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    End point title
    		 The therapeutic effect on the change in controlled attenuation parameter (CAP)
    End point description
    The therapeutic effect on the change in controlled attenuation parameter (CAP)
    End point type
    Primary
    End point timeframe
    to week 12
    End point values
    		 Month 3 Screening
    Number of subjects analysed
    38
    45
    Units: dB/m
        geometric mean (standard deviation)
    266.52 ± 1.27
    295.2 ± 1.17
    Statistical analysis title
    		 Change from screening to week 12
    Statistical analysis description
    Analysed using a mixed model for repeated measurements (MMRM) using all available data until withdrawal from study, with sex, site, and time in weeks as fixed factors, and the baseline value as a covariate. The baseline value-by time interaction was also included in the model. An unstructured covariance structure was used to model the within-patient errors. Least squares means for the change from baseline was presented with two-sided 95% confidence intervals (CIs).
    Comparison groups
    Month 3 v Screening
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    264.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 247.96
         upper limit
    		 283

    Primary: Liver function

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    End point title
    		 Liver function
    End point description
    Liver function was evaluated by measurement of transaminases, γ-glutamyl transferase (γGT), change from baseline in bilirubin, albumin, and International Normalized Ratio (INR). The mean values of bilirubin, albumin, and INR were unchanged at Month 3, so only γ-glutamyl transferase (γGT) are presented
    End point type
    Primary
    End point timeframe
    Baseline to weeks 1,2,4,8, and 12
    End point values
    		 Week 1 Week 2 Month 1 Month 2 Month 3 Screening
    Number of subjects analysed
    42
    42
    42
    39
    39
    45
    Units: IU/L
        geometric mean (standard deviation)
    65.99 ± 3.34
    62.67 ± 3.23
    55.77 ± 2.98
    61.88 ± 3.34
    62.59 ± 3.41
    72.51 ± 3.14
    Statistical analysis title
    		 screening vs week 12
    Comparison groups
    Month 3 v Screening
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 geometric mean
    Point estimate
    60.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 48.96
         upper limit
    		 74.21

    Primary: Change from baseline in Clinical Global Impression, Severity of illness (CGI-S)

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    End point title
    		 Change from baseline in Clinical Global Impression, Severity of illness (CGI-S)
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to weeks 4 and 12
    End point values
    		 Baseline Month 1 Month 3
    Number of subjects analysed
    45
    42
    39
    Units: Scale
        arithmetic mean (standard deviation)
    3.89 ± 0.93
    3.02 ± 1.05
    2.74 ± 0.91
    Statistical analysis title
    		 Adjusted Change from Baseline to week 4
    Comparison groups
    Baseline v Month 1
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 -0.5
    Statistical analysis title
    		 Adjusted Change from Baseline to week 12
    Comparison groups
    Baseline v Month 3
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 -0.7

    Primary: Clinical Global Impression, global improvement (CGI-I)

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    End point title
    		 Clinical Global Impression, global improvement (CGI-I) [9]
    End point description
    A 7-point scale ranging from 1 (Normal - not at all ill) to 7 (among the most extremely ill patients).
    End point type
    Primary
    End point timeframe
    Weeks 4 and 12
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Summerised using descriptive statistics
    End point values
    		 Month 1 Month 3
    Number of subjects analysed
    42
    39
    Units: score
        arithmetic mean (standard deviation)
    2.83 ± 0.91
    2.67 ± 0.93
    No statistical analyses for this end point

    Primary: Change in the Short-Form 36-Item Health Survey (SF-36): Mental component

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    End point title
    		 Change in the Short-Form 36-Item Health Survey (SF-36): Mental component [10]
    End point description
    The scores range from 0 to 100, with higher scores indicating better quality of life
    End point type
    Primary
    End point timeframe
    week 12
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Summerised using descriptive statistics
    End point values
    		 Month 3 Screening
    Number of subjects analysed
    39
    45
    Units: Scale
        arithmetic mean (standard deviation)
    47.52 ± 11.41
    42.66 ± 13.7
    No statistical analyses for this end point

    Primary: Change in the Short-Form 36-Item Health Survey (SF-36): physical component

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    End point title
    		 Change in the Short-Form 36-Item Health Survey (SF-36): physical component [11]
    End point description
    The scores range from 0 to 100, with higher scores indicating better quality of life
    End point type
    Primary
    End point timeframe
    week 12
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Summerised using descriptive statistics
    End point values
    		 Month 3 Screening
    Number of subjects analysed
    39
    45
    Units: Scale
        arithmetic mean (standard deviation)
    52.76 ± 6.44
    51.58 ± 7.18
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose to follow-up
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    NALMEFENE
    Reporting group description
    		 NALMEFENE

    Serious adverse events
    		 NALMEFENE
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 45 (6.67%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Joint injury
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Alcohol detoxification
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 NALMEFENE
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 45 (68.89%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    14 / 45 (31.11%)
         occurrences all number
    14
    Headache
         subjects affected / exposed
    6 / 45 (13.33%)
         occurrences all number
    9
    Paraesthesia
         subjects affected / exposed
    4 / 45 (8.89%)
         occurrences all number
    6
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    9 / 45 (20.00%)
         occurrences all number
    9
    Malaise
         subjects affected / exposed
    4 / 45 (8.89%)
         occurrences all number
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences all number
    5
    Nausea
         subjects affected / exposed
    9 / 45 (20.00%)
         occurrences all number
    10
    Vomiting
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences all number
    5
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Dyshidrotic eczema
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    9 / 45 (20.00%)
         occurrences all number
    9
    Restlessness
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences all number
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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