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    Clinical Trial Results:
    A Randomized, Double-Blind, Parallel-Group, Placebo- and Active-Controlled Study to Evaluate the Efficacy and Safety of 2 doses of MIN-117 in Adult Subjects with Major Depressive Disorder

    Summary
    EudraCT number
    		 2015-000306-18
    Trial protocol
    		 LV   PL   FI  
    Global end of trial date
    05 Apr 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Aug 2018
    First version publication date
    15 Aug 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MIN-117C01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Minerva Neurosciences, Inc.
    Sponsor organisation address
    1601 Trapelo Road, Suite 286, Waltham, United States, 02451
    Public contact
    Joseph Reilly, Minerva Neurosciences, Inc., +1 6176007373, jreilly@minervaneurosciences.com
    Scientific contact
    Jay Saoud, Minerva Neurosciences, Inc., +1 6176007375, jsaoud@minervaneurosciences.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
    05 Apr 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Apr 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of MIN-117 0.5 mg and 2.5 mg compared to placebo in reducing the symptoms of a major depressive episode as measured by the change from Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score over 6 weeks of treatment.
    Protection of trial subjects
    Prior to study initiation, the protocol and associated documents were approved by an Independent Ethics Committee. The study was conducted in accordance with the Declaration of Helsinki and with Good Clinical Practices. Throughout the trial, safety assessments were performed and evaluated to ensure subject safety.
    Background therapy
    		 -
    Evidence for comparator
    		 Paroxetine was used as a positive control based on having a reference molecule that had a demonstrated antidepressant effect and one that exhibited some side effects like cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117.
    Actual start date of recruitment
    26 Jun 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Finland: 34
    Country: Number of subjects enrolled
    Latvia: 6
    Country: Number of subjects enrolled
    Moldova, Republic of: 30
    Country: Number of subjects enrolled
    Poland: 14
    Worldwide total number of subjects
    84
    EEA total number of subjects
    54
    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)
    82
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Enrolled subjects were recruited for this study at 10 study centers in 4 countries (Finland, Poland, Latvia, and Moldova).

    Pre-assignment
    Screening details
    		 Subjects were screened for eligibility to participate in the study within 28 days before dosing.

    Period 1
    Period 1 title
    Overall Trial (Overall Period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was matched in appearance to MIN-117 capsules. Placebo was administered in a single dose in the morning at approximately the same time each day with or without food according to the food intake habit of the subject. Capsules were to be swallowed with water and not divided, crushed, chewed, or placed in water.

    Arm title
    		 MIN-117 0.5 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    MIN-117
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    A single dose was administered in the morning at approximately the same time each day with or without food according to food intake habit of the subject. Capsules were to be swallowed whole with water.

    Arm title
    		 MIN-117 2.5 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    MIN-117
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    A single dose was administered in the morning at approximately the same time each day with or without food according to food intake habit of the subject. Capsules were to be swallowed whole with water.

    Arm title
    		 Paroxetine 20 mg
    Arm description
    		 A Paroxetine treatment group was included as a positive control because of its demonstrated antidepressant effect with some side effects like cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. The Paroxetine group was compared to Placebo separately to assess assay sensitivity.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Paroxetine
    Investigational medicinal product code
    Other name
    Deroxat
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    A single dose was administered in the morning at approximately the same time each day with or without food according to food intake habit of the subject. Capsules were to be swallowed whole with water.

    Number of subjects in period 1
    		Placebo MIN-117 0.5 mg MIN-117 2.5 mg Paroxetine 20 mg
    Started
    21
    21
    21
    21
    Completed
    18
    20
    20
    16
    Not completed
    3
    1
    1
    5
         Consent withdrawn by subject
    2
    1
    1
    1
         Randomized but not treated
    1
    -
    -
    1
         Adverse event, non-fatal
    -
    -
    -
    2
         Lost to follow-up
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    MIN-117 0.5 mg
    Reporting group description
    		 -

    Reporting group title
    MIN-117 2.5 mg
    Reporting group description
    		 -

    Reporting group title
    Paroxetine 20 mg
    Reporting group description
    		 A Paroxetine treatment group was included as a positive control because of its demonstrated antidepressant effect with some side effects like cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. The Paroxetine group was compared to Placebo separately to assess assay sensitivity.

    Reporting group values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg Paroxetine 20 mg Total
    Number of subjects
    		 21 21 21 21 84
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.4 ± 13.3 50.0 ± 11.9 46.3 ± 13.0 48.5 ± 11.5 -
    Gender categorical
    Units: Subjects
        Female
    		 14 16 12 15 57
        Male
    		 7 5 9 6 27
    Race
    Units: Subjects
        Caucasian
    		 21 21 21 21 84
    Body Mass Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 24.75 ± 4.06 26.51 ± 5.27 25.45 ± 4.14 24.94 ± 2.92 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 167.7 ± 8.7 166.4 ± 9.0 170.0 ± 7.8 168.8 ± 8.7 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 69.81 ± 13.99 73.51 ± 16.82 73.18 ± 13.28 71.85 ± 12.48 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    MIN-117 0.5 mg
    Reporting group description
    		 -

    Reporting group title
    MIN-117 2.5 mg
    Reporting group description
    		 -

    Reporting group title
    Paroxetine 20 mg
    Reporting group description
    		 A Paroxetine treatment group was included as a positive control because of its demonstrated antidepressant effect with some side effects like cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. The Paroxetine group was compared to Placebo separately to assess assay sensitivity.

    Primary: Change from Baseline to Week 6 in MADRS Total Score

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    End point title
    		 Change from Baseline to Week 6 in MADRS Total Score [1]
    End point description
    Adjusted least-squares mean change from Baseline to Week 6 in Montogomery-Asberg-Depression Rating Scale Total Score from Mixed Model Repeated Measures (MMRM) analysis, intent-to-treat (ITT) population.
    End point type
    Primary
    End point timeframe
    Baseline to Week 6
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    20
    21
    21
    Units: NA
        least squares mean (standard error)
    -9.27 ± 1.92
    -11.26 ± 1.86
    -12.08 ± 1.83
    Statistical analysis title
    		 Change from Baseline to Wk 6 in MADRS Total Score
    Statistical analysis description
    MMRM with treatment (placebo, MIN-117 0.5 mg, MIN-117 2.5 mg), visit, pooled study center, and treatment-by-visit interaction terms as fixed effects, subject nested in treatment as a random effect with baseline value as covariates. An unstructured covariance matrix is used.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 ≤ 0.4453 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Notes
    [2] - MMRM: MIN-117 0.5 mg vs. Placebo; MIN-117 2.5 mg vs. Placebo
    [3] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.4453 MIN-117 2.5 mg vs. Placebo: p ≤ 0.2841

    Secondary: Change from Baseline to Week 6 in CGI-S

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    End point title
    		 Change from Baseline to Week 6 in CGI-S [4]
    End point description
    Change from Baseline to Week 6 in Clinical Global Impression-Severity of Illness Scale Score (CGI-S), intent-to-treat (ITT) population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    18
    20
    21
    Units: NA
        arithmetic mean (standard deviation)
    -1.2 ± 1.0
    -1.1 ± 1.2
    -1.2 ± 1.0
    Statistical analysis title
    		 Change from Baseline to Week 6 in CGI-S
    Statistical analysis description
    Analysis of covariance of ranked data with treatment as a factor and Baseline CGI-S value as a covariate.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 ≤ 0.8877 [6]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [5] - ANCOVA on ranked data: MIN-117 0.5 mg vs. Placebo; MIN-117 2.5 mg vs. Placebo
    [6] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.8877 MIN-117 2.5 mg vs. Placebo: p ≤ 0.8944

    Secondary: Observed Data to Week 6 in CGI-I

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    End point title
    		 Observed Data to Week 6 in CGI-I [7]
    End point description
    Observed data to Week 6 in Clinical Global Impression-Global Improvement Scale Score (CGI-I) intent-to-treat (ITT) population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    18
    20
    21
    Units: NA
        arithmetic mean (standard deviation)
    7.6 ± 11.3
    5.6 ± 11.8
    9.3 ± 9.7
    Statistical analysis title
    		 Observed Data to Week 6 in CGI-I ANCOVA
    Statistical analysis description
    Analysis of covariance of ranked data with treatment as a factor and Baseline CGI-I value as a covariate.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 ≤ 0.9514 [9]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [8] - ANCOVA on ranked data: MIN-117 0.5 mg vs. Placebo; MIN-117 2.5 mg vs. Placebo
    [9] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.9514 MIN-117 2.5 mg vs. Placebo: p ≤ 0.4258

    Secondary: Change from Baseline to Week 6 in A-SEX

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    End point title
    		 Change from Baseline to Week 6 in A-SEX [10]
    End point description
    Mean change from Baseline to Week 6 in Arizona Sexual Experience Scale Total Score (A-SEX), intent-to-treat (ITT) population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    18
    20
    21
    Units: NA
        arithmetic mean (standard deviation)
    -0.5 ± 3.1
    -1.9 ± 3.3
    -1.6 ± 4.7
    Statistical analysis title
    		 Change from Baseline to Week 6 in A-SEX ANCOVA
    Statistical analysis description
    Analysis of covariance of ranked data with treatment as a factor and Baseline Arizona Sexual Experience Scale Total Score (A-SEX) value as a covariate.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 ≤ 0.2236 [12]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [11] - ANCOVA on ranked data: MIN-117 0.5 mg vs. Placebo; MIN-117 2.5 mg vs. Placebo
    [12] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.2236 MIN-117 2.5 mg vs. Placebo: p ≤ 0.1719

    Secondary: Change from Baseline to Week 2 in MADRS Total Score

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    End point title
    		 Change from Baseline to Week 2 in MADRS Total Score [13]
    End point description
    Adjusted least-squares mean change from Baseline to Week 2 in Montogomery-Asberg-Depression Rating Scale (MADRS) Total Score from MMRM analysis, ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 2
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    20
    21
    21
    Units: NA
        least squares mean (standard error)
    -9.81 ± 1.90
    -11.83 ± 1.85
    -11.88 ± 1.82
    Statistical analysis title
    		 Change from Baseline to Week 2 in MADRS
    Statistical analysis description
    MMRM with treatment (placebo, MIN-117 0.5 mg, MIN-117 2.5 mg), visit, pooled study center, and treatment-by-visit interaction terms as fixed effects, subject nested in treatment as a random effect with baseline value as covariates. An unstructured covariance matrix is used.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 ≤ 0.4264 [15]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Notes
    [14] - ANCOVA on ranked data: MIN-117 0.5 mg vs. Placebo; MIN-117 2.5 mg vs. Placebo
    [15] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.4264 MIN-117 2.5 mg vs. Placebo: p ≤ 0.4190

    Secondary: Change from Baseline to Week 6 in DSST Cognition Score

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    End point title
    		 Change from Baseline to Week 6 in DSST Cognition Score [16]
    End point description
    Change from Baseline to Week 6 in Digit-Symbol Substitution Test (DSST) Cognition Score, intent-to-treat (ITT) population
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    18
    20
    20
    Units: NA
        arithmetic mean (standard deviation)
    7.6 ± 11.3
    5.6 ± 11.8
    9.3 ± 9.7
    Statistical analysis title
    		 Change from Baseline to Week 6 in DSST ANCOVA
    Statistical analysis description
    Analysis of covariance of ranked data with treatment as a factor and Baseline Digit-Symbol Substitution Test (DSST) Cognition Score value as a covariate.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 ≤ 0.9848 [18]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [17] - ANCOVA on ranked data: MIN-117 0.5 mg vs. Placebo; MIN-117 2.5 mg vs. Placebo
    [18] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.9848 MIN-117 2.5 mg vs. Placebo: p ≤ 0.3461

    Secondary: Change from Baseline to Week 6 in Digit Span Backwards Task

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    End point title
    		 Change from Baseline to Week 6 in Digit Span Backwards Task [19]
    End point description
    Mean change from Baseline to Week 6 in Digit Span Backwards Task Cognition Score, intent-to-treat (ITT) population
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    18
    20
    20
    Units: NA
        arithmetic mean (standard deviation)
    0 ± 4.6
    2.8 ± 11.3
    0.6 ± 1.4
    Statistical analysis title
    		 Change from Baseline to Week 6 in DSBT
    Statistical analysis description
    Analysis of covariance of ranked data with treatment as a factor and Baseline in Digit Scan Backwards task value as a covariate.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 ≤ 0.4269 [21]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [20] - ANCOVA on ranked data: MIN-117 0.5 mg vs. Placebo; MIN-117 2.5 mg vs. Placebo
    [21] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.4269 MIN-117 2.5 mg vs. Placebo: p ≤ 0.8548

    Other pre-specified: Change from Baseline to Week 6 in Sleep Efficiency

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    End point title
    		 Change from Baseline to Week 6 in Sleep Efficiency [22]
    End point description
    Change from Baseline to Week 6 in summary of sleep efficiency (percent time in bed), intent-to-treat (ITT) population
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 6
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    15
    16
    17
    Units: Percent Time in Bed
        arithmetic mean (standard deviation)
    0.2 ± 14.8
    -4.9 ± 18.8
    -1.0 ± 7.1
    Statistical analysis title
    		 Sleep Efficiency -- ANCOVA for ranked data
    Statistical analysis description
    Changes from Baseline in Somno-Art- and PSG-derived sleep parameters were analyzed using an ANCOVA of ranked data, with treatment (MIN-117 0.5 mg, MIN-117 2.5 mg, and Placebo) as a factor and Baseline value as a covariate.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 ≤ 0.0501 [24]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [23] - ANCOVA on ranked data: MIN-117 0.5 mg vs. Placebo; MIN-117 2.5 mg vs. Placebo
    [24] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.0501 MIN-117 2.5 mg vs. Placebo: p ≤ 0.3873

    Other pre-specified: Change from Baseline to Week 6 in Latency to Sleep Onset

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    End point title
    		 Change from Baseline to Week 6 in Latency to Sleep Onset [25]
    End point description
    Change from Baseline to Week 6 in Latency to Sleep Onset (minutes), intent-to-treat (ITT) population
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 6
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    15
    16
    17
    Units: Minutes
        arithmetic mean (standard deviation)
    -2.8 ± 39.4
    2.6 ± 32.7
    -1.2 ± 26.2
    Statistical analysis title
    		 Latency to Sleep - ANCOVA of ranked data
    Statistical analysis description
    Changes from Baseline in Somno-Art- and PSG-derived sleep parameters were analyzed using an ANCOVA of ranked data, with treatment (MIN-117 0.5 mg, MIN-117 2.5 mg, and Placebo) as a factor and Baseline value as a covariate.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.4022 [26]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [26] - 0.5 mg vs. placebo p ≤ 0.4022 2.5 mg vs. placebo p ≤ 0.6637

    Other pre-specified: Change from Baseline to Week 6 in Latency to Continuous Sleep

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    End point title
    		 Change from Baseline to Week 6 in Latency to Continuous Sleep [27]
    End point description
    Change from Baseline to Week 6 in Latency to Continuous Sleep (minutes), intent-to-treat (ITT) population
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 6
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    15
    16
    17
    Units: minutes
        arithmetic mean (standard deviation)
    8.9 ± 42.7
    10.3 ± 41.0
    -3.7 ± 33.2
    Statistical analysis title
    		 Latency to Continuous Sleep-ANCOVA of ranked data
    Statistical analysis description
    Changes from Baseline in Somno-Art- and PSG-derived sleep parameters were analyzed using an ANCOVA of ranked data, with treatment (MIN-117 0.5 mg, MIN-117 2.5 mg, and Placebo) as a factor and Baseline value as a covariate.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [28]
    P-value
    		 ≤ 0.5297 [29]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [28] - ANCOVA on ranked data: MIN-117 0.5 mg vs. Placebo; MIN-117 2.5 mg vs. Placebo
    [29] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.5297 MIN-117 2.5 mg vs. Placebo: p ≤ 0.9399

    Other pre-specified: Change from Baseline to Week 6 in Stage REM Latency

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    End point title
    		 Change from Baseline to Week 6 in Stage REM Latency [30]
    End point description
    Change from Baseline to Week 6 in Stage REM Latency (minutes), intent-to-treat (ITT) population
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 6
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    15
    16
    17
    Units: minutes
        arithmetic mean (standard deviation)
    -1.1 ± 67.5
    22.4 ± 67.8
    -7.8 ± 57.5
    Statistical analysis title
    		 Stage REM Latency - ANCOVA of ranked data
    Statistical analysis description
    Changes from Baseline in Somno-Art- and PSG-derived sleep parameters were analyzed using an ANCOVA of ranked data, with treatment (MIN-117 0.5 mg, MIN-117 2.5 mg, and Placebo) as a factor and Baseline value as a covariate.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 ≤ 0.1188 [32]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [31] - MIN-117 0.5 mg vs. Placebo MIN-117 2.5 mg vs. Placebo
    [32] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.1188 MIN-117 2.5 mg vs. Placebo: p ≤ 0.6120

    Other pre-specified: Change from Baseline to Week 6 in Total Sleep Time

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    End point title
    		 Change from Baseline to Week 6 in Total Sleep Time [33]
    End point description
    Change from Baseline to Week 6 in Total Sleep Time (minutes), intent-to-treat (ITT) population
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 6
    Notes
    [33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    15
    16
    17
    Units: minutes
        arithmetic mean (standard deviation)
    3.1 ± 70.5
    -23.5 ± 90.9
    -5.1 ± 34.8
    Statistical analysis title
    		 Total Sleep Time - ANCOVA of ranked data
    Statistical analysis description
    Changes from Baseline in Somno-Art- and PSG-derived sleep parameters were analyzed using an ANCOVA of ranked data, with treatment (MIN-117 0.5 mg, MIN-117 2.5 mg, and Placebo) as a factor and Baseline value as a covariate.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [34]
    P-value
    		 ≤ 0.0347 [35]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [34] - ANCOVA on ranked data: MIN-117 0.5 mg vs. Placebo; MIN-117 2.5 mg vs. Placebo
    [35] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.0347 MIN-117 2.5 mg vs. Placebo: p ≤ 0.2725

    Other pre-specified: Change from Baseline to Week 6 in Wake After Sleep Onset

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    End point title
    		 Change from Baseline to Week 6 in Wake After Sleep Onset [36]
    End point description
    Change from Baseline to Week 6 in Wake After Sleep Onset (minutes), intent-to-treat (ITT) population
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 6
    Notes
    [36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    15
    16
    17
    Units: minutes
        arithmetic mean (standard deviation)
    2.5 ± 41.9
    21.0 ± 70.6
    5.7 ± 36.9
    Statistical analysis title
    		 Wake After Sleep Onset - ANCOVA of ranked data
    Statistical analysis description
    Changes from Baseline in Somno-Art- and PSG-derived sleep parameters were analyzed using an ANCOVA of ranked data, with treatment (MIN-117 0.5 mg, MIN-117 2.5 mg, and Placebo) as a factor and Baseline value as a covariate.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other [37]
    P-value
    		 ≤ 0.1086 [38]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [37] - ANCOVA on ranked data: MIN-117 0.5 mg vs. Placebo; MIN-117 2.5 mg vs. Placebo
    [38] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.1086 MIN-117 2.5 mg vs. Placebo: p ≤ 0.4767

    Other pre-specified: Change from Baseline to Week 6 in Time in Stage N3

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    End point title
    		 Change from Baseline to Week 6 in Time in Stage N3 [39]
    End point description
    Change from Baseline to Week 6 in Time in Stage N3 (minutes), intent-to-treat (ITT) population
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 6
    Notes
    [39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    15
    16
    17
    Units: minutes
        arithmetic mean (standard deviation)
    -2.3 ± 29.1
    1.5 ± 55.4
    -2.6 ± 17.9
    Statistical analysis title
    		 Time in Stage N3 - ANCOVA of ranked data
    Statistical analysis description
    Changes from Baseline in Somno-Art- and PSG-derived sleep parameters were analyzed using an ANCOVA of ranked data, with treatment (MIN-117 0.5 mg, MIN-117 2.5 mg, and Placebo) as a factor and Baseline value as a covariate.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other [40]
    P-value
    		 ≤ 0.7525 [41]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [40] - ANCOVA on ranked data: MIN-117 0.5 mg vs. Placebo; MIN-117 2.5 mg vs. Placebo
    [41] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.7525 MIN-117 2.5 mg vs. Placebo: p ≤ 0.9088

    Other pre-specified: Change from Baseline to Week 6 in Percent of Time in Stage N3

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    End point title
    		 Change from Baseline to Week 6 in Percent of Time in Stage N3 [42]
    End point description
    Change from Baseline to Week 6 in Percent of Time in Stage N3 (% total sleep time), intent-to-treat (ITT) population
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 6
    Notes
    [42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    15
    16
    17
    Units: % total sleep time
        arithmetic mean (standard deviation)
    -0.1 ± 5.8
    0.9 ± 12.7
    -0.7 ± 4.0
    Statistical analysis title
    		 % Time in Stage N3 - ANCOVA of ranked data
    Statistical analysis description
    Changes from Baseline in Somno-Art- and PSG-derived sleep parameters were analyzed using an ANCOVA of ranked data, with treatment (MIN-117 0.5 mg, MIN-117 2.5 mg, and Placebo) as a factor and Baseline value as a covariate.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [43]
    P-value
    		 ≤ 0.9272 [44]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [43] - ANCOVA on ranked data: MIN-117 0.5 mg vs. Placebo; MIN-117 2.5 mg vs. Placebo
    [44] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.9272 MIN-117 2.5 mg vs. Placebo: p ≤ 0.8988

    Other pre-specified: Change from Baseline to Week 6 in Time in Stage N2

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    End point title
    		 Change from Baseline to Week 6 in Time in Stage N2 [45]
    End point description
    Change from Baseline to Week 6 in Time in Stage N2 (minutes), intent-to-treat (ITT) population
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 6
    Notes
    [45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    15
    16
    17
    Units: minutes
        arithmetic mean (standard deviation)
    22.0 ± 51.2
    -7.7 ± 60.6
    -2.4 ± 46.8
    Statistical analysis title
    		 Time in Stage N2 (min) - ANCOVA of ranked data
    Statistical analysis description
    Changes from Baseline in Somno-Art- and PSG-derived sleep parameters were analyzed using an ANCOVA of ranked data, with treatment (MIN-117 0.5 mg, MIN-117 2.5 mg, and Placebo) as a factor and Baseline value as a covariate.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [46]
    P-value
    		 ≤ 0.1982 [47]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [46] - ANCOVA on ranked data: MIN-117 0.5 mg vs. Placebo; MIN-117 2.5 mg vs. Placebo
    [47] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.1982 MIN-117 2.5 mg vs. Placebo: p ≤ 0.0880

    Other pre-specified: Change from Baseline to Week 6 in Percent Time in Stage N2

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    End point title
    		 Change from Baseline to Week 6 in Percent Time in Stage N2 [48]
    End point description
    Change from Baseline to Week 6 in Percent Time in Stage N2 (% total sleep time), intent-to-treat (ITT) population
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 6
    Notes
    [48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    15
    16
    17
    Units: % total sleep time
        arithmetic mean (standard deviation)
    2.9 ± 13.2
    2.2 ± 12.2
    0.1 ± 9.5
    Statistical analysis title
    		 % Time in Stage N2 - ANCOVA of ranked data
    Statistical analysis description
    Changes from Baseline in Somno-Art- and PSG-derived sleep parameters were analyzed using an ANCOVA of ranked data, with treatment (MIN-117 0.5 mg, MIN-117 2.5 mg, and Placebo) as a factor and Baseline value as a covariate.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [49]
    P-value
    		 ≤ 0.7308 [50]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [49] - ANCOVA on ranked data: MIN-117 0.5 mg vs. Placebo; MIN-117 2.5 mg vs. Placebo
    [50] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.7308 MIN-117 2.5 mg vs. Placebo: p ≤ 0.1641

    Other pre-specified: Change from Baseline to Week 6 in Time in Stage REM

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    End point title
    		 Change from Baseline to Week 6 in Time in Stage REM [51]
    End point description
    Change from Baseline to Week 6 in Time in Stage REM (minutes), intent-to-treat (ITT) population
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 6
    Notes
    [51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    15
    16
    17
    Units: minutes
        arithmetic mean (standard deviation)
    -17.4 ± 35.9
    -14.2 ± 33.7
    -6.1 ± 37.0
    Statistical analysis title
    		 Time in Stage REM (min) - ANCOVA of ranked data
    Statistical analysis description
    Changes from Baseline in Somno-Art- and PSG-derived sleep parameters were analyzed using an ANCOVA of ranked data, with treatment (MIN-117 0.5 mg, MIN-117 2.5 mg, and Placebo) as a factor and Baseline value as a covariate.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [52]
    P-value
    		 ≤ 0.5658 [53]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [52] - ANCOVA on ranked data: MIN-117 0.5 mg vs. Placebo; MIN-117 2.5 mg vs. Placebo
    [53] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.5658 MIN-117 2.5 mg vs. Placebo: p ≤ 0.5747

    Other pre-specified: Change from Baseline to Week 6 in Percentage of Time in REM Stage

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    End point title
    		 Change from Baseline to Week 6 in Percentage of Time in REM Stage [54]
    End point description
    Change from Baseline to Week 6 in Percentage of Time in REM Stage (% total sleep time), intent-to-treat (ITT) population
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 6
    Notes
    [54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    15
    16
    17
    Units: % total sleep time
        arithmetic mean (standard deviation)
    -3.8 ± 9.8
    -3.3 ± 6.4
    -1.4 ± 10.8
    Statistical analysis title
    		 % Time in Stage REM - ANCOVA of ranked data
    Statistical analysis description
    Changes from Baseline in Somno-Art- and PSG-derived sleep parameters were analyzed using an ANCOVA of ranked data, with treatment (MIN-117 0.5 mg, MIN-117 2.5 mg, and Placebo) as a factor and Baseline value as a covariate.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [55]
    P-value
    		 ≤ 0.8823 [56]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [55] - ANCOVA on ranked data: MIN-117 0.5 mg vs. Placebo; MIN-117 2.5 mg vs. Placebo
    [56] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.8823 MIN-117 2.5 mg vs. Placebo: p ≤ 0.3716

    Other pre-specified: Change from Baseline to Week 6 in Certain Density in Stage REM

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    End point title
    		 Change from Baseline to Week 6 in Certain Density in Stage REM [57]
    End point description
    Change from Baseline to Week 6 in Certain Density in Stage REM (number per minute), intent-to-treat (ITT) population
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 6
    Notes
    [57] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    15
    16
    17
    Units: number per minute
        arithmetic mean (standard deviation)
    -2.9 ± 4.6
    -3.3 ± 5.6
    -0.4 ± 7.1
    Statistical analysis title
    		 Certain Density in Stage REM - ANCOVA ranked data
    Statistical analysis description
    Changes from Baseline in Somno-Art- and PSG-derived sleep parameters were analyzed using an ANCOVA of ranked data, with treatment (MIN-117 0.5 mg, MIN-117 2.5 mg, and Placebo) as a factor and Baseline value as a covariate.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [58]
    P-value
    		 ≤ 0.6097 [59]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [58] - ANCOVA for ranked data: MIN-117 0.5 mg vs. Placebo; MIN-117 2.5 mg vs. Placebo
    [59] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.6097 MIN-117 2.5 mg vs. Placebo: p ≤ 0.1647

    Other pre-specified: Change from Baseline to Week 6 in Total Sleep Period

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    End point title
    		 Change from Baseline to Week 6 in Total Sleep Period [60]
    End point description
    Change from Baseline to Week 6 in Total Sleep Period (minutes), intent-to-treat (ITT) population
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 6
    Notes
    [60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    15
    16
    17
    Units: minutes
        arithmetic mean (standard deviation)
    14.9 ± 77.3
    -21.0 ± 55.3
    -3.8 ± 28.3
    Statistical analysis title
    		 Total Sleep Period - ANCOVA of ranked data
    Statistical analysis description
    Changes from Baseline in Somno-Art- and PSG-derived sleep parameters were analyzed using an ANCOVA of ranked data, with treatment (MIN-117 0.5 mg, MIN-117 2.5 mg, and Placebo) as a factor and Baseline value as a covariate.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [61]
    P-value
    		 ≤ 0.0172 [62]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [61] - ANCOVA on ranked data: MIN-117 0.5 mg vs. Placebo; MIN-117 2.5 mg vs. Placebo
    [62] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.0172 MIN-117 2.5 mg vs. Placebo: p ≤ 0.3344

    Other pre-specified: Change from Baseline to Week 6 in Awakening Index

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    End point title
    		 Change from Baseline to Week 6 in Awakening Index [63]
    End point description
    Change from Baseline to Week 6 in Awakening Index, intent-to-treat (ITT) population
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 6
    Notes
    [63] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    15
    16
    17
    Units: NA
        arithmetic mean (standard deviation)
    1.0 ± 3.7
    0.4 ± 1.5
    0.1 ± 1.4
    Statistical analysis title
    		 Awakening Index - ANCOVA of ranked data
    Statistical analysis description
    Changes from Baseline in Somno-Art- and PSG-derived sleep parameters were analyzed using an ANCOVA of ranked data, with treatment (MIN-117 0.5 mg, MIN-117 2.5 mg, and Placebo) as a factor and Baseline value as a covariate.
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [64]
    P-value
    		 ≤ 0.6869 [65]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [64] - MIN-117 0.5 mg vs. Placebo MIN-117 2.5 mg vs. Placebo
    [65] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.6869 MIN-117 2.5 mg vs. Placebo: p ≤ 0.4591

    Other pre-specified: Change from Baseline to Week 6 in Hamilton Anxiety Rating Scale-A Total Scores

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    End point title
    		 Change from Baseline to Week 6 in Hamilton Anxiety Rating Scale-A Total Scores [66]
    End point description
    Change from Baseline to Week 6 in Hamilton Anxiety Rating Scale-A Total Scores, intent-to-treat (ITT) population
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 6
    Notes
    [66] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for the Paroxetine group vs. Placebo are not presented. Study objectives were to evaluate the efficacy of MIN-117 0.5 and 2.5 mg compared to Placebo in reducing symptoms of a major depressive episode. The Paroxetine group was included as a positive control because of its demonstrated antidepressant effect with some side effects of cognitive impairment and sexual dysfunctions, which might be preserved or improved by MIN-117. Paroxetine was compared to Placebo to test assay sensitivity.
    End point values
    		 Placebo MIN-117 0.5 mg MIN-117 2.5 mg
    Number of subjects analysed
    18
    20
    21
    Units: NA
        arithmetic mean (standard deviation)
    -7.4 ± 5.5
    -10.1 ± 5.4
    -9.9 ± 8.0
    Statistical analysis title
    		 Hamilton Anxiety Scale A - ANCOVA of ranked data
    Statistical analysis description
    Analysis of change from Baseline in Hamilton Anxiety Scale using ANCOVA of ranked data
    Comparison groups
    Placebo v MIN-117 0.5 mg v MIN-117 2.5 mg
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [67]
    P-value
    		 ≤ 0.2871 [68]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [67] - ANCOVA on ranked data: MIN-117 0.5 mg vs. Placebo; MIN-117 2.5 mg vs. Placebo
    [68] - MIN-117 0.5 mg vs. Placebo: p ≤ 0.2871 MIN-117 2.5 mg vs. Placebo: p ≤ 0.2751

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events (AEs) were reported from the time of signed informed consent until completion of last study-related procedure. Serious adverse events including spontaneously reported events within 30 days after the last dose were reported.
    Adverse event reporting additional description
    AEs were classified as treatment-emergent AEs (TEAEs) if the AEs were not present before the first dose of double-blind study medication or were present before the first dose but increased in severity on or after the first dose. AEs occurring >14 days after last dose were not considered TEAEs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Safety Population - Placebo
    Reporting group description
    		 -

    Reporting group title
    Safety Population - MIN-117 0.5 mg
    Reporting group description
    		 -

    Reporting group title
    Safety Population - MIN-117 2.5 mg
    Reporting group description
    		 -

    Reporting group title
    Safety Population - Paroxetine 20 mg
    Reporting group description
    		 -

    Serious adverse events
    		 Safety Population - Placebo Safety Population - MIN-117 0.5 mg Safety Population - MIN-117 2.5 mg Safety Population - Paroxetine 20 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Safety Population - Placebo Safety Population - MIN-117 0.5 mg Safety Population - MIN-117 2.5 mg Safety Population - Paroxetine 20 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 20 (45.00%)
    11 / 21 (52.38%)
    11 / 21 (52.38%)
    13 / 20 (65.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pallor
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Reproductive system and breast disorders
    Dyspareunia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Fibrocystic breast disease
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Libido decreased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    1
    Tension
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Investigations
    Blood triglycerides increased
         subjects affected / exposed
    0 / 20 (0.00%)
    3 / 21 (14.29%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    1
    Blood pressure systolic increased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Low density lipoprotein increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Transaminases increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    1
    Weight increased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    0
    2
    Blood cholesterol increased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    1
    Electrocardiogram PR prolongation
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Venous injury
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sinus arrhythmia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tachycardia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    1
    QTcF Interval Increased
    Additional description: 12-lead ECG data - QTcF interval increase between 30 and 50 ms or greater than 60 ms from Baseline.
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    4 / 20 (20.00%)
         occurrences all number
    3
    1
    0
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 21 (9.52%)
    2 / 21 (9.52%)
    3 / 20 (15.00%)
         occurrences all number
    0
    2
    2
    3
    Headache
         subjects affected / exposed
    3 / 20 (15.00%)
    3 / 21 (14.29%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    3
    3
    1
    0
    Restless legs syndrome
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Somnolence
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    0
    1
    Eye disorders
    Photophobia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 21 (4.76%)
    3 / 21 (14.29%)
    3 / 20 (15.00%)
         occurrences all number
    1
    1
    3
    3
    Diarrhoea
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Salivary hypersecretion
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Constipation
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash macular
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Muscle tightness
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 21 (4.76%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    2 / 21 (9.52%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    2
    2
    Bronchitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Cystitis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Otitis media
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jun 2015
    Protocol version 1.4 was issued: genotype was individualized among all pharmacodynamic parameters and was made optional. Protocol was submitted and approved in Finland, Latvia, Moldova, and Poland. All subjects were randomized under version 1.4.

    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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