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    Clinical Trial Results:
    A Phase III, Randomized, Double-Blind, Placebo-Controlled, Efficacy, and Safety Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension

    Summary
    EudraCT number
    		 2017-004378-32
    Trial protocol
    		 GB   ES   FR   IT  
    Global end of trial date
    06 Jul 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Mar 2021
    First version publication date
    07 Mar 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    WN39434
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03504917
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann- La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global-roche-genentech-trials@gene.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 Jun 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jul 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This study will evaluate the efficacy, safety, and pharmacokinetics of 10 mg of oral administration balovaptan once a day (QD) compared with matching placebo in adults (18 years and older) with autism spectrum disorder (ASD)
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP) guidelines according to the regulations and procedures described in the protocol.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Jan 2018
    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
    United States: 241
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    Canada: 19
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    France: 8
    Worldwide total number of subjects
    322
    EEA total number of subjects
    50
    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)
    322
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 322 Subjects were randomized. 1 subject did not receive the treatment and in the ITT Population, 321 subjects received at least one dose of the study treatment. The Study was discontinued early before the planned sample size was reached.

    Pre-assignment
    Screening details
    		 Subjects subjects received matching placebo in Blinded Treatment Period for 24 Weeks and 10 mg of oral administration balovaptan once a day (QD) during the Open Label Extension Treatment Period.

    Period 1
    Period 1 title
    Blinded Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Balovaptan
    Arm description
    		 Subjects received 10 mg of oral administration balovaptan once a day (QD).
    Arm type
    		 Experimental

    Investigational medicinal product name
    balovaptan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg of oral administration balovaptan once a day (QD).

    Arm title
    		 Placebo
    Arm description
    		 Subjects received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD) in OLE Treatment period
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo

    Number of subjects in period 1 [1]
    		Balovaptan Placebo
    Started
    163
    158
    Completed
    103
    102
    Not completed
    60
    56
         Consent withdrawn by subject
    12
    9
         Physician decision
    1
    -
         Adverse event, non-fatal
    4
    4
         Study terminated by sponsor
    39
    34
         Non-compliance with study drug
    -
    1
         Lost to follow-up
    1
    4
         Unable due to relocation, withdrawals, a partner
    1
    3
         Protocol deviation
    1
    -
         Lack of efficacy
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 1 Subjects was not involved in the treatment start.
    Period 2
    Period 2 title
    Open Label Extension Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Balovaptan
    Arm description
    		 Subjects received 10 mg of oral administration balovaptan once a day (QD).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Balovaptan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg of oral administration balovaptan once a day (QD).

    Arm title
    		 Placebo
    Arm description
    		 Subjects received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD) in OLE Treatment period
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo

    Number of subjects in period 2 [2]
    		Balovaptan Placebo
    Started
    100
    97
    Completed
    0
    0
    Not completed
    100
    97
         Consent withdrawn by subject
    8
    2
         left country no interest withdrawal spouse unable
    -
    1
         Adverse event, non-fatal
    7
    -
         Study terminated by sponsor
    81
    88
         Non-compliance with study drug
    -
    1
         Lost to follow-up
    1
    4
         Lack of efficacy
    3
    1
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The study was pre-maturely terminated therefore number of started subjects did not complete.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Balovaptan
    Reporting group description
    		 Subjects received 10 mg of oral administration balovaptan once a day (QD).

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD) in OLE Treatment period

    Reporting group values
    		 Balovaptan Placebo Total
    Number of subjects
    		 163 158 321
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 163 158 321
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 27.6 ( 9.7 ) 27.6 ( 9.8 ) -
    Sex: Female, Male
    Units: Subject
        Female
    		 35 30 65
        Male
    		 128 128 256
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 15 13 28
        Not Hispanic or Latino
    		 145 142 287
        Unknown or Not Reported
    		 3 3 6
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 2 2
        Asian
    		 3 5 8
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 9 6 15
        White
    		 143 140 283
        More than one race
    		 3 1 4
        Unknown or Not Reported
    		 5 4 9

    End points

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    End points reporting groups
    Reporting group title
    Balovaptan
    Reporting group description
    		 Subjects received 10 mg of oral administration balovaptan once a day (QD).

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD) in OLE Treatment period
    Reporting group title
    Balovaptan
    Reporting group description
    		 Subjects received 10 mg of oral administration balovaptan once a day (QD).

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD) in OLE Treatment period

    Primary: Change from baseline at Week 24 on the Vineland Adaptive Behavior Scales (Vineland-II) two-domain composite (2DC) score.

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    End point title
    		 Change from baseline at Week 24 on the Vineland Adaptive Behavior Scales (Vineland-II) two-domain composite (2DC) score. [1]
    End point description
    Vineland™-II Adaptive Behavior Scales 2-Domain Composite (2DC) Score is defined as mean of the Communication domain standard score & Socialization domain standard score. If any of the 2 individual domain standard scores is missing 2DC score is not computed. Vineland™-II is an instrument that measures communication, daily living skills, socialization, motor skills and maladaptive behavior of individuals with developmental disabilities. Survey Interview Form will be administered to a subject’s reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject’s activities and behavior. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning.
    End point type
    Primary
    End point timeframe
    Week 24 (Blinded Treatment Period)
    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: Only descriptive statistics was planned to be reported in the endpoint.
    End point values
    		 Balovaptan Placebo
    Number of subjects analysed
    111
    99
    Units: Number
        arithmetic mean (standard deviation)
    4.56 ( 10.85 )
    6.83 ( 12.18 )
    No statistical analyses for this end point

    Secondary: Change from baseline at Week 12 on the Vineland-II 2DC score

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    End point title
    		 Change from baseline at Week 12 on the Vineland-II 2DC score
    End point description
    Vineland™-II Adaptive Behavior Scales 2-Domain Composite (2DC) Score is defined as mean of the Communication domain standard score & Socialization domain standard score. If any of the 2 individual domain standard scores is missing 2DC score is not computed. Vineland™-II is an instrument that measures communication, daily living skills, socialization, motor skills and maladaptive behavior of individuals with developmental disabilities. Survey Interview Form will be administered to a subject’s reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject’s activities and behavior. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning.
    End point type
    Secondary
    End point timeframe
    Week 12 (Blinded Treatment Period)
    End point values
    		 Balovaptan Placebo
    Number of subjects analysed
    150
    140
    Units: Number
        arithmetic mean (standard deviation)
    3.47 ( 10.00 )
    4.85 ( 12.64 )
    No statistical analyses for this end point

    Secondary: Change from baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on summary and total scores

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    End point title
    		 Change from baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on summary and total scores
    End point description
    The Pediatric Quality of Life Inventory PedsQL™4.0 Generic Core Scale assessment consists of a 23 item questionnaire encompassing 4 core scale domains: Physical Functioning (8 items); Emotional Functioning (5 items); Social Functioning (5 items); and School Functioning (5 items). Items are scored on a 5 point Likert-type response scale (0=never a problem; 1=almost never a problem; 2=sometimes a problem; 3=often a problem; and 4=almost always a problem). Once scored, items will be reverse scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better health-related quality of life.
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 24 (Blinded Treatment Period)
    End point values
    		 Balovaptan Placebo
    Number of subjects analysed
    163 [2]
    158 [3]
    Units: Number
    arithmetic mean (standard deviation)
        Week 12 Total Score
    4.1 ( 11.2 )
    5.0 ( 10.2 )
        Week 12 Psychosocial Health Summary
    4.9 ( 13.2 )
    5.5 ( 12.7 )
        Week 12 Physical Health Summary
    2.5 ( 13.3 )
    4.3 ( 12.3 )
        Week 24 Total Score
    8.0 ( 13.7 )
    6.0 ( 11.6 )
        Week 24 Psychosocial Health Summary
    10.0 ( 15.4 )
    6.9 ( 14.1 )
        Week 24 Physical Health Summary
    4.3 ( 15.5 )
    4.4 ( 14.5 )
    Notes
    [2] - Subject number analyzed Week 12-144 Week 24-106
    [3] - Subject number analyzed Week 12-124, but 125 for psychosocial health Week 24-92
    No statistical analyses for this end point

    Secondary: Change from baseline at Weeks 12 and 24 in the Vineland-II adaptive behavior composite standard score

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    End point title
    		 Change from baseline at Weeks 12 and 24 in the Vineland-II adaptive behavior composite standard score
    End point description
    The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject’s reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject’s activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. Only descriptive statistics presented instead of the planned estimated due to the early discontinuation of the study due to futility.
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 24 (Blinded Treatment Period)
    End point values
    		 Balovaptan Placebo
    Number of subjects analysed
    163 [4]
    158 [5]
    Units: Number
    arithmetic mean (standard deviation)
        Change from baseline Week 12
    2.87 ( 6.99 )
    3.99 ( 10.01 )
        Change from baseline Week 24
    4.32 ( 8.43 )
    5.26 ( 9.69 )
    Notes
    [4] - Subject number analyzed Week 12-150 Week 24-111
    [5] - Subject number analyzed Week 12-140 Week 24-99
    No statistical analyses for this end point

    Secondary: Change from baseline at Week 12 and 24 on the Vineland-II Socialization domain standard score

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    End point title
    		 Change from baseline at Week 12 and 24 on the Vineland-II Socialization domain standard score
    End point description
    The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject’s reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject’s activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. Only descriptive statistics presented instead of the planned estimand due to the early discontinuation of the study due to futility.
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 24 (Blinded Treatment Period)
    End point values
    		 Balovaptan Placebo
    Number of subjects analysed
    163 [6]
    158 [7]
    Units: Number
    arithmetic mean (standard deviation)
        Week 12
    3.63 ( 11.58 )
    5.26 ( 12.71 )
        Week 24
    5.54 ( 13.54 )
    6.86 ( 11.75 )
    Notes
    [6] - Subject number analyzed Week 12-150 Week 24-111
    [7] - Subject number analyzed Week 12-140 Week 24-99
    No statistical analyses for this end point

    Secondary: Change from baseline at Weeks 12 and 24 on the Vineland-II Communication domain standard score

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    End point title
    		 Change from baseline at Weeks 12 and 24 on the Vineland-II Communication domain standard score
    End point description
    The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject’s reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject’s activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning.
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 24 (Blinded Treatment Period)
    End point values
    		 Balovaptan Placebo
    Number of subjects analysed
    163 [8]
    158 [9]
    Units: Number
    arithmetic mean (standard deviation)
        Week 12
    3.30 ( 13.74 )
    4.44 ( 16.58 )
        Week 24
    3.59 ( 16.30 )
    6.81 ( 17.50 )
    Notes
    [8] - Subject number analyzed Week 12-150 Week 24-111
    [9] - Subject number analyzed Week 12-150 Week 24-111
    No statistical analyses for this end point

    Secondary: Change from baseline at Weeks 12 and 24 on the Vineland-II Daily Living Skills domain standard score

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    End point title
    		 Change from baseline at Weeks 12 and 24 on the Vineland-II Daily Living Skills domain standard score
    End point description
    The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject’s reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject’s activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. Only descriptive statistics presented due to the early discontinuation of the study due to futility.
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 24 (Blinded Treatment Period)
    End point values
    		 Balovaptan Placebo
    Number of subjects analysed
    163 [10]
    158 [11]
    Units: Number
    arithmetic mean (standard deviation)
        Week 12
    2.93 ( 8.44 )
    2.74 ( 9.20 )
        Week 24
    5.14 ( 9.34 )
    3.02 ( 9.04 )
    Notes
    [10] - Subject number analyzed Week 12-150 Week 24-111
    [11] - Subject number analyzed Week 12-140 Week 24-99
    No statistical analyses for this end point

    Secondary: Change from baseline in severity of clinical impressions as measured by Clinical Global Impression-Severity (CGI-S)

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    End point title
    		 Change from baseline in severity of clinical impressions as measured by Clinical Global Impression-Severity (CGI-S)
    End point description
    The CGI-S reflects the rater’s impression of the subject’s current autism severity on a 7-point scale ranging from no symptoms (1) to very severe symptoms (7). Changes in CGI-S score were calculated as increase or decrease in absolute CGI-S scores between Baseline and Weeks 12 and 24.
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 24 (Blinded Treatment Period)
    End point values
    		 Balovaptan Placebo
    Number of subjects analysed
    163 [12]
    158 [13]
    Units: Subjects
    number (not applicable)
        Week 12 -3
    0
    0
        Week 12 -2
    3
    3
        Week 12 -1
    32
    34
        Week 12 0
    110
    98
        Week 12 +1
    1
    1
        Week 12 +2
    1
    0
        Week 12 +3
    0
    0
        Week 24 -3
    0
    1
        Week 24 -2
    6
    10
        Week 24 -1
    30
    20
        Week 24 0
    72
    68
        Week 24 +1
    1
    1
        Week 24 +2
    0
    0
        Week 24 +3
    0
    0
    Notes
    [12] - Subject number analyzed Week 12-147 Week 24-109
    [13] - Subject number analyzed Week 12-136 Week 24-100
    No statistical analyses for this end point

    Secondary: Improvements in clinical impressions, as measured by Clinical Global Impression-Improvement (CGI-I)

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    End point title
    		 Improvements in clinical impressions, as measured by Clinical Global Impression-Improvement (CGI-I)
    End point description
    This is a 7-point Likert scale that assesses improvement of the patient's condition. Scores range from the worst score of 7 (Very much worse) to the best score of 1 (Very much improved). Lower scores are better on this scale, and indicate greater improvement.
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 24 (Blinded Treatment Period)
    End point values
    		 Balovaptan Placebo
    Number of subjects analysed
    163 [14]
    158 [15]
    Units: Number
    number (not applicable)
        Week 12 1 Very much improved
    0
    0
        Week 12 2 Much improved
    15
    20
        Week 12 3 Minimally improved
    54
    59
        Week 12 4 No change
    74
    56
        Week 12 5 Minimally worse
    5
    1
        Week 12 6 Much worse
    0
    0
        Week 12 7 Very much worse
    0
    0
        Week 24 1 Very much improved
    0
    2
        Week 24 2 Much improved
    17
    24
        Week 24 3 Minimally improved
    48
    40
        Week 24 4 No change
    42
    33
        Week 24 5 Minimally worse
    1
    1
        Week 24 6 Much worse
    1
    0
        Week 24 7 Very much worse
    0
    0
    Notes
    [14] - Subject number analyzed Week 12-148 Week 24-109
    [15] - Subject number analyzed Week 12-136 Week 24-100
    No statistical analyses for this end point

    Secondary: Change from baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) total and domain scores

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    End point title
    		 Change from baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) total and domain scores
    End point description
    The HAM-A is a 14-item, rater administered interview, assessing the severity of anxiety symptoms during the past 7 days. Seven items assess psychic anxiety and seven assess somatic anxiety. Each item utilizes a 5-point symptom severity response scale, ranging from none (0) to very severe (4). A total score is calculated that ranges from 0 to 56; higher scores are indicative of more severe anxiety.
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 24 (Blinded Treatment Period)
    End point values
    		 Balovaptan Placebo
    Number of subjects analysed
    163 [16]
    158 [17]
    Units: Number
    arithmetic mean (standard deviation)
        Week 12 Total
    -1.7 ( 4.9 )
    -2.8 ( 4.4 )
        Week 12 Psychic Anxiety Subscale
    -1.3 ( 3.5 )
    -1.8 ( 3.2 )
        Week 12 Somatic Anxiety Subscale
    -0.4 ( 2.4 )
    -1.0 ( 2.5 )
        Week 24 Total
    -2.7 ( 4.5 )
    -2.8 ( 5.7 )
        Week 24 Psychic Anxiety Subscale
    -2.1 ( 3.4 )
    -1.8 ( 3.9 )
        Week 24 Somatic Anxiety Subscale
    -0.6 ( 2.2 )
    -1.0 ( 2.9 )
    Notes
    [16] - Subject number analyzed Week 12-153 Week 24-115
    [17] - Subject number analyzed Week 12-143 Week 24-104
    No statistical analyses for this end point

    Secondary: Proportion of subjects with a >=6-point improvement in Vineland-II 2DC score

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    End point title
    		 Proportion of subjects with a >=6-point improvement in Vineland-II 2DC score
    End point description
    Vineland™-II Adaptive Behavior Scales 2-Domain Composite (2DC) Score is defined as mean of the Communication domain standard score & Socialization domain standard score. If any of the 2 individual domain standard scores is missing 2DC score is not computed. Vineland™-II is an instrument that measures communication, daily living skills, socialization, motor skills and maladaptive behavior of individuals with developmental disabilities. Survey Interview Form will be administered to a subject’s reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject’s activities and behavior. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. All participants who have an improvement of at least 6 points are included in the >=6 score threshold
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 24 (Blinded Treatment Period)
    End point values
    		 Balovaptan Placebo
    Number of subjects analysed
    163 [18]
    158 [19]
    Units: Percentage of Subjects
    number (not applicable)
        Week 12
    34.4
    42.1
        Week 24
    43.0
    48.4
    Notes
    [18] - Subject number analyzed Week 12-128 Week 24-100
    [19] - Subject number analyzed Week 12-114 Week 24-93
    No statistical analyses for this end point

    Secondary: Percentage of subjects with adverse events

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    End point title
    		 Percentage of subjects with adverse events
    End point description
    According to the ICH guideline for Good Clinical Practice, an adverse event is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The Blinded Treatment Period continued for 24 weeks, Open Label Extension (OLE) Treatment Period continued up to 2 years. The study was pre-maturely terminated, therefore did not reach the planned end date.
    End point type
    Secondary
    End point timeframe
    Week 24 and Up to Approximately 2 Years
    End point values
    		 Balovaptan Balovaptan Placebo Placebo
    Number of subjects analysed
    163
    100
    158
    97 [20]
    Units: Percentage of Subjects
        number (not applicable)
    60.1
    59.0
    65.8
    55.7
    Notes
    [20] - Subjects received placebo in blinded and 10mg balovaptan daily in open label treatment period
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to the end of Safety Period, up to 2 years
    Adverse event reporting additional description
    In the Open Label Extension (OLE) Treatment Period, the subjects received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period. Other Adverse Events are reported at 5% frequency threshold.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Balovaptan in Blinded Treatment Period
    Reporting group description
    		 Subjects 10 mg of oral administration balovaptan once a day (QD).

    Reporting group title
    Placebo Blinded Treatment Period
    Reporting group description
    		 Subjects received matching placebo.

    Reporting group title
    Balovaptan in Open Label Extension Treatment Period
    Reporting group description
    		 Subjects received 10 mg of oral administration balovaptan once a day (QD).

    Reporting group title
    Placebo in Open Label Extension Treatment Period
    Reporting group description
    		 Subjects received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period

    Serious adverse events
    		 Balovaptan in Blinded Treatment Period Placebo Blinded Treatment Period Balovaptan in Open Label Extension Treatment Period Placebo in Open Label Extension Treatment Period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 163 (1.23%)
    5 / 158 (3.16%)
    0 / 100 (0.00%)
    2 / 97 (2.06%)
         number of deaths (all causes)
    0
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 158 (0.00%)
    0 / 100 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 158 (0.63%)
    0 / 100 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Schizoaffective disorder
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 158 (0.00%)
    0 / 100 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 163 (0.61%)
    1 / 158 (0.63%)
    0 / 100 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Panic disorder
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 158 (0.63%)
    0 / 100 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 158 (0.63%)
    0 / 100 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 158 (0.63%)
    0 / 100 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 158 (0.63%)
    0 / 100 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 158 (0.00%)
    0 / 100 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 158 (0.00%)
    0 / 100 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 158 (0.00%)
    0 / 100 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Balovaptan in Blinded Treatment Period Placebo Blinded Treatment Period Balovaptan in Open Label Extension Treatment Period Placebo in Open Label Extension Treatment Period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 163 (30.06%)
    59 / 158 (37.34%)
    28 / 100 (28.00%)
    30 / 97 (30.93%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 163 (1.23%)
    10 / 158 (6.33%)
    2 / 100 (2.00%)
    1 / 97 (1.03%)
         occurrences all number
    2
    10
    2
    1
    Headache
         subjects affected / exposed
    8 / 163 (4.91%)
    7 / 158 (4.43%)
    5 / 100 (5.00%)
    10 / 97 (10.31%)
         occurrences all number
    13
    9
    5
    17
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    11 / 163 (6.75%)
    14 / 158 (8.86%)
    5 / 100 (5.00%)
    4 / 97 (4.12%)
         occurrences all number
    15
    15
    5
    4
    Nausea
         subjects affected / exposed
    4 / 163 (2.45%)
    7 / 158 (4.43%)
    1 / 100 (1.00%)
    5 / 97 (5.15%)
         occurrences all number
    4
    8
    1
    5
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    5 / 163 (3.07%)
    8 / 158 (5.06%)
    0 / 100 (0.00%)
    3 / 97 (3.09%)
         occurrences all number
    5
    8
    0
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    8 / 163 (4.91%)
    7 / 158 (4.43%)
    8 / 100 (8.00%)
    3 / 97 (3.09%)
         occurrences all number
    11
    7
    8
    4
    Insomnia
         subjects affected / exposed
    5 / 163 (3.07%)
    8 / 158 (5.06%)
    3 / 100 (3.00%)
    3 / 97 (3.09%)
         occurrences all number
    5
    8
    3
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    14 / 163 (8.59%)
    19 / 158 (12.03%)
    7 / 100 (7.00%)
    4 / 97 (4.12%)
         occurrences all number
    14
    22
    10
    4
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 163 (6.13%)
    9 / 158 (5.70%)
    6 / 100 (6.00%)
    7 / 97 (7.22%)
         occurrences all number
    13
    11
    7
    11
    Gastroenteritis
         subjects affected / exposed
    2 / 163 (1.23%)
    0 / 158 (0.00%)
    1 / 100 (1.00%)
    5 / 97 (5.15%)
         occurrences all number
    2
    0
    1
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Feb 2019
    Protocol WN39434 has been amended primarily to update the requirements for cardiac monitoring in response to specific requests received from the U.S. Food and Drug Administration (FDA) and to remove the capillary blood draw option.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    04 Mar 2020
    The study is pre-maturely terminated without a restart date, futility analysis decision.
    -

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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