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    Clinical Trial Results:
    A Phase II Multi-Center, Randomized, Double-Blind, 24-Week, Parallel Group, Placebo-Controlled Study to Investigate the Efficacy and Safety of Balovaptan (RO5285119) in Children and Adolescents Age 5-17 With Autism Spectrum Disorder (ASD)

    Summary
    EudraCT number
    		 2020-003173-22
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    30 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Dec 2020
    First version publication date
    23 Dec 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BP30153
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02901431
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001918-PIP01-15
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Jun 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this study is to evaluate the efficacy of 24-week treatment with balovaptan (RO5285119) 10 mg equivalent compared to placebo as measured by the change from baseline on the Vineland™-II Adaptive Behavior Scales, second edition (Vineland™-II) Two Domain Composite (2DC) (average of Communication and Socialization domains).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Nov 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 339
    Worldwide total number of subjects
    339
    EEA total number of subjects
    0
    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)
    127
    Adolescents (12-17 years)
    212
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 A total of 339 participants were enrolled from 44 sites in the United States.

    Pre-assignment
    Screening details
    		 For the Main Study Part and Open Extension Study Part, treatment groups were categorized based on the tertiles of individual participants PK exposure at Week 12. To allow clear analysis by exposure tertiles, participants with dose adjustment were excluded from the analysis by tertiles.

    Period 1
    Period 1 title
    PK Part and Main Study Part
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 PK Part - Placebo
    Arm description
    		 Participants received a matching placebo orally. Approximate treatment duration was up to 8 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a matching placebo orally. Approximate treatment duration was up to 8 weeks.

    Arm title
    		 PK Part - Balovaptan (RO5285119) 4 mg/d equivalent
    Arm description
    		 Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 8 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Balovaptan
    Investigational medicinal product code
    Other name
    RO5285119
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 8 weeks.

    Arm title
    		 PK Part - Balovaptan (RO5285119) 10 mg/d equivalent
    Arm description
    		 Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 8 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Balovaptan
    Investigational medicinal product code
    Other name
    RO5285119
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 8 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Participants received a matching placebo orally. Approximate treatment duration was up to 24 weeks in Main Study Part.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a matching placebo orally. Approximate treatment duration was up to 24 weeks in Main Study Part.

    Arm title
    		 Low Exposure Tertile
    Arm description
    		 Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks in Main Study Part.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Balovaptan
    Investigational medicinal product code
    Other name
    RO5285119
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment groups were categorized based on the tertiles of individual participant's PK exposure at week 12. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks in Main Study Part.

    Arm title
    		 Medium Exposure Tertile
    Arm description
    		 Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks in Main Study Part.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Balovaptan
    Investigational medicinal product code
    Other name
    RO5285119
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment groups were categorized based on the tertiles of individual participant's PK exposure at week 12. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks in Main Study Part.

    Arm title
    		 High Exposure Tertile
    Arm description
    		 Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks in Main Study Part.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Balovaptan
    Investigational medicinal product code
    Other name
    RO5285119
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment groups were categorized based on the tertiles of individual participant's PK exposure at week 12. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks in Main Study Part.

    Arm title
    		 Dose-Adjusters
    Arm description
    		 Participants with dose adjustment who were excluded from the analysis by tertiles. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks in Main Study Part.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Balovaptan
    Investigational medicinal product code
    Other name
    RO5285119
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with dose adjustment who were excluded from the analysis by tertiles. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks in Main Study Part.

    Number of subjects in period 1
    		PK Part - Placebo PK Part - Balovaptan (RO5285119) 4 mg/d equivalent PK Part - Balovaptan (RO5285119) 10 mg/d equivalent Placebo Low Exposure Tertile Medium Exposure Tertile High Exposure Tertile Dose-Adjusters
    Started
    12
    11
    15
    112
    57
    66
    66
    7
    Completed
    5
    5
    6
    86
    50
    54
    55
    7
    Not completed
    7
    6
    9
    26
    7
    12
    11
    0
         Consent withdrawn by subject
    1
    1
    3
    18
    3
    5
    6
    -
         Physician decision
    -
    -
    -
    1
    -
    -
    1
    -
         Adverse event, non-fatal
    -
    1
    -
    3
    3
    4
    1
    -
         Stopped treatment after 8 weeks
    1
    -
    1
    -
    -
    -
    -
    -
         Discontinued per Sponsor
    -
    3
    -
    -
    -
    -
    -
    -
         Pending IMC/SOC Dose Confirmation
    2
    -
    -
    -
    -
    -
    -
    -
         Stopped per Sponsor pending dose confirmation
    1
    -
    4
    -
    -
    -
    -
    -
         Lost to follow-up
    -
    -
    1
    3
    1
    2
    3
    -
         Withdrawal by Caregiver
    -
    -
    -
    -
    -
    1
    -
    -
         8 weeks of treatment ran out
    2
    -
    -
    -
    -
    -
    -
    -
         Pending dose confirmation
    -
    1
    -
    -
    -
    -
    -
    -
         Lack of efficacy
    -
    -
    -
    1
    -
    -
    -
    -
    Period 2
    Period 2 title
    Open Label Part
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Placebo
    Arm description
    		 Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 52 weeks in Open Label Extension Part.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 52 weeks in Open Label Extension Part.

    Arm title
    		 Low Exposure Tertile
    Arm description
    		 Tertiles were used as derived from the main study part at Week 12. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 52 weeks in Open Label Extension Part.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Balovaptan
    Investigational medicinal product code
    Other name
    RO5285119
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment groups were categorized based on the tertiles of individual participant's PK exposure at week 12. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 52 weeks in Open Label Extension Part.

    Arm title
    		 Medium Exposure Tertile
    Arm description
    		 Tertiles were used as derived from the main study part at Week 12. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 52 weeks in Open Label Extension Part.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Balovaptan
    Investigational medicinal product code
    Other name
    RO5285119
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment groups were categorized based on the tertiles of individual participant's PK exposure at week 12. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 52 weeks in Open Label Extension Part.

    Arm title
    		 High Exposure Tertile
    Arm description
    		 Tertiles were used as derived from the main study part at Week 12. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 52 weeks in Open Label Extension Part.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Balovaptan
    Investigational medicinal product code
    Other name
    RO5285119
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment groups were categorized based on the tertiles of individual participant's PK exposure at week 12. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 52 weeks in Open Label Extension Part.

    Arm title
    		 Dose-Adjusters
    Arm description
    		 Participants with dose adjustment who were excluded from the analysis by tertiles. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 52 weeks in Open Label Extension Part.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Balovaptan
    Investigational medicinal product code
    Other name
    RO5285119
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with dose adjustment who were excluded from the analysis by tertiles. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 52 weeks in Open Label Extension Part.

    Number of subjects in period 2
    		Placebo Low Exposure Tertile Medium Exposure Tertile High Exposure Tertile Dose-Adjusters
    Started
    68
    35
    40
    46
    5
    Completed
    20
    11
    11
    7
    2
    Not completed
    48
    24
    29
    39
    3
         Physician decision
    1
    1
    -
    -
    -
         Consent withdrawn by subject
    6
    5
    7
    3
    1
         Adverse event, non-fatal
    4
    4
    -
    4
    1
         Study Terminated By Sponsor
    35
    12
    21
    31
    -
         Lost to follow-up
    2
    2
    1
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PK Part - Placebo
    Reporting group description
    		 Participants received a matching placebo orally. Approximate treatment duration was up to 8 weeks.

    Reporting group title
    PK Part - Balovaptan (RO5285119) 4 mg/d equivalent
    Reporting group description
    		 Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 8 weeks.

    Reporting group title
    PK Part - Balovaptan (RO5285119) 10 mg/d equivalent
    Reporting group description
    		 Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 8 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received a matching placebo orally. Approximate treatment duration was up to 24 weeks in Main Study Part.

    Reporting group title
    Low Exposure Tertile
    Reporting group description
    		 Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks in Main Study Part.

    Reporting group title
    Medium Exposure Tertile
    Reporting group description
    		 Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks in Main Study Part.

    Reporting group title
    High Exposure Tertile
    Reporting group description
    		 Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks in Main Study Part.

    Reporting group title
    Dose-Adjusters
    Reporting group description
    		 Participants with dose adjustment who were excluded from the analysis by tertiles. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks in Main Study Part.

    Reporting group values
    		 PK Part - Placebo PK Part - Balovaptan (RO5285119) 4 mg/d equivalent PK Part - Balovaptan (RO5285119) 10 mg/d equivalent Placebo Low Exposure Tertile Medium Exposure Tertile High Exposure Tertile Dose-Adjusters Total
    Number of subjects
    		 12 11 15 112 57 66 66 7
    Age categorical
    Units: Subjects
    Age Continuous
    Participants in the PK part and Main Study Part.
    Units: years
        arithmetic mean (standard deviation)
    		 8.9 ± 3.8 9.9 ± 3.3 10.4 ± 3.5 12.5 ± 3.0 13.3 ± 2.3 12.6 ± 3.0 11.8 ± 3.3 12.6 ± 2.1 -
    Sex: Female, Male
    The overall total numbers of baseline participants is lower than the sum of the groups because 7 re-starters are counted in both the PK part and Main Study Part of the study.
    Units: Participants
        Female
    		 3 1 4 17 9 8 11 0 53
        Male
    		 9 10 11 95 48 58 55 7 293

    End points

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    End points reporting groups
    Reporting group title
    PK Part - Placebo
    Reporting group description
    		 Participants received a matching placebo orally. Approximate treatment duration was up to 8 weeks.

    Reporting group title
    PK Part - Balovaptan (RO5285119) 4 mg/d equivalent
    Reporting group description
    		 Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 8 weeks.

    Reporting group title
    PK Part - Balovaptan (RO5285119) 10 mg/d equivalent
    Reporting group description
    		 Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 8 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received a matching placebo orally. Approximate treatment duration was up to 24 weeks in Main Study Part.

    Reporting group title
    Low Exposure Tertile
    Reporting group description
    		 Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks in Main Study Part.

    Reporting group title
    Medium Exposure Tertile
    Reporting group description
    		 Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks in Main Study Part.

    Reporting group title
    High Exposure Tertile
    Reporting group description
    		 Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks in Main Study Part.

    Reporting group title
    Dose-Adjusters
    Reporting group description
    		 Participants with dose adjustment who were excluded from the analysis by tertiles. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks in Main Study Part.
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 52 weeks in Open Label Extension Part.

    Reporting group title
    Low Exposure Tertile
    Reporting group description
    		 Tertiles were used as derived from the main study part at Week 12. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 52 weeks in Open Label Extension Part.

    Reporting group title
    Medium Exposure Tertile
    Reporting group description
    		 Tertiles were used as derived from the main study part at Week 12. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 52 weeks in Open Label Extension Part.

    Reporting group title
    High Exposure Tertile
    Reporting group description
    		 Tertiles were used as derived from the main study part at Week 12. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 52 weeks in Open Label Extension Part.

    Reporting group title
    Dose-Adjusters
    Reporting group description
    		 Participants with dose adjustment who were excluded from the analysis by tertiles. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 52 weeks in Open Label Extension Part.

    Subject analysis set title
    PK Part - Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants received a matching placebo orally. Approximate treatment duration was up to 8 weeks.

    Subject analysis set title
    PK Part - Balovaptan (RO5285119) 4 mg/d equivalent
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 8 weeks.

    Subject analysis set title
    PK Part - Balovaptan (RO5285119) 10 mg/d equivalent
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 mg/d of balovaptan (RO5285119). Approximate treatment duration was up to 8 weeks.

    Subject analysis set title
    Main Study Part - Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants in the Main Study Part received a matching placebo orally. Approximate treatment duration was up to 24 weeks.

    Subject analysis set title
    Main Study Part - Low Exposure Tertile
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Main Study Part in the Low Exposure Tertile received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Assignment to tertile groups was based on week 12 PK exposure. Approximate treatment duration was up to 24 weeks.

    Subject analysis set title
    Main Study Part - Medium Exposure Tertile
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Main Study Part in the Medium Exposure Tertile received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Assignment to tertile groups was based on week 12 PK exposure. Approximate treatment duration was up to 24 weeks.

    Subject analysis set title
    Main Study Part - High Exposure Tertile
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Main Study Part in the High Exposure Tertile received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Assignment to tertile groups was based on week 12 PK exposure. Approximate treatment duration was up to 24 weeks.

    Subject analysis set title
    Main Study Part - Dose-Adjusters
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with dose adjustment who were excluded from the analysis by tertiles. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks in Main Study Part.

    Subject analysis set title
    Main Study Part, Low Exposure Tertile
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Main Study Part in the Low Exposure Tertile received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks.

    Subject analysis set title
    Main Study Part, Medium Exposure Tertile
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Main Study Part in the Medium Exposure Tertile received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks.

    Subject analysis set title
    Main Study Part, High Exposure Tertile
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Main Study Part in the High Exposure Tertile received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks.

    Subject analysis set title
    Main Study Part - All Treated
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants in the Main Study Part received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). This group includes participants from the low, medium, and high exposure tertiles, as well as the Dose-Adjusters. Approximate treatment duration was up to 24 weeks.

    Subject analysis set title
    Open Label Extension Part, Low Exposure Tertile
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Open Label Extension Part of the study in the Low Exposure Tertile received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 52 weeks.

    Subject analysis set title
    Open Label Extension Part, Medium Exposure Tertile
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Open Label Extension Part of the study in the Medium Exposure Tertile received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 52 weeks in Open Label Extension Part.

    Subject analysis set title
    Open Label Extension Part, High Exposure Tertile
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the Open Label Extension Part of the study in the High Exposure Tertile received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up 52 weeks.

    Subject analysis set title
    Open Label Extension Part, All Treated
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All participants in the Open Label Extension Part of the study received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). This group includes participants from the low, medium, and high exposure tertiles, as well as the Dose-Adjusters. Approximate treatment duration was up to 52 weeks.

    Subject analysis set title
    Efficacy Inferential - Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subset of the Efficacy Population used for analyses of primary and secondary efficacy endpoints. It was divided by randomized treatment and included patients taking balovaptan 10 mg eq dose and patients from the concurrently randomized PBO group in the corresponding randomization stage. Patients with dose adjustments or interruptions, or who were on a different dose than the final dose for their age group, were excluded.

    Subject analysis set title
    Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subset of the Efficacy Population used for analyses of primary and secondary efficacy endpoints. It was divided by randomized treatment and included patients taking balovaptan 10 mg eq dose and patients from the concurrently randomized PBO group in the corresponding randomization stage. Patients with dose adjustments or interruptions, or who were on a different dose than the final dose for their age group, were excluded.

    Primary: Change From Baseline in Vineland™-II Adaptive Behavior Scale Two Domain Composite (2DC) Score at Week 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo

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    End point title
    		 Change From Baseline in Vineland™-II Adaptive Behavior Scale Two Domain Composite (2DC) Score at Week 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo
    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 caregiver in this study, during which the rater or clinician will ask to the caregiver 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. Mixed model with repeated measures (MMRM) was used for analysis with assessments at baseline, Week 12 and Week 24.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Efficacy Inferential - Placebo Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects analysed
    81
    86
    Units: Score on a scale
        least squares mean (standard error)
    2.34 ± 1.15
    2.17 ± 1.11
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Mixed Model Repeat Measurements (MMRM) was applied.
    Comparison groups
    Efficacy Inferential - Placebo v Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.911
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in Adjusted LSMeans
    Point estimate
    -0.16
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2.56
         upper limit
    		 2.23

    Secondary: Change from Baseline in Vineland™-II Composite Standard Score After 12 Weeks and 24 Weeks of Treatment for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo

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    End point title
    		 Change from Baseline in Vineland™-II Composite Standard Score After 12 Weeks and 24 Weeks of Treatment for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo
    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 caregiver in this study, during which the rater or clinician will ask to the caregiver 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
    Baseline, Weeks 12 and 24
    End point values
    		 Efficacy Inferential - Placebo Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects analysed
    81
    86
    Units: Score on a scale
    least squares mean (standard error)
        Week 12
    1.45 ± 1.07
    1.74 ± 1.04
        Week 24
    2.20 ± 1.19
    1.97 ± 1.15
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Week 12
    Comparison groups
    Efficacy Inferential - Placebo v Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in adjused LSMean
    Point estimate
    0.29
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.85
         upper limit
    		 2.43
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Week 24
    Comparison groups
    Efficacy Inferential - Placebo v Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in adjusted LSMean
    Point estimate
    -0.23
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2.67
         upper limit
    		 2.22

    Secondary: Change From Baseline in Vineland™-II Adaptive Behavior Scale Communication, Socialization, and Daily Living Skills Domain Standard Scores at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo

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    End point title
    		 Change From Baseline in Vineland™-II Adaptive Behavior Scale Communication, Socialization, and Daily Living Skills Domain Standard Scores at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo
    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 caregiver in this study, during which the rater or clinician will ask to the caregiver open ended questions relating to the subject’s activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, and Daily Living Skills. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. Measure Type is Adjusted least-squares means.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12 and 24
    End point values
    		 Efficacy Inferential - Placebo Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects analysed
    81
    86
    Units: Score on a scale
    least squares mean (standard error)
        Communication Domain Standard Score, Week 12
    1.86 ± 1.06
    1.64 ± 1.03
        Communication Domain Standard Score, Week 24
    1.51 ± 1.13
    2.21 ± 1.09
        Socialization Domain Standard Score, Week 12
    1.69 ± 1.31
    2.20 ± 1.26
        Socialization Domain Standard Score, Week 24
    2.87 ± 1.50
    2.26 ± 1.45
        Daily Living Skills Domain Standard Score, Week 12
    -0.01 ± 1.38
    2.13 ± 1.35
        Daily Living Skills Domain Standard Score, Week 24
    1.44 ± 1.49
    1.61 ± 1.45
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Communication Domain Standard Score, Week 12
    Comparison groups
    Efficacy Inferential - Placebo v Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in adjusted LSMean
    Point estimate
    -0.22
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2.36
         upper limit
    		 1.92
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Communication Domain Standard Score, Week 24
    Comparison groups
    Efficacy Inferential - Placebo v Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in adjusted LSMean
    Point estimate
    0.71
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 3.02
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Socialization Domain Standard Score, Week 12
    Comparison groups
    Efficacy Inferential - Placebo v Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in adjusted LSMean
    Point estimate
    0.51
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 3.12
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Efficacy Inferential - Placebo v Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    Method
    Parameter type
    		 Difference in adjusted LSMean
    Point estimate
    -0.61
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -3.74
         upper limit
    		 2.51
    Notes
    [1] - Socialization Domain Standard Score, Week 24
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Efficacy Inferential - Placebo v Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    Method
    Parameter type
    		 Difference in adjusted LSMean
    Point estimate
    2.14
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.63
         upper limit
    		 4.9
    Notes
    [2] - Daily Living Skills Domain Standard Score, Week 12
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Efficacy Inferential - Placebo v Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    Method
    Parameter type
    		 Differences in adjusted LSMean
    Point estimate
    0.18
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2.87
         upper limit
    		 3.22
    Notes
    [3] - Daily Living Skills Domain Standard Score, Week 24

    Secondary: Proportion of Subjects with >=6 Points Improvement in the Vineland-II 2DC Score for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo

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    End point title
    		 Proportion of Subjects with >=6 Points Improvement in the Vineland-II 2DC Score for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo
    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 caregiver in this study, during which the rater or clinician will ask to the caregiver 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 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
    Baseline, Weeks 12 and 24
    End point values
    		 Efficacy Inferential - Placebo Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects analysed
    66 [4]
    70 [5]
    Units: Percentage of participants
    number (not applicable)
        Week 12
    30.3
    27.1
        Week 24
    34.4
    32.8
    Notes
    [4] - Week 12, n=66 Week 24, n=61
    [5] - Week 12, n=70 Week 24, n=67
    No statistical analyses for this end point

    Secondary: Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo

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    End point title
    		 Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo
    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).
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12 and 24
    End point values
    		 Efficacy Inferential - Placebo Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects analysed
    67 [6]
    74 [7]
    Units: Percentage of participants
    number (not applicable)
        -3 (Very much improved), Week 12
    1.5
    0
        -2 (Much improved), Week 12
    1.5
    2.7
        -1 (Minimally improved), Week 12
    31.3
    31.1
        0 (No change), Week 12
    65.7
    63.5
        +1 (Minimally worse), Week 12
    0
    2.7
        +2 (Much worse), Week 12
    0
    0
        +3 (Very Much worse), Week 12
    0
    0
        -3 (Very much improved), Week 24
    1.6
    0
        -2 (Much improved), Week 24
    6.5
    4.3
        -1 (Minimally improved), Week 24
    32.3
    31.9
        0 (No change), Week 24
    59.7
    63.8
        +1 (Minimally worse), Week 24
    0
    0
        +2 (Much worse), Week 24
    0
    0
        +3 (Very much worse), Week 24
    0
    0
    Notes
    [6] - Week 12, n=67 Week 24, n=62
    [7] - Week 12, n=74 Week 24, n=69
    No statistical analyses for this end point

    Secondary: Change From Baseline in Ohio Autism Clinical Impressions Scale-Severity (OACIS-S) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo

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    End point title
    		 Change From Baseline in Ohio Autism Clinical Impressions Scale-Severity (OACIS-S) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo
    End point description
    The OACIS-S is a 10-item, clinician-completed measures based upon interview and/or observation. The OACIS-S assess severity and improvement, respectively, in social interaction, aberrant behavior, repetitive or ritualistic behavior, verbal communication, nonverbal communication skills, hyperactivity and inattention, anxiety and fearfulness, sensory sensitivities, restricted and narrow interests, and a global rating of autism. Each item of the OACIS-S is rated on a 7-point scale ranging from no symptoms (1) to very severe symptoms (7).
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12 and 24
    End point values
    		 Efficacy Inferential - Placebo Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects analysed
    67 [8]
    73 [9]
    Units: Percentage of participants
    number (not applicable)
        -3 (Very much improved), Week 12
    3.0
    0
        -2 (Much improved), Week 12
    6.0
    6.8
        -1 (Minimally improved), Week 12
    28.4
    34.2
        0 (No change), Week 12
    59.7
    57.5
        +1 (Minimally worse), Week 12
    3.0
    1.4
        +2 (Much worse), Week 12
    0
    0
        +3 (Very much worse), Week 12
    0
    0
        -3 (Very much improved), Week 24
    6.5
    0
        -2 (Much improved), Week 24
    8.1
    7.5
        -1 (Minimally improved), Week 24
    33.9
    28.4
        0 (No change), Week 24
    48.4
    61.2
        +1 (Minimally worse), Week 24
    3.2
    3.0
        +2 (Much worse), Week 24
    0
    0
        +3 (Very much worse), Week 24
    0
    0
    Notes
    [8] - Week 12, n=67 Week 24, n=62
    [9] - Week 12, n=73 Week 24, n=67
    No statistical analyses for this end point

    Secondary: Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo

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    End point title
    		 Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo
    End point description
    The CGI rating scales are tools used to evaluate both the severity of illness and change from baseline. The CGI-I is used to assess the clinical change as compared to symptoms at baseline using a 7-point scale, ranging from very much improved (1) to very much worse (7). For this study modified versions will be used.
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 24
    End point values
    		 Efficacy Inferential - Placebo Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects analysed
    67 [10]
    74 [11]
    Units: Percentage of participants
    number (not applicable)
        1 - Very much improved, Week 12
    0
    0
        2 - Much improved, Week 12
    22.4
    21.6
        3 - Minimally improved, Week 12
    49.3
    35.1
        4 - No change, Week 12
    22.4
    43.2
        5 - Minimally worse, Week 12
    6.0
    0
        6 - Much worse, Week 12
    0
    0
        7 - Very much worse, Week 12
    0
    0
        1 - Very much improved, Week 24
    0
    4.4
        2 - Much improved, Week 24
    30.6
    26.5
        3 - Minimally improved, Week 24
    48.4
    30.9
        4 - No change, Week 24
    19.4
    36.8
        5 - Minimally worse, Week 24
    1.6
    1.5
        6 - Much worse, Week 24
    0
    0
        7 - Very much worse, Week 24
    0
    0
    Notes
    [10] - Week 12, n=67 Week 24, n=62
    [11] - Week 12, n=74 Week 24, n=68
    No statistical analyses for this end point

    Secondary: Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo

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    End point title
    		 Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo
    End point description
    The OACIS-I is a 10-item, clinician-completed measures based upon interview and/or observation. The OACIS-I assess severity and improvement, respectively, in social interaction, aberrant behavior, repetitive or ritualistic behavior, verbal communication, nonverbal communication skills, hyperactivity and inattention, anxiety and fearfulness, sensory sensitivities, restricted and narrow interests, and a global rating of autism. The OACIS-I is used to assess the clinical change as compared to symptoms at baseline using a 7-point scale, ranging from very much improved (1) to very much worse (7).
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 24
    End point values
    		 Efficacy Inferential - Placebo Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects analysed
    67 [12]
    74 [13]
    Units: Percentage of participants
    number (not applicable)
        1 - Very much improved, Week 12
    1.5
    0
        2 - Much improved, Week 12
    16.4
    20.3
        3 - Minimally improved, Week 12
    38.8
    25.7
        4 - No change, Week 12
    40.3
    54.1
        5 - Minimally worse, Week 12
    3.0
    0
        6 - Much worse, Week 12
    0
    0
        7 - Very much worse, Week 12
    0
    0
        1 - Very much improved, Week 24
    0
    2.9
        2 - Much improved, Week 24
    25.8
    22.1
        3 - Minimally improved, Week 24
    46.8
    25.0
        4 - No change, Week 24
    25.8
    50.0
        5 - Minimally worse, Week 24
    1.6
    0
        6 - Much worse, Week 24
    0
    0
        7 - Very much worse, Week 24
    0
    0
    Notes
    [12] - Week 12, n=67 Week 24, n=62
    [13] - Week 12, n=74 Week 24, n=68
    No statistical analyses for this end point

    Secondary: Change from Baseline in Patient-Reported Pediatric Quality of Life (PedsQL) v4.0 Generic Core Scale after 12 Weeks and 24 Weeks of Treatment for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo

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    End point title
    		 Change from Baseline in Patient-Reported Pediatric Quality of Life (PedsQL) v4.0 Generic Core Scale after 12 Weeks and 24 Weeks of Treatment for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo
    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). For children aged 8 years and above, the PedsQL 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). For children aged 5-7 years, scoring is based on a three-point scale (0=Not at all, 2=Sometimes, 4=A lot). 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
    Baseline, Weeks 12 and 24
    End point values
    		 Efficacy Inferential - Placebo Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects analysed
    81 [14]
    86 [15]
    Units: Score on scale
    least squares mean (standard error)
        Change From Baseline at Week 12
    2.42 ± 1.49
    6.16 ± 1.41
        Change From Baseline at Week 24
    3.70 ± 1.50
    5.98 ± 1.44
    Notes
    [14] - Value at baseline, n=81;Change from baseline at Week 12, n=62; Change from baseline at Week 24, n=59
    [15] - Value at baseline, n=86;Change from baseline at Week 12, n=72; Change from baseline at Week 24, n=65
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Week 12
    Comparison groups
    Efficacy Inferential - Placebo v Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference of Adjusted LS Means
    Point estimate
    3.74
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 6.7
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Week 24
    Comparison groups
    Efficacy Inferential - Placebo v Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference of Adjusted LS means
    Point estimate
    2.28
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.73
         upper limit
    		 5.29

    Secondary: Change from Baseline in Vineland-II Composite Standard Score in Adolescents and Children Independently at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo

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    End point title
    		 Change from Baseline in Vineland-II Composite Standard Score in Adolescents and Children Independently at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo
    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 caregiver in this study, during which the rater or clinician will ask to the caregiver 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
    Baseline, Weeks 12 and 24
    End point values
    		 Efficacy Inferential - Placebo Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects analysed
    81
    86
    Units: Score on scale
    arithmetic mean (standard deviation)
        5-12 Years Age, Absolute Value at Baseline
    73.9 ± 9.7
    77.3 ± 10.9
        5-12 Years Age, Change From Baseline at Week 12
    3.6 ± 8.4
    1.2 ± 7.8
        5-12 Years Age, Change From Baseline at Week 24
    4.8 ± 9.1
    1.0 ± 8.4
        13-17 Years Age, Absolute Value at Baseline
    71.0 ± 10.3
    73.5 ± 8.9
        13-17 Years Age, Change From Baseline at Week 12
    1.8 ± 4.8
    3.7 ± 9.4
        13-17 Years Age, Change From Baseline at Week 24
    2.7 ± 8.6
    3.3 ± 8.7
    No statistical analyses for this end point

    Secondary: Change From Baseline in Vineland-II Adaptive Behavior Scale 2DC Score at Week 12 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo

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    End point title
    		 Change From Baseline in Vineland-II Adaptive Behavior Scale 2DC Score at Week 12 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo
    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 caregiver in this study, during which the rater or clinician will ask to the caregiver 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
    Baseline, Week 12
    End point values
    		 Efficacy Inferential - Placebo Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects analysed
    81
    86
    Units: Score on scale
        least squares mean (standard error)
    1.87 ± 1.00
    1.88 ± 0.97
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Efficacy Inferential - Placebo v Efficacy Inferential - Balovaptan 10 mg/d equivalent
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.992
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in Adjusted LS Means
    Point estimate
    0.01
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.99
         upper limit
    		 2.01

    Secondary: Percentage of Participants With Adverse Events for Treatment With Balovaptan

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    End point title
    		 Percentage of Participants With Adverse Events for Treatment With Balovaptan
    End point description
    Treatment groups were categorized based on the tertiles of individual participant's PK exposure at Week 12. To allow clear analysis by exposure tertiles, dose adjusters were excluded from the analysis by tertiles. Dose-Adjusters were included in the "All Treated" group in the Main Study Part and Open Label Extension Part.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24 and up to Week 76
    End point values
    		 Main Study Part, Low Exposure Tertile Main Study Part, Medium Exposure Tertile Main Study Part, High Exposure Tertile Main Study Part - All Treated Open Label Extension Part, Low Exposure Tertile Open Label Extension Part, Medium Exposure Tertile Open Label Extension Part, High Exposure Tertile Open Label Extension Part, All Treated
    Number of subjects analysed
    57
    66
    66
    196
    35
    40
    46
    126
    Units: Percentage of Participants
        number (not applicable)
    77.2
    71.2
    66.7
    71.4
    68.6
    70.0
    78.3
    72.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first study drug to the data cutoff date: 30 June 2020 (up to 43 months)
    Adverse event reporting additional description
    Treatment groups were categorized based on the tertiles of individual participant's PK exposure at Week 12. To allow clear analysis by exposure tertiles, dose adjusters were excluded from the analysis by tertiles. Dose-Adjusters are reported as a separate group.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    PK Part - Placebo
    Reporting group description
    		 Participants in the PK Part of the study who received a matching placebo orally. Approximate treatment duration was up to 8 weeks.

    Reporting group title
    PK Part - Balovaptan (RO5285119) 4 mg/d equivalent
    Reporting group description
    		 Participants in the PK Part of the study who received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 8 weeks.

    Reporting group title
    PK Part - Balovaptan (RO5285119) 10 mg/d equivalent
    Reporting group description
    		 Participants in the PK Part of the study who received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 8 weeks.

    Reporting group title
    Main Study Part - Placebo
    Reporting group description
    		 Participants in the Main Study Part received a matching placebo orally. Approximate treatment duration was up to 24 weeks.

    Reporting group title
    Main Study Part - Low Exposure Tertile
    Reporting group description
    		 Participants in the Main Study Part in the Low Exposure Tertile received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks.

    Reporting group title
    Main Study Part - Medium Exposure Tertile
    Reporting group description
    		 Participants in the Main Study Part in the Medium Exposure Tertile received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks.

    Reporting group title
    Main Study Part - High Exposure Tertile
    Reporting group description
    		 Participants in the Main Study Part in the High Exposure Tertile received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks.

    Reporting group title
    Main Study Part - Dose-Adjusters
    Reporting group description
    		 Participants with dose adjustment who were excluded from the analysis by tertiles. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks in Main Study Part.

    Reporting group title
    Open Label Extension Part - Placebo
    Reporting group description
    		 Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 52 weeks in Open Label Extension Part.

    Reporting group title
    Open Label Extension Part - Low Exposure Tertile
    Reporting group description
    		 Participants in the Open Label Extension Part of the study in the Low Exposure Tertile received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 52 weeks.

    Reporting group title
    Open Label Extension Part - Medium Exposure Tertile
    Reporting group description
    		 Participants in the Open Label Extension Part of the study in the Medium Exposure Tertile received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 52 weeks in Open Label Extension Part.

    Reporting group title
    Open Label Extension Part - High Exposure Tertile
    Reporting group description
    		 Participants in the Open Label Extension Part of the study in the High Exposure Tertile received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up 52 weeks.

    Reporting group title
    Open Label Extension Part - Dose-Adjusters
    Reporting group description
    		 Participants with dose adjustment who were excluded from the analysis by tertiles. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 52 weeks in Open Label Extension Part.

    Serious adverse events
    		 PK Part - Placebo PK Part - Balovaptan (RO5285119) 4 mg/d equivalent PK Part - Balovaptan (RO5285119) 10 mg/d equivalent Main Study Part - Placebo Main Study Part - Low Exposure Tertile Main Study Part - Medium Exposure Tertile Main Study Part - High Exposure Tertile Main Study Part - Dose-Adjusters Open Label Extension Part - Placebo Open Label Extension Part - Low Exposure Tertile Open Label Extension Part - Medium Exposure Tertile Open Label Extension Part - High Exposure Tertile Open Label Extension Part - Dose-Adjusters
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
    4 / 112 (3.57%)
    1 / 57 (1.75%)
    0 / 66 (0.00%)
    1 / 66 (1.52%)
    0 / 7 (0.00%)
    2 / 68 (2.94%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Laryngospasm
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    1 / 68 (1.47%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    1 / 112 (0.89%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    1 / 68 (1.47%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    1 / 112 (0.89%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional self-injury
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    1 / 112 (0.89%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    1 / 57 (1.75%)
    0 / 66 (0.00%)
    1 / 66 (1.52%)
    0 / 7 (0.00%)
    1 / 68 (1.47%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    1 / 112 (0.89%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 PK Part - Placebo PK Part - Balovaptan (RO5285119) 4 mg/d equivalent PK Part - Balovaptan (RO5285119) 10 mg/d equivalent Main Study Part - Placebo Main Study Part - Low Exposure Tertile Main Study Part - Medium Exposure Tertile Main Study Part - High Exposure Tertile Main Study Part - Dose-Adjusters Open Label Extension Part - Placebo Open Label Extension Part - Low Exposure Tertile Open Label Extension Part - Medium Exposure Tertile Open Label Extension Part - High Exposure Tertile Open Label Extension Part - Dose-Adjusters
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 12 (58.33%)
    7 / 11 (63.64%)
    7 / 15 (46.67%)
    58 / 112 (51.79%)
    34 / 57 (59.65%)
    31 / 66 (46.97%)
    34 / 66 (51.52%)
    5 / 7 (71.43%)
    35 / 68 (51.47%)
    21 / 35 (60.00%)
    25 / 40 (62.50%)
    27 / 46 (58.70%)
    3 / 5 (60.00%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 15 (6.67%)
    4 / 112 (3.57%)
    4 / 57 (7.02%)
    4 / 66 (6.06%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    3 / 35 (8.57%)
    2 / 40 (5.00%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    4
    4
    4
    0
    0
    0
    3
    3
    3
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Reproductive system and breast disorders
    Gynaecomastia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 15 (6.67%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 11 (0.00%)
    1 / 15 (6.67%)
    5 / 112 (4.46%)
    3 / 57 (5.26%)
    1 / 66 (1.52%)
    2 / 66 (3.03%)
    0 / 7 (0.00%)
    5 / 68 (7.35%)
    0 / 35 (0.00%)
    1 / 40 (2.50%)
    4 / 46 (8.70%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    1
    5
    4
    1
    2
    0
    5
    0
    1
    4
    0
    Nasal congestion
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    5 / 112 (4.46%)
    3 / 57 (5.26%)
    0 / 66 (0.00%)
    6 / 66 (9.09%)
    1 / 7 (14.29%)
    2 / 68 (2.94%)
    2 / 35 (5.71%)
    3 / 40 (7.50%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    6
    3
    0
    7
    1
    2
    2
    3
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    7 / 112 (6.25%)
    2 / 57 (3.51%)
    3 / 66 (4.55%)
    4 / 66 (6.06%)
    0 / 7 (0.00%)
    3 / 68 (4.41%)
    1 / 35 (2.86%)
    2 / 40 (5.00%)
    4 / 46 (8.70%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    7
    2
    3
    4
    0
    3
    2
    2
    4
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    1 / 112 (0.89%)
    5 / 57 (8.77%)
    2 / 66 (3.03%)
    3 / 66 (4.55%)
    0 / 7 (0.00%)
    1 / 68 (1.47%)
    3 / 35 (8.57%)
    1 / 40 (2.50%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    1
    5
    2
    4
    0
    3
    3
    1
    4
    0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    2 / 68 (2.94%)
    1 / 35 (2.86%)
    2 / 40 (5.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    1
    2
    1
    0
    Anxiety
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    5 / 68 (7.35%)
    2 / 35 (5.71%)
    4 / 40 (10.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    5
    2
    4
    1
    0
    Impulsive behaviour
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    2 / 68 (2.94%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    2
    Irritability
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 11 (18.18%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Mood swings
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Nightmare
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Stereotypy
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 15 (6.67%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Suicidal ideation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Middle insomnia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    1 / 112 (0.89%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    1 / 7 (14.29%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Investigations
    Weight increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    1 / 68 (1.47%)
    2 / 35 (5.71%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    2
    0
    0
    0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    2 / 68 (2.94%)
    2 / 35 (5.71%)
    2 / 40 (5.00%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    2
    2
    3
    0
    Arthropod bite
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Contusion
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    1 / 112 (0.89%)
    2 / 57 (3.51%)
    1 / 66 (1.52%)
    0 / 66 (0.00%)
    1 / 7 (14.29%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    1
    0
    1
    0
    0
    0
    0
    0
    Facial bones fracture
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 15 (6.67%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    1 / 112 (0.89%)
    3 / 57 (5.26%)
    1 / 66 (1.52%)
    0 / 66 (0.00%)
    1 / 7 (14.29%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    1
    4
    1
    0
    1
    0
    0
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    2 / 15 (13.33%)
    16 / 112 (14.29%)
    6 / 57 (10.53%)
    7 / 66 (10.61%)
    8 / 66 (12.12%)
    0 / 7 (0.00%)
    4 / 68 (5.88%)
    3 / 35 (8.57%)
    2 / 40 (5.00%)
    5 / 46 (10.87%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    2
    16
    8
    9
    15
    0
    5
    4
    2
    7
    0
    Poor quality sleep
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    1 / 35 (2.86%)
    0 / 40 (0.00%)
    1 / 46 (2.17%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    1
    Seizure
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    2 / 40 (5.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Syncope
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Tremor
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    2 / 35 (5.71%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Neutropenia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    5 / 112 (4.46%)
    1 / 57 (1.75%)
    0 / 66 (0.00%)
    6 / 66 (9.09%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    7
    1
    0
    8
    0
    0
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    2 / 15 (13.33%)
    6 / 112 (5.36%)
    1 / 57 (1.75%)
    2 / 66 (3.03%)
    4 / 66 (6.06%)
    0 / 7 (0.00%)
    3 / 68 (4.41%)
    2 / 35 (5.71%)
    0 / 40 (0.00%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    3
    7
    1
    2
    15
    0
    3
    2
    0
    2
    0
    Constipation
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    4 / 112 (3.57%)
    5 / 57 (8.77%)
    4 / 66 (6.06%)
    7 / 66 (10.61%)
    0 / 7 (0.00%)
    3 / 68 (4.41%)
    2 / 35 (5.71%)
    1 / 40 (2.50%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    5
    5
    4
    8
    0
    5
    2
    1
    3
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 15 (6.67%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    7 / 112 (6.25%)
    3 / 57 (5.26%)
    2 / 66 (3.03%)
    4 / 66 (6.06%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    8
    3
    2
    4
    0
    0
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    6 / 112 (5.36%)
    5 / 57 (8.77%)
    4 / 66 (6.06%)
    4 / 66 (6.06%)
    0 / 7 (0.00%)
    2 / 68 (2.94%)
    2 / 35 (5.71%)
    1 / 40 (2.50%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    8
    5
    7
    4
    0
    2
    4
    1
    3
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 15 (6.67%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    1 / 68 (1.47%)
    0 / 35 (0.00%)
    2 / 40 (5.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    1
    0
    2
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    2 / 40 (5.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Ear infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    4 / 68 (5.88%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    4
    0
    0
    3
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    5 / 112 (4.46%)
    1 / 57 (1.75%)
    3 / 66 (4.55%)
    3 / 66 (4.55%)
    1 / 7 (14.29%)
    4 / 68 (5.88%)
    3 / 35 (8.57%)
    0 / 40 (0.00%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    6
    1
    3
    3
    1
    4
    3
    0
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    15 / 112 (13.39%)
    8 / 57 (14.04%)
    12 / 66 (18.18%)
    11 / 66 (16.67%)
    2 / 7 (28.57%)
    9 / 68 (13.24%)
    5 / 35 (14.29%)
    10 / 40 (25.00%)
    6 / 46 (13.04%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    15
    10
    17
    12
    2
    11
    5
    14
    7
    0
    Otitis media
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 15 (6.67%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    2 / 68 (2.94%)
    0 / 35 (0.00%)
    1 / 40 (2.50%)
    1 / 46 (2.17%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    2
    0
    1
    2
    1
    Rhinitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    1 / 66 (1.52%)
    1 / 66 (1.52%)
    1 / 7 (14.29%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    2
    1
    0
    0
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    3 / 68 (4.41%)
    0 / 35 (0.00%)
    3 / 40 (7.50%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    3
    0
    3
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    4 / 112 (3.57%)
    2 / 57 (3.51%)
    3 / 66 (4.55%)
    5 / 66 (7.58%)
    0 / 7 (0.00%)
    3 / 68 (4.41%)
    4 / 35 (11.43%)
    3 / 40 (7.50%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    5
    2
    3
    7
    0
    4
    6
    3
    3
    0
    Viral infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    3 / 57 (5.26%)
    2 / 66 (3.03%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    3
    0
    0
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
    0 / 112 (0.00%)
    0 / 57 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 7 (0.00%)
    0 / 68 (0.00%)
    0 / 35 (0.00%)
    0 / 40 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Aug 2016
    Protocol was amended to include age range change to 13-17 years for adolescents and 5-12 years for children. The PK schedule was revised so that the visit with the most intense PK sampling was moved from Week 1 to Week 2. This was to ensure that PK assessments were taken within the first cohorts of 24 adolescents and 24 children at steady state for all major metabolites.
    30 Jan 2017
    Protocol was amended to include participants who were obliged to stop dosing on or before Week 8, due to lack of sufficient data to inform IMC/ SOC decision on final dose, were allowed to re-start in the main study.
    19 May 2017
    Protocol was amended to include a change in the exclusion criterion for body mass index (BMI). BMI at or above the 95th percentile for the same age and sex was considered to be safe. The 99th percentile was used instead.
    29 Mar 2018
    Protocol was amended to include updated text to specify that the primary endpoint will be assessed based on the change from baseline on the Vineland™-II Adaptive Behavior Scales, second edition (Vineland™-II) Two Domain Composite (2DC) instead of Vineland™-II Adaptive Behavior Scales, second edition (Vineland™-II) Composite standard score. The following secondary objectives were added: Proportion of participants with >=6-point improvement in the Vineland™-II 2DC score to evaluate clinically meaningful response; Patient-reported Pediatric Quality of Life (PedsQL) v4.0 Generic Core Scale after 12 weeks and 24 weeks of treatment; Evaluate safety and tolerability of up to 76 weeks of treatment with balovaptan. The secondary objective was changed from “Change from baseline on the Vineland™-II Composite standard score after 12 weeks and 24 weeks of treatment” to “Change from baseline on the Vineland™-II 2DC score after 12 weeks and 24 weeks of treatment”. An Open Label Extension was added. The total duration of the study was updated from 39 weeks to 91 weeks and the end of study was updated from 31 weeks to 83 weeks.
    19 Dec 2018
    Protocol was amended to include study design change to a single dose (10 mg equivalent balovaptan) compared with Placebo in accordance to a randomization ratio of 1:1 of balovaptan 10 mg equivalent: Placebo. Adolescent participants who had been discontinued because of lack of dose confirmation (per protocol prior to Week 8) were to be replaced in the study. The total sample size of the study was increased to 340 participants. The initial starting dose (main study) was changed following review of available safety and PK data from the study. A table was added to outline updated starting doses for adolescents and children, aged 8 to 17 years.

    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.
    Limited data collected in OLE part because study was terminated early after primary analysis.
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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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