Trial Outcomes & Findings for A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension (NCT NCT03504917)

Results Overview

Vineland™-II Adaptive Behavior Scales 2-Domain Composite (2DC) Score is defined as mean of the Communication domain standard score \& Socialization domain standard score. If any of the 2 individual domain standard scores is missing 2DC score is not computed. Vineland™-II is an instrument that measures communication, daily living skills, socialization, motor skills and maladaptive behavior of individuals with developmental disabilities. Survey Interview Form will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

322 participants

Primary outcome timeframe

Week 24

Results posted on

2021-10-27

Participant Flow

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

Participants received matching placebo in Blinded Treatment Period for 24 Weeks and 10 mg of oral administration balovaptan once a day (QD) during the Open Label Extension Treatment Period.

Participant milestones

Participant milestones
Measure	Balovaptan Participants received 10 mg of oral administration balovaptan once a day (QD).	Placebo Participants received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD) in OLE Treatment period
Blinded Treatment Period STARTED	163	158
Blinded Treatment Period COMPLETED	103	102
Blinded Treatment Period NOT COMPLETED	60	56
Open Label Extension Treatment Period STARTED	100	97
Open Label Extension Treatment Period COMPLETED	0	0
Open Label Extension Treatment Period NOT COMPLETED	100	97

Reasons for withdrawal

Reasons for withdrawal
Measure	Balovaptan Participants received 10 mg of oral administration balovaptan once a day (QD).	Placebo Participants received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD) in OLE Treatment period
Blinded Treatment Period Protocol Violation	1	0
Blinded Treatment Period Withdrawal by Subject	12	9
Blinded Treatment Period Lack of Efficacy	1	1
Blinded Treatment Period Lost to Follow-up	1	4
Blinded Treatment Period Adverse Event	4	4
Blinded Treatment Period Physician Decision	1	0
Blinded Treatment Period Unable due to leaving the study site, non-interest, withdrawal, and a partner inability	1	3
Blinded Treatment Period Study terminated by sponsor	39	34
Blinded Treatment Period Non-compliance with study drug	0	1
Open Label Extension Treatment Period The participant left the study site	0	1
Open Label Extension Treatment Period Withdrawal by Subject	8	2
Open Label Extension Treatment Period Lost to Follow-up	1	4
Open Label Extension Treatment Period Lack of Efficacy	3	1
Open Label Extension Treatment Period Adverse Event	7	0
Open Label Extension Treatment Period Non-compliance with study drug	0	1
Open Label Extension Treatment Period Study terminated by sponsor	81	88

Baseline Characteristics

A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Balovaptan n=163 Participants Participants received 10 mg of oral administration balovaptan once a day (QD).	Placebo n=158 Participants Participants received matching placebo.	Total n=321 Participants Total of all reporting groups
Age, Continuous	27.6 Years STANDARD_DEVIATION 9.7 • n=5 Participants	27.6 Years STANDARD_DEVIATION 9.8 • n=7 Participants	27.6 Years STANDARD_DEVIATION 9.7 • n=5 Participants
Sex: Female, Male Female	35 Participants n=5 Participants	30 Participants n=7 Participants	65 Participants n=5 Participants
Sex: Female, Male Male	128 Participants n=5 Participants	128 Participants n=7 Participants	256 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	15 Participants n=5 Participants	13 Participants n=7 Participants	28 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	145 Participants n=5 Participants	142 Participants n=7 Participants	287 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants	5 Participants n=7 Participants	8 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	9 Participants n=5 Participants	6 Participants n=7 Participants	15 Participants n=5 Participants
Race (NIH/OMB) White	143 Participants n=5 Participants	140 Participants n=7 Participants	283 Participants n=5 Participants
Race (NIH/OMB) More than one race	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	5 Participants n=5 Participants	4 Participants n=7 Participants	9 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 24

Population: ITT Population

Vineland™-II Adaptive Behavior Scales 2-Domain Composite (2DC) Score is defined as mean of the Communication domain standard score \& Socialization domain standard score. If any of the 2 individual domain standard scores is missing 2DC score is not computed. Vineland™-II is an instrument that measures communication, daily living skills, socialization, motor skills and maladaptive behavior of individuals with developmental disabilities. Survey Interview Form will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning.

Outcome measures

Outcome measures
Measure	Balovaptan n=111 Participants Participants received 10 mg of oral administration balovaptan once a day (QD).	Placebo n=99 Participants Participants received matching placebo.	Balovaptan OLE Participants received 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period	Placebo OLE Participants received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period
Change From Baseline at Week 24 on the Vineland Adaptive Behavior Scales (Vineland-II) Two-domain Composite (2DC) Score.	4.56 Score Standard Deviation 10.85	6.83 Score Standard Deviation 12.18	—	—

SECONDARY outcome

Timeframe: Week 12

Population: ITT Population

Vineland™-II Adaptive Behavior Scales 2-Domain Composite (2DC) Score is defined as mean of the Communication domain standard score \& Socialization domain standard score. If any of the 2 individual domain standard scores is missing 2DC score is not computed. Vineland™-II is an instrument that measures communication, daily living skills, socialization, motor skills and maladaptive behavior of individuals with developmental disabilities. Survey Interview Form will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning.

Outcome measures

Outcome measures
Measure	Balovaptan n=150 Participants Participants received 10 mg of oral administration balovaptan once a day (QD).	Placebo n=140 Participants Participants received matching placebo.	Balovaptan OLE Participants received 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period	Placebo OLE Participants received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period
Change From Baseline at Week 12 on the Vineland-II 2DC Score	3.47 Score Standard Deviation 10.00	4.85 Score Standard Deviation 12.64	—	—

SECONDARY outcome

Timeframe: Weeks 12 and 24

Population: ITT Population

The Pediatric Quality of Life Inventory PedsQL™4.0 Generic Core Scale assessment consists of a 23 item questionnaire encompassing 4 core scale domains: Physical Functioning (8 items); Emotional Functioning (5 items); Social Functioning (5 items); and School Functioning (5 items). Items are scored on a 5 point Likert-type response scale (0=never a problem; 1=almost never a problem; 2=sometimes a problem; 3=often a problem; and 4=almost always a problem). Once scored, items will be reverse scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better health-related quality of life.

Outcome measures

Outcome measures
Measure	Balovaptan n=163 Participants Participants received 10 mg of oral administration balovaptan once a day (QD).	Placebo n=158 Participants Participants received matching placebo.	Balovaptan OLE Participants received 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period	Placebo OLE Participants received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period
Change From Baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on Summary and Total Scores Total Score at Week 24	8.0 Score Standard Deviation 13.7	6.0 Score Standard Deviation 11.6	—	—
Change From Baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on Summary and Total Scores Total Score at Week 12	4.1 Score Standard Deviation 11.2	5.0 Score Standard Deviation 10.2	—	—
Change From Baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on Summary and Total Scores Psychosocial Health Summary Score at Week 12	4.9 Score Standard Deviation 13.2	5.5 Score Standard Deviation 12.7	—	—
Change From Baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on Summary and Total Scores Physical Health Summary Score at Week 12	2.5 Score Standard Deviation 13.3	4.3 Score Standard Deviation 12.3	—	—
Change From Baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on Summary and Total Scores Psychosocial Health Summary Score at Week 24	10.0 Score Standard Deviation 15.4	6.9 Score Standard Deviation 14.1	—	—
Change From Baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on Summary and Total Scores Physical Health Summary Score at Week 24	4.3 Score Standard Deviation 15.5	4.4 Score Standard Deviation 14.5	—	—

SECONDARY outcome

Timeframe: Weeks 12 and 24

Population: ITT Population

The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. Only descriptive statistics presented instead of the planned estimated due to the early discontinuation of the study due to futility.

Outcome measures

Outcome measures
Measure	Balovaptan n=163 Participants Participants received 10 mg of oral administration balovaptan once a day (QD).	Placebo n=157 Participants Participants received matching placebo.	Balovaptan OLE Participants received 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period	Placebo OLE Participants received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period
Change From Baseline at Weeks 12 and 24 in the Vineland-II Adaptive Behavior Composite Standard Score Week 12	2.87 Score Standard Deviation 6.99	3.99 Score Standard Deviation 10.01	—	—
Change From Baseline at Weeks 12 and 24 in the Vineland-II Adaptive Behavior Composite Standard Score Week 24	4.32 Score Standard Deviation 8.43	5.26 Score Standard Deviation 9.69	—	—

SECONDARY outcome

Timeframe: Baseline, Weeks 12 and 24

Population: ITT Population

The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. Only descriptive statistics presented instead of the planned estimand due to the early discontinuation of the study due to futility.

Outcome measures

Outcome measures
Measure	Balovaptan n=163 Participants Participants received 10 mg of oral administration balovaptan once a day (QD).	Placebo n=158 Participants Participants received matching placebo.	Balovaptan OLE Participants received 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period	Placebo OLE Participants received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period
Change From Baseline at Week 12 and 24 on the Vineland-II Socialization Domain Standard Score 12 Week	3.63 Score Standard Deviation 11.58	5.26 Score Standard Deviation 12.71	—	—
Change From Baseline at Week 12 and 24 on the Vineland-II Socialization Domain Standard Score 24 Week	5.54 Score Standard Deviation 13.54	6.86 Score Standard Deviation 11.75	—	—

SECONDARY outcome

Timeframe: Weeks 12 and 24

Population: ITT Population

The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning.

Outcome measures

Outcome measures
Measure	Balovaptan n=163 Participants Participants received 10 mg of oral administration balovaptan once a day (QD).	Placebo n=158 Participants Participants received matching placebo.	Balovaptan OLE Participants received 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period	Placebo OLE Participants received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period
Change From Baseline at Weeks 12 and 24 on the Vineland-II Communication Domain Standard Score Week 12	3.30 Score Standard Deviation 13.74	4.44 Score Standard Deviation 16.58	—	—
Change From Baseline at Weeks 12 and 24 on the Vineland-II Communication Domain Standard Score Week 24	3.59 Score Standard Deviation 16.30	6.81 Score Standard Deviation 17.50	—	—

SECONDARY outcome

Timeframe: Weeks 12 and 24

Population: ITT Population

The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. Only descriptive statistics presented instead of the planned estimated due to the early discontinuation of the study due to futility.

Outcome measures

Outcome measures
Measure	Balovaptan n=163 Participants Participants received 10 mg of oral administration balovaptan once a day (QD).	Placebo n=158 Participants Participants received matching placebo.	Balovaptan OLE Participants received 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period	Placebo OLE Participants received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period
Change From Baseline at Weeks 12 and 24 on the Vineland-II Daily Living Skills Domain Standard Score Week 12	2.93 Score Standard Deviation 8.44	2.74 Score Standard Deviation 9.20	—	—
Change From Baseline at Weeks 12 and 24 on the Vineland-II Daily Living Skills Domain Standard Score Week 24	5.14 Score Standard Deviation 9.34	3.02 Score Standard Deviation 9.04	—	—

SECONDARY outcome

Timeframe: Weeks 12 and 24

Population: ITT Population

The CGI-S reflects the rater's impression of the subject's current autism severity on a 7-point scale ranging from no symptoms (1) to very severe symptoms (7). Changes in CGI-S score were calculated as increase or decrease in absolute CGI-S scores between Baseline and Weeks 12 and 24. Percentage of participants reported for each change in score from baseline.

Outcome measures

Outcome measures
Measure	Balovaptan n=147 Participants Participants received 10 mg of oral administration balovaptan once a day (QD).	Placebo n=136 Participants Participants received matching placebo.	Balovaptan OLE Participants received 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period	Placebo OLE Participants received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period
Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) Week 12 +2	0.7 Percentage of Participants	0 Percentage of Participants	—	—
Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) Week 12 +3	0 Percentage of Participants	0 Percentage of Participants	—	—
Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) Week 24 -1	27.5 Percentage of Participants	20.0 Percentage of Participants	—	—
Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) Week 24 +1	0.9 Percentage of Participants	1.0 Percentage of Participants	—	—
Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) Week 24 -2	5.5 Percentage of Participants	10.0 Percentage of Participants	—	—
Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) Week 12 -3	0 Percentage of Participants	0 Percentage of Participants	—	—
Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) Week 12 -2	2.0 Percentage of Participants	2.2 Percentage of Participants	—	—
Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) Week 24 0	66.1 Percentage of Participants	68.0 Percentage of Participants	—	—
Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) Week 24 +2	0 Percentage of Participants	0 Percentage of Participants	—	—
Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) Week 24 +3	0 Percentage of Participants	0 Percentage of Participants	—	—
Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) Week 12 -1	21.8 Percentage of Participants	25.0 Percentage of Participants	—	—
Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) Week 12 0	74.8 Percentage of Participants	72.1 Percentage of Participants	—	—
Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) Week 12 +1	0.7 Percentage of Participants	0.7 Percentage of Participants	—	—
Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) Week 24 -3	0 Percentage of Participants	1.0 Percentage of Participants	—	—

SECONDARY outcome

Timeframe: Weeks 12 and 24

Population: ITT Population

This is a 7-point Likert scale that assesses improvement of the patient's condition. Scores range from the worst score of 7 (Very much worse) to the best score of 1 (Very much improved). Lower scores are better on this scale, and indicate greater improvement. Percentage of participants reported for each score.

Outcome measures

Outcome measures
Measure	Balovaptan n=148 Participants Participants received 10 mg of oral administration balovaptan once a day (QD).	Placebo n=136 Participants Participants received matching placebo.	Balovaptan OLE Participants received 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period	Placebo OLE Participants received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period
Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) Week 24 2	15.6 Percentage of Participants	24.0 Percentage of Participants	—	—
Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) Week 24 3	44.0 Percentage of Participants	40.0 Percentage of Participants	—	—
Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) Week 12 1	0 Percentage of Participants	0 Percentage of Participants	—	—
Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) Week 12 2	10.1 Percentage of Participants	14.7 Percentage of Participants	—	—
Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) Week 12 3	36.5 Percentage of Participants	43.4 Percentage of Participants	—	—
Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) Week 12 4	50.0 Percentage of Participants	41.2 Percentage of Participants	—	—
Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) Week 12 5	3.4 Percentage of Participants	0.7 Percentage of Participants	—	—
Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) Week 12 6	0 Percentage of Participants	0 Percentage of Participants	—	—
Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) Week 12 7	0 Percentage of Participants	0 Percentage of Participants	—	—
Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) Week 24 1	0 Percentage of Participants	2.0 Percentage of Participants	—	—
Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) Week 24 4	38.5 Percentage of Participants	33.0 Percentage of Participants	—	—
Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) Week 24 5	0.9 Percentage of Participants	1.0 Percentage of Participants	—	—
Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) Week 24 6	0.9 Percentage of Participants	0 Percentage of Participants	—	—
Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) Week 24 7	0 Percentage of Participants	0 Percentage of Participants	—	—

SECONDARY outcome

Timeframe: Weeks 12 and 24

Population: ITT Population

The HAM-A is a 14-item, rater administered interview, assessing the severity of anxiety symptoms during the past 7 days. Seven items assess psychic anxiety and seven assess somatic anxiety. Each item utilizes a 5-point symptom severity response scale, ranging from none (0) to very severe (4). A total score is calculated that ranges from 0 to 56; higher scores are indicative of more severe anxiety.

Outcome measures

Outcome measures
Measure	Balovaptan n=163 Participants Participants received 10 mg of oral administration balovaptan once a day (QD).	Placebo n=158 Participants Participants received matching placebo.	Balovaptan OLE Participants received 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period	Placebo OLE Participants received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period
Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores Week 12 Total	-1.7 Score Standard Deviation 4.9	-2.8 Score Standard Deviation 4.4	—	—
Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores Week 12 Psychic Anxiety Subscale	-1.3 Score Standard Deviation 3.5	-1.8 Score Standard Deviation 3.2	—	—
Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores Week 12 Somatic Anxiety Subscale	-0.4 Score Standard Deviation 2.4	-1.0 Score Standard Deviation 2.5	—	—
Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores Week 24 Total	-2.7 Score Standard Deviation 4.5	-2.8 Score Standard Deviation 5.7	—	—
Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores Week 24 Psychic Anxiety Subscale	-2.1 Score Standard Deviation 3.4	-1.8 Score Standard Deviation 3.9	—	—
Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores Week 24 Somatic Anxiety Subscale	-0.6 Score Standard Deviation 2.2	-0.1 Score Standard Deviation 2.9	—	—

SECONDARY outcome

Timeframe: Weeks 12 and 24

Population: ITT Population

The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning All participants who have an improvement of at least 6 points are included in the \>=6 score threshold

Outcome measures

Outcome measures
Measure	Balovaptan n=128 Participants Participants received 10 mg of oral administration balovaptan once a day (QD).	Placebo n=114 Participants Participants received matching placebo.	Balovaptan OLE Participants received 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period	Placebo OLE Participants received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period
Proportion of Subjects With a >=6-point Improvement in Vineland-II 2DC Score Week 12 >=6	34.4 Percentage of Participants	42.1 Percentage of Participants	—	—
Proportion of Subjects With a >=6-point Improvement in Vineland-II 2DC Score Week 24 >=6	43 Percentage of Participants	48.4 Percentage of Participants	—	—

SECONDARY outcome

Timeframe: Week 24 and Up to Approximately 2 Years

Population: Safety Population

According to the ICH guideline for Good Clinical Practice, an adverse event is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The Blinded Treatment Period continued for 24 weeks, Open Label Extension (OLE) Treatment Period continued up to 2 years. The study was pre-maturely terminated, therefore did not reach the planned end date.

Outcome measures

Outcome measures
Measure	Balovaptan n=163 Participants Participants received 10 mg of oral administration balovaptan once a day (QD).	Placebo n=158 Participants Participants received matching placebo.	Balovaptan OLE n=100 Participants Participants received 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period	Placebo OLE n=97 Participants Participants received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period
Percentage of Participants With Adverse Events	60.1 Percentage of Participants	65.8 Percentage of Participants	59.0 Percentage of Participants	55.7 Percentage of Participants

Adverse Events

Balovaptan in Blinded Treatment Period

Serious events: 2 serious events

Other events: 49 other events

Deaths: 0 deaths

Placebo Blinded Treatment Period

Serious events: 5 serious events

Other events: 59 other events

Deaths: 1 deaths

Balovaptan in Open Label Extension Treatment Period

Serious events: 0 serious events

Other events: 28 other events

Deaths: 0 deaths

Placebo in Open Label Extension Treatment Period

Serious events: 2 serious events

Other events: 30 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Balovaptan in Blinded Treatment Period n=163 participants at risk Participants received 10 mg of oral administration balovaptan once a day (QD).	Placebo Blinded Treatment Period n=158 participants at risk Participants received matching placebo.	Balovaptan in Open Label Extension Treatment Period n=100 participants at risk Participants received 10 mg of oral administration balovaptan once a day (QD).	Placebo in Open Label Extension Treatment Period n=97 participants at risk Participants received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period
Psychiatric disorders Panic disorder	0.00% 0/163 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.63% 1/158 • Number of events 1 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/100 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/97 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.
Gastrointestinal disorders Colitis	0.00% 0/163 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.63% 1/158 • Number of events 1 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/100 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/97 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.
Infections and infestations Abscess limb	0.00% 0/163 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.63% 1/158 • Number of events 1 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/100 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/97 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.
Infections and infestations Urosepsis	0.00% 0/163 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.63% 1/158 • Number of events 1 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/100 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/97 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.
Psychiatric disorders Completed suicide	0.00% 0/163 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.63% 1/158 • Number of events 1 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/100 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/97 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.
Psychiatric disorders Schizoaffective disorder	0.61% 1/163 • Number of events 2 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/158 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/100 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/97 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.
Psychiatric disorders Suicidal ideation	0.61% 1/163 • Number of events 1 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.63% 1/158 • Number of events 1 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/100 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/97 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.
Infections and infestations Urinary tract infection	0.00% 0/163 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/158 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/100 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	1.0% 1/97 • Number of events 1 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.
Infections and infestations Pharyngitis streptococcal	0.00% 0/163 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/158 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/100 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	1.0% 1/97 • Number of events 1 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.
Infections and infestations Sepsis	0.00% 0/163 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/158 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/100 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	1.0% 1/97 • Number of events 1 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.
Injury, poisoning and procedural complications Femur fracture	0.00% 0/163 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/158 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/100 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	1.0% 1/97 • Number of events 1 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.

Other adverse events

Other adverse events
Measure	Balovaptan in Blinded Treatment Period n=163 participants at risk Participants received 10 mg of oral administration balovaptan once a day (QD).	Placebo Blinded Treatment Period n=158 participants at risk Participants received matching placebo.	Balovaptan in Open Label Extension Treatment Period n=100 participants at risk Participants received 10 mg of oral administration balovaptan once a day (QD).	Placebo in Open Label Extension Treatment Period n=97 participants at risk Participants received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period
Gastrointestinal disorders Diarrhoea	6.7% 11/163 • Number of events 15 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	8.9% 14/158 • Number of events 15 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	5.0% 5/100 • Number of events 5 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	4.1% 4/97 • Number of events 4 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.
Infections and infestations Nasopharyngitis	8.6% 14/163 • Number of events 14 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	12.0% 19/158 • Number of events 22 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	7.0% 7/100 • Number of events 10 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	4.1% 4/97 • Number of events 4 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.
Infections and infestations Upper respiratory tract infection	6.1% 10/163 • Number of events 13 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	5.7% 9/158 • Number of events 11 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	6.0% 6/100 • Number of events 7 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	7.2% 7/97 • Number of events 11 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.
Nervous system disorders Dizziness	1.2% 2/163 • Number of events 2 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	6.3% 10/158 • Number of events 10 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	2.0% 2/100 • Number of events 2 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	1.0% 1/97 • Number of events 1 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.
Nervous system disorders Headache	4.9% 8/163 • Number of events 13 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	4.4% 7/158 • Number of events 9 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	5.0% 5/100 • Number of events 5 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	10.3% 10/97 • Number of events 17 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.
Psychiatric disorders Anxiety	4.9% 8/163 • Number of events 11 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	4.4% 7/158 • Number of events 7 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	8.0% 8/100 • Number of events 8 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	3.1% 3/97 • Number of events 4 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.
Psychiatric disorders Insomnia	3.1% 5/163 • Number of events 5 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	5.1% 8/158 • Number of events 8 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	3.0% 3/100 • Number of events 3 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	3.1% 3/97 • Number of events 3 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	3.1% 5/163 • Number of events 5 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	5.1% 8/158 • Number of events 8 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/100 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	3.1% 3/97 • Number of events 3 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.
Gastrointestinal disorders Nausea	2.5% 4/163 • Number of events 4 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	4.4% 7/158 • Number of events 8 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	1.0% 1/100 • Number of events 1 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	5.2% 5/97 • Number of events 5 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.
Infections and infestations Gastroenteritis	1.2% 2/163 • Number of events 2 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	0.00% 0/158 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	1.0% 1/100 • Number of events 1 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.	5.2% 5/97 • Number of events 5 • From baseline to the end of Safety Period, up to 2 years The proportion of patients with at least one AE in the balovaptan and placebo treatment arms in the Blinded Treatment period and Open Label Extension (OLE)Treatment period. Other Adverse Events are reported at 5% frequency threshold. In the Open Label Extension (OLE) Treatment Period, the participants received active treatment, i.e. 10mg balovaptan QD. Placebo was only given during the blinded treatment period but not during OLE Treatment Period.

Additional Information

Reference Study ID Number: WN39434

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Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
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