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

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03504917
• Collaborator: (none)
• Enrollment: 322
• Locations: 51
• Arms: 2
• Actual Duration (Months): 22.8
• Patients Per Site: 6.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study will evaluate the efficacy, safety, and pharmacokinetics of 10 mg of oral administration balovaptan once a day (QD) compared with matching placebo in adults (18 years and older) with autism spectrum disorder (ASD).

Condition or Disease	Intervention/Treatment	Phase
Autism Spectrum Disorder	Drug: Balovaptan; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 322 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomized, Double-Blind, Placebo-Controlled, Efficacy, and Safety Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
• Actual Study Start Date: Aug 8, 2018
• Actual Primary Completion Date: Mar 4, 2020
• Actual Study Completion Date: Jul 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Balovaptan	Drug: Balovaptan; Participants will receive 10 mg of oral administration balovaptan once a day (QD).
Placebo Comparator: Placebo	Drug: Placebo; Participants will receive matching placebo.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline at Week 24 on the Vineland Adaptive Behavior Scales (Vineland-II) Two-domain Composite (2DC) Score. [Week 24]

   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.

Secondary Outcome Measures

1. Change From Baseline at Week 12 on the Vineland-II 2DC Score [Week 12]

   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.

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 [Weeks 12 and 24]

   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.

3. Change From Baseline at Weeks 12 and 24 in the Vineland-II Adaptive Behavior Composite Standard Score [Weeks 12 and 24]

   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.

4. Change From Baseline at Week 12 and 24 on the Vineland-II Socialization Domain Standard Score [Baseline, Weeks 12 and 24]

   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.

5. Change From Baseline at Weeks 12 and 24 on the Vineland-II Communication Domain Standard Score [Weeks 12 and 24]

   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.

6. Change From Baseline at Weeks 12 and 24 on the Vineland-II Daily Living Skills Domain Standard Score [Weeks 12 and 24]

   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.

7. Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) [Weeks 12 and 24]

   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.

8. Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) [Weeks 12 and 24]

   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.

9. Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores [Weeks 12 and 24]

   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.

10. Proportion of Subjects With a >=6-point Improvement in Vineland-II 2DC Score [Weeks 12 and 24]

    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

11. Percentage of Participants With Adverse Events [Week 24 and Up to Approximately 2 Years]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subject meets the DSM-5 criteria for ASD for an autism diagnosis and is confirmed using ADOS-2 criteria

• SRS-2, proxy version, total t-score >=66 at screening

• A full scale IQ score >=70 on the WASI®-II

• Subject has an appropriate study partner, in the opinion of the investigator

• For women of childbearing potential: agreement to remain abstinent or use a contraceptive method with a failure rate of <1% per year during the treatment period and for at least 28 days after the last dose of study drug

• Treatment with permitted medications (at a stable dose for 12 weeks before screening) and behavioral therapy regimens (regimens stable for 6 weeks before screening), with the intent that such treatments remain stable throughout the study and with no expected changes before the Week 24 visit

Exclusion Criteria:

• Pregnancy or breastfeeding, or intention to become pregnant during the study

• Previous initiation of new or major change in psychosocial intervention within 6 weeks prior to screening

• Unstable or uncontrolled clinically significant affective or psychotic disorders and/or neurologic disorder that may interfere with the assessment of safety or efficacy endpoints

• Substance use disorders during the last 12 months

• Significant risk for suicidal behavior, in the opinion of the investigator

• Epilepsy or seizure disorder considered not well controlled within the past 6 months or changes in anticonvulsive therapy within the last 6 months

• Clinical diagnosis of peripheral neuropathy

• Within the last 2 years, unstable or clinically significant cardiovascular disease

• Uncontrolled hypertension

• Unexplained syncopal episode within the last 12 months

• Confirmed elevation above upper limit of normal of CK-MB, high sensitivity cardiac troponin T, cardiac troponin I, and/or N-terminal pro B-type natriuretic peptide

• Positive serology results for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV) 1 or 2

• History of coagulopathies, bleeding disorders, blood dyscrasias, hematological malignancies, myelosuppression (including iatrogenic), or current major bleeding event

• Concomitant disease or condition that could interfere with, or treatment of which might interfere with, the conduct of the study, or what would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study

• Confirmed clinically significant abnormality in parameters of hematology

• Confirmed clinically significant abnormality in parameters of clinical chemistry, coagulation, or urinalysis

• Medical history of malignancy, if not considered cured

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Harmonex Neuroscience Research	Dothan	Alabama	United States	36303
2	Southwest Autism Research & Resource Center	Phoenix	Arizona	United States	85006
3	Woodland Research Northwest, LLC	Rogers	Arkansas	United States	72758
4	University of California , Los Angeles (UCLA); Child, Adolescent Psychiatry	Los Angeles	California	United States	90095
5	PCSD Feighner Research	San Diego	California	United States	92108
6	University of California at San Francisco	San Francisco	California	United States	94115
7	MCB Clinical Research Centers	Colorado Springs	Colorado	United States	80910
8	Yale University / Yale-New Haven Hospital	New Haven	Connecticut	United States	06519-1124
9	Sarkis Clinical Trials	Gainesville	Florida	United States	32607
10	APG- Advanced Psychiatric Group	Orlando	Florida	United States	32803
11	IMIC Inc.	Palmetto Bay	Florida	United States	33157
12	Rush University Medical Center	Chicago	Illinois	United States	60612
13	Uni of Chicago; Centre For Advanced Medicine	Chicago	Illinois	United States	60637
14	Lake Charles Clinical Trials, LLC	Lake Charles	Louisiana	United States	70601
15	The Johns Hopkins Hospital	Baltimore	Maryland	United States	21287
16	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
17	University of Minnesota Medical Center-Fairview	Minneapolis	Minnesota	United States	55414
18	Millennium Psychiatric Associates, LLC	Saint Louis	Missouri	United States	63132
19	Hapworth Research Inc.	New York	New York	United States	10019
20	Center for Autism and the Developing Brain	New York	New York	United States	10032
21	Nathan S. Kline Institute for Psychiatric Research	Orangeburg	New York	United States	10962
22	Richmond Behavioral Associates	Staten Island	New York	United States	10312
23	University Hospitals	Cleveland	Ohio	United States	44106
24	Ohio State University	Columbus	Ohio	United States	43210
25	Cutting Edge Research Group	Oklahoma City	Oklahoma	United States	73116
26	UPMC Western Psychiatric Institute and Clinic	Pittsburgh	Pennsylvania	United States	15203
27	Vanderbilt University Medical Center; Department of Psychiatry	Nashville	Tennessee	United States	37212
28	BioBehavioral Research of Austin, PC	Austin	Texas	United States	78759
29	Red Oak Psychiatry Associates, PA	Houston	Texas	United States	77090
30	Aspen Clinical Research	Orem	Utah	United States	84058
31	Northwest Clinical Research Center	Bellevue	Washington	United States	98007
32	Seattle Children's Hospital	Seattle	Washington	United States	98105
33	Okanagan Clinical Trials	Kelowna	British Columbia	Canada	V1Y 1Z9
34	Holland Bloorview Kids Rehabilitation Hospital; Autism Research Centre	East York	Ontario	Canada	M4G 1R8
35	University of Western Ontario	London	Ontario	Canada	N6A 4G5
36	McGill University Health Centre - Glen Site	Montreal	Quebec	Canada	H4A 3J1
37	Hopital Charles Perrens; Centre de Ressources Autisme Aquitaine	Bordeaux		France	33076
38	Hospices Civils de Lyon; Centre d'Investigation Clinique Pédiatrique	LYON Cedex		France	69003
39	Centre hospitalier du Rouvray; CRAHN Centre de Ressources Autisme Haute-Normandie	Sotteville Les Rouen		France	76300
40	ASST di Pavia; Dip. di Scienze del Sistema Nervoso e del Comportamento	Pavia	Lombardia	Italy	27100
41	AUSL di Piacenza; Psichiatria di Collegamento	Piacenza	Lombardia	Italy	29121
42	ASL TO2; Centro Pilota Regione Piemonte - Dip. Salute Mentale	Torino	Piemonte	Italy	10138
43	A.O.U. Policlinico - V. Emanuele - P.O. Gaspare Rodolico; Dip. Terapia integrata disturbi resistenti	Catania	Sicilia	Italy	95123
44	Hospital Mutua de Terrassa; Departamento de Psiquiatria	Terrassa	Barcelona	Spain	08221
45	Hospital Universitari Vall d'Hebron; Sevicio de Psiquiatría	Barcelona		Spain	08035
46	Hospital General Universitario Gregorio Marañon; Servicio de Psiquiatria del niño y del adolescente	Madrid		Spain	28009
47	Hospital Universitario Rio Hortega; Departamento de Psiquiatria	Valladolid		Spain	47012
48	Western General Hospital; Wellcome Trust CRF	Edinburgh		United Kingdom	EH4 2XU
49	Queen Elizabeth University Hospital; Clinical Research Facility	Glasgow		United Kingdom	G51 4TF
50	Kings College Hospital; Kings Clinical Research Facility	London		United Kingdom	SE5 9RS
51	RE:Cognition Health; RE:Cognition Health	London		United Kingdom	W1G 9JF

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 1, 2019

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT03504917
• Other Study ID Numbers: WN39434
• First Posted: Apr 20, 2018
• Last Update Posted: Oct 27, 2021
• Last Verified: Oct 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Autistic Disorder; Autism Spectrum Disorder; Child Development Disorders, Pervasive

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	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.

Arm/Group Title	Balovaptan	Placebo
Arm/Group Description	Participants received 10 mg of oral administration balovaptan once a day (QD).	Participants received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD) in OLE Treatment period
Period Title: Blinded Treatment Period
STARTED	163	158
COMPLETED	103	102
NOT COMPLETED	60	56
Period Title: Blinded Treatment Period
STARTED	100	97
COMPLETED	0	0
NOT COMPLETED	100	97

Baseline Characteristics

Arm/Group Title	Balovaptan	Placebo	Total
Arm/Group Description	Participants received 10 mg of oral administration balovaptan once a day (QD).	Participants received matching placebo.	Total of all reporting groups
Overall Participants	163	158	321
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	27.6 (9.7)	27.6 (9.8)	27.6 (9.7)
Sex: Female, Male (Count of Participants)
Female	35 21.5%	30 19%	65 20.2%
Male	128 78.5%	128 81%	256 79.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	15 9.2%	13 8.2%	28 8.7%
Not Hispanic or Latino	145 89%	142 89.9%	287 89.4%
Unknown or Not Reported	3 1.8%	3 1.9%	6 1.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	2 1.3%	2 0.6%
Asian	3 1.8%	5 3.2%	8 2.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	9 5.5%	6 3.8%	15 4.7%
White	143 87.7%	140 88.6%	283 88.2%
More than one race	3 1.8%	1 0.6%	4 1.2%
Unknown or Not Reported	5 3.1%	4 2.5%	9 2.8%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline at Week 24 on the Vineland Adaptive Behavior Scales (Vineland-II) Two-domain Composite (2DC) Score.
Description	Vineland™-II Adaptive Behavior Scales 2-Domain Composite (2DC) Score is defined as mean of the Communication domain standard score & Socialization domain standard score. If any of the 2 individual domain standard scores is missing 2DC score is not computed. Vineland™-II is an instrument that measures communication, daily living skills, socialization, motor skills and maladaptive behavior of individuals with developmental disabilities. Survey Interview Form will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Balovaptan	Placebo
Arm/Group Description	Participants received 10 mg of oral administration balovaptan once a day (QD).	Participants received matching placebo.
Measure Participants	111	99
Mean (Standard Deviation) [Score]	4.56 (10.85)	6.83 (12.18)

2. Secondary Outcome

Title	Change From Baseline at Week 12 on the Vineland-II 2DC Score
Description	Vineland™-II Adaptive Behavior Scales 2-Domain Composite (2DC) Score is defined as mean of the Communication domain standard score & Socialization domain standard score. If any of the 2 individual domain standard scores is missing 2DC score is not computed. Vineland™-II is an instrument that measures communication, daily living skills, socialization, motor skills and maladaptive behavior of individuals with developmental disabilities. Survey Interview Form will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Balovaptan	Placebo
Arm/Group Description	Participants received 10 mg of oral administration balovaptan once a day (QD).	Participants received matching placebo.
Measure Participants	150	140
Mean (Standard Deviation) [Score]	3.47 (10.00)	4.85 (12.64)

3. Secondary Outcome

Title	Change From Baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on Summary and Total Scores
Description	The Pediatric Quality of Life Inventory PedsQL™4.0 Generic Core Scale assessment consists of a 23 item questionnaire encompassing 4 core scale domains: Physical Functioning (8 items); Emotional Functioning (5 items); Social Functioning (5 items); and School Functioning (5 items). Items are scored on a 5 point Likert-type response scale (0=never a problem; 1=almost never a problem; 2=sometimes a problem; 3=often a problem; and 4=almost always a problem). Once scored, items will be reverse scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better health-related quality of life.
Time Frame	Weeks 12 and 24

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Balovaptan	Placebo
Arm/Group Description	Participants received 10 mg of oral administration balovaptan once a day (QD).	Participants received matching placebo.
Measure Participants	163	158
Total Score at Week 12	4.1 (11.2)	5.0 (10.2)
Psychosocial Health Summary Score at Week 12	4.9 (13.2)	5.5 (12.7)
Physical Health Summary Score at Week 12	2.5 (13.3)	4.3 (12.3)
Total Score at Week 24	8.0 (13.7)	6.0 (11.6)
Psychosocial Health Summary Score at Week 24	10.0 (15.4)	6.9 (14.1)
Physical Health Summary Score at Week 24	4.3 (15.5)	4.4 (14.5)

4. Secondary Outcome

Title	Change From Baseline at Weeks 12 and 24 in the Vineland-II Adaptive Behavior Composite Standard Score
Description	The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. Only descriptive statistics presented instead of the planned estimated due to the early discontinuation of the study due to futility.
Time Frame	Weeks 12 and 24

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Balovaptan	Placebo
Arm/Group Description	Participants received 10 mg of oral administration balovaptan once a day (QD).	Participants received matching placebo.
Measure Participants	163	157
Week 12	2.87 (6.99)	3.99 (10.01)
Week 24	4.32 (8.43)	5.26 (9.69)

5. Secondary Outcome

Title	Change From Baseline at Week 12 and 24 on the Vineland-II Socialization Domain Standard Score
Description	The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. Only descriptive statistics presented instead of the planned estimand due to the early discontinuation of the study due to futility.
Time Frame	Baseline, Weeks 12 and 24

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Balovaptan	Placebo
Arm/Group Description	Participants received 10 mg of oral administration balovaptan once a day (QD).	Participants received matching placebo.
Measure Participants	163	158
12 Week	3.63 (11.58)	5.26 (12.71)
24 Week	5.54 (13.54)	6.86 (11.75)

6. Secondary Outcome

Title	Change From Baseline at Weeks 12 and 24 on the Vineland-II Communication Domain Standard Score
Description	The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning.
Time Frame	Weeks 12 and 24

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Balovaptan	Placebo
Arm/Group Description	Participants received 10 mg of oral administration balovaptan once a day (QD).	Participants received matching placebo.
Measure Participants	163	158
Week 12	3.30 (13.74)	4.44 (16.58)
Week 24	3.59 (16.30)	6.81 (17.50)

7. Secondary Outcome

Title	Change From Baseline at Weeks 12 and 24 on the Vineland-II Daily Living Skills Domain Standard Score
Description	The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. Only descriptive statistics presented instead of the planned estimated due to the early discontinuation of the study due to futility.
Time Frame	Weeks 12 and 24

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Balovaptan	Placebo
Arm/Group Description	Participants received 10 mg of oral administration balovaptan once a day (QD).	Participants received matching placebo.
Measure Participants	163	158
Week 12	2.93 (8.44)	2.74 (9.20)
Week 24	5.14 (9.34)	3.02 (9.04)

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Balovaptan	Placebo
Arm/Group Description	Participants received 10 mg of oral administration balovaptan once a day (QD).	Participants received matching placebo.
Measure Participants	147	136
Week 12 -3	0 0%	0 0%
Week 12 -2	2.0 1.2%	2.2 1.4%
Week 12 -1	21.8 13.4%	25.0 15.8%
Week 12 0	74.8 45.9%	72.1 45.6%
Week 12 +1	0.7 0.4%	0.7 0.4%
Week 12 +2	0.7 0.4%	0 0%
Week 12 +3	0 0%	0 0%
Week 24 -3	0 0%	1.0 0.6%
Week 24 -2	5.5 3.4%	10.0 6.3%
Week 24 -1	27.5 16.9%	20.0 12.7%
Week 24 0	66.1 40.6%	68.0 43%
Week 24 +1	0.9 0.6%	1.0 0.6%
Week 24 +2	0 0%	0 0%
Week 24 +3	0 0%	0 0%

9. Secondary Outcome

Title	Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I)
Description	This is a 7-point Likert scale that assesses improvement of the patient's condition. Scores range from the worst score of 7 (Very much worse) to the best score of 1 (Very much improved). Lower scores are better on this scale, and indicate greater improvement. Percentage of participants reported for each score.
Time Frame	Weeks 12 and 24

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Balovaptan	Placebo
Arm/Group Description	Participants received 10 mg of oral administration balovaptan once a day (QD).	Participants received matching placebo.
Measure Participants	148	136
Week 12 1	0 0%	0 0%
Week 12 2	10.1 6.2%	14.7 9.3%
Week 12 3	36.5 22.4%	43.4 27.5%
Week 12 4	50.0 30.7%	41.2 26.1%
Week 12 5	3.4 2.1%	0.7 0.4%
Week 12 6	0 0%	0 0%
Week 12 7	0 0%	0 0%
Week 24 1	0 0%	2.0 1.3%
Week 24 2	15.6 9.6%	24.0 15.2%
Week 24 3	44.0 27%	40.0 25.3%
Week 24 4	38.5 23.6%	33.0 20.9%
Week 24 5	0.9 0.6%	1.0 0.6%
Week 24 6	0.9 0.6%	0 0%
Week 24 7	0 0%	0 0%

10. Secondary Outcome

Title	Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores
Description	The HAM-A is a 14-item, rater administered interview, assessing the severity of anxiety symptoms during the past 7 days. Seven items assess psychic anxiety and seven assess somatic anxiety. Each item utilizes a 5-point symptom severity response scale, ranging from none (0) to very severe (4). A total score is calculated that ranges from 0 to 56; higher scores are indicative of more severe anxiety.
Time Frame	Weeks 12 and 24

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Balovaptan	Placebo
Arm/Group Description	Participants received 10 mg of oral administration balovaptan once a day (QD).	Participants received matching placebo.
Measure Participants	163	158
Week 12 Total	-1.7 (4.9)	-2.8 (4.4)
Week 12 Psychic Anxiety Subscale	-1.3 (3.5)	-1.8 (3.2)
Week 12 Somatic Anxiety Subscale	-0.4 (2.4)	-1.0 (2.5)
Week 24 Total	-2.7 (4.5)	-2.8 (5.7)
Week 24 Psychic Anxiety Subscale	-2.1 (3.4)	-1.8 (3.9)
Week 24 Somatic Anxiety Subscale	-0.6 (2.2)	-0.1 (2.9)

11. Secondary Outcome

Title	Proportion of Subjects With a >=6-point Improvement in Vineland-II 2DC Score
Description	The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning All participants who have an improvement of at least 6 points are included in the >=6 score threshold
Time Frame	Weeks 12 and 24

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Balovaptan	Placebo
Arm/Group Description	Participants received 10 mg of oral administration balovaptan once a day (QD).	Participants received matching placebo.
Measure Participants	128	114
Week 12 >=6	34.4 21.1%	42.1 26.6%
Week 24 >=6	43 26.4%	48.4 30.6%

12. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Balovaptan Treatment	Placebo Treatment	Balovaptan OLE	Placebo OLE
Arm/Group Description	Participants received 10 mg of oral administration balovaptan once a day (QD). Blinded Treatment Period	Participants received matching placebo. Blinded Treatment Period	Participants received 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period	Participants received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period
Measure Participants	163	158	100	97
Number [Percentage of Participants]	60.1 36.9%	65.8 41.6%	59.0 18.4%	55.7 NaN

Adverse Events

Time Frame	From baseline to the end of Safety Period, up to 2 years
Adverse Event Reporting Description	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.
Arm/Group Title	Balovaptan in Blinded Treatment Period		Placebo Blinded Treatment Period		Balovaptan in Open Label Extension Treatment Period		Placebo in Open Label Extension Treatment Period
Arm/Group Description	Participants received 10 mg of oral administration balovaptan once a day (QD).		Participants received matching placebo.		Participants received 10 mg of oral administration balovaptan once a day (QD).		Participants received matching placebo in Blinded Treatment Period and 10 mg of oral administration balovaptan once a day (QD). OLE Treatment Period
All Cause Mortality
	Balovaptan in Blinded Treatment Period		Placebo Blinded Treatment Period		Balovaptan in Open Label Extension Treatment Period		Placebo in Open Label Extension Treatment Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/163 (0%)		1/158 (0.6%)		0/100 (0%)		0/97 (0%)
Serious Adverse Events
	Balovaptan in Blinded Treatment Period		Placebo Blinded Treatment Period		Balovaptan in Open Label Extension Treatment Period		Placebo in Open Label Extension Treatment Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/163 (1.2%)		5/158 (3.2%)		0/100 (0%)		2/97 (2.1%)
Gastrointestinal disorders
Colitis	0/163 (0%)	0	1/158 (0.6%)	1	0/100 (0%)	0	0/97 (0%)	0
Infections and infestations
Abscess limb	0/163 (0%)	0	1/158 (0.6%)	1	0/100 (0%)	0	0/97 (0%)	0
Urosepsis	0/163 (0%)	0	1/158 (0.6%)	1	0/100 (0%)	0	0/97 (0%)	0
Urinary tract infection	0/163 (0%)	0	0/158 (0%)	0	0/100 (0%)	0	1/97 (1%)	1
Pharyngitis streptococcal	0/163 (0%)	0	0/158 (0%)	0	0/100 (0%)	0	1/97 (1%)	1
Sepsis	0/163 (0%)	0	0/158 (0%)	0	0/100 (0%)	0	1/97 (1%)	1
Injury, poisoning and procedural complications
Femur fracture	0/163 (0%)	0	0/158 (0%)	0	0/100 (0%)	0	1/97 (1%)	1
Psychiatric disorders
Panic disorder	0/163 (0%)	0	1/158 (0.6%)	1	0/100 (0%)	0	0/97 (0%)	0
Completed suicide	0/163 (0%)	0	1/158 (0.6%)	1	0/100 (0%)	0	0/97 (0%)	0
Schizoaffective disorder	1/163 (0.6%)	2	0/158 (0%)	0	0/100 (0%)	0	0/97 (0%)	0
Suicidal ideation	1/163 (0.6%)	1	1/158 (0.6%)	1	0/100 (0%)	0	0/97 (0%)	0
Other (Not Including Serious) Adverse Events
	Balovaptan in Blinded Treatment Period		Placebo Blinded Treatment Period		Balovaptan in Open Label Extension Treatment Period		Placebo in Open Label Extension Treatment Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	49/163 (30.1%)		59/158 (37.3%)		28/100 (28%)		30/97 (30.9%)
Gastrointestinal disorders
Diarrhoea	11/163 (6.7%)	15	14/158 (8.9%)	15	5/100 (5%)	5	4/97 (4.1%)	4
Nausea	4/163 (2.5%)	4	7/158 (4.4%)	8	1/100 (1%)	1	5/97 (5.2%)	5
Infections and infestations
Nasopharyngitis	14/163 (8.6%)	14	19/158 (12%)	22	7/100 (7%)	10	4/97 (4.1%)	4
Upper respiratory tract infection	10/163 (6.1%)	13	9/158 (5.7%)	11	6/100 (6%)	7	7/97 (7.2%)	11
Gastroenteritis	2/163 (1.2%)	2	0/158 (0%)	0	1/100 (1%)	1	5/97 (5.2%)	5
Nervous system disorders
Dizziness	2/163 (1.2%)	2	10/158 (6.3%)	10	2/100 (2%)	2	1/97 (1%)	1
Headache	8/163 (4.9%)	13	7/158 (4.4%)	9	5/100 (5%)	5	10/97 (10.3%)	17
Psychiatric disorders
Anxiety	8/163 (4.9%)	11	7/158 (4.4%)	7	8/100 (8%)	8	3/97 (3.1%)	4
Insomnia	5/163 (3.1%)	5	8/158 (5.1%)	8	3/100 (3%)	3	3/97 (3.1%)	3
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	5/163 (3.1%)	5	8/158 (5.1%)	8	0/100 (0%)	0	3/97 (3.1%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.