A Study to Investigate the Efficacy and Safety of Balovaptan (RO5285119) in Participants With Autism Spectrum Disorder (ASD)

Study Overview
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Brief Summary
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For participants enrolled prior to Version 6 of the protocol: This was a Phase II multi-center, randomized, double-blind, 24-week, 3-arm, parallel group, placebo-controlled study to investigate the efficacy, safety, and pharmacokinetics of balovaptan in children and adolescents aged 5-17 years with ASD who are high functioning (intelligence quotient [IQ] greater than or equal to [>=] 70). For participants enrolled according to Version 6 of the protocol: This was a Phase II multi-center, randomized, double-blind, 24-week, parallel group, placebo-controlled, 2-arm study with participants assigned either to a 10 milligram (mg) or equivalent dose of balovaptan, or placebo. All other study parameters remained as stated above. There are three parts to this study: PK Part (Study part 1) included up to 8 weeks of treatment, Main Treatment Part (Study part 2) included 24 week of treatment, and the Open Label Extension Part (Study part 3) included Week 24 to Week 76 of treatment. All participants that completed the 24-week treatment period were eligible to participate in an optional 52-week open-label extension (OLE) during which they received balovaptan treatment.

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

Conditions
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Autism Spectrum Disorder

Intervention / Treatment
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* Drug: Placebo
* Drug: RO5285119


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Fluent in English Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for ASD or International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD10) criteria for Autism diagnosis confirmed by Autism Diagnostic Observational Schedule (ADOS-2) criteria Social Responsiveness Scale, second edition (SRS-2) (T-score) >= 66 Clinical Global Impressions of Severity (CGI-S) >= 4 (moderately ill) at screening IQ >= 70 as assessed by Wechsler Abbreviated Scale of Intelligence Scale: Second Edition (WASI-II) or Wechsler Preschool and Primary Scale of Intelligence: Fourth Edition (WPPSI-IV) intelligence test Language, hearing, and vision compatible with the study measurements as judged by the investigator Inclusion Criteria for the OLE: Have completed the blinded treatment phase of the study OR were required to stop dosing at or before Week 8 Have no adverse events that would prohibit starting the OLE Exclusion Criteria: Initiation of a major change in psychosocial intervention (including investigational) within 4 weeks prior to screening Unstable or uncontrolled clinically significant psychiatric and/or neurological disorder that may interfere with the safety or efficacy endpoints Known personal or family history of cerebral aneurysm Risk of suicidal behavior Seizure within the past 6 months Medical history of alcohol or substance abuse/dependence Concurrent cardio-vascular disease not considered well controlled by the Investigator Clinically significant abnormality on electrocardiogram at screening Concomitant disease or condition (pulmonary, gastro-intestinal, hepatic, renal, metabolic, immunological system, or obesity that could interfere with the conduct of the study Evidence for current gastro-intestinal bleeding, e.g., active stomach ulcer disease History of coagulopathies, bleeding disorders, or blood dyscrasias Positive serology for hepatitis B (HBV), hepatitis C (HCV), human immunodeficiency virus (HIV) 1, or HIV 2 Confirmed clinically significant abnormality in parameters of hematology, clinical chemistry, coagulation, or urinalysis Medical history of malignancy if not considered cured Participation in an investigational drug study within 90 days or 5 times the half-life of the investigational molecule (whichever is longer) prior to randomization Loss of blood over 250 milliliters within three months prior to screening Allowed medications have not been stable since 4 weeks before screening, and allowed medications for treatment of epilepsy have not been stable since 3 months before screening Use of prohibited medications within 2 weeks prior to screening visit or 5 times the half-life prior to randomization (whichever is longer)

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received a matching placebo orally. Approximate treatment duration was up to 24 weeks. | Drug: Placebo<br>* Participants received a matching placebo orally. Approximate treatment duration was up to 24 weeks.<br>|
| Experimental: Balovaptan (RO5285119) 10 mg/d equivalent<br>Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks (up to 52 additional weeks for those enrolled in the OLE). | Drug: RO5285119<br>* Participants received age-adjusted total daily oral dose approximately equivalent to the adult doses of either 4 mg/d or 10 mg/d of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks (up to 52 additional weeks for those enrolled in the OLE).<br>|
| Experimental: Balovaptan (RO5285119) 4 mg/d equivalent<br>Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 mg/d of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks. This arm is open only to those participants enrolled prior to Version 6 of the study protocol. | Drug: RO5285119<br>* Participants received age-adjusted total daily oral dose approximately equivalent to the adult doses of either 4 mg/d or 10 mg/d of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks (up to 52 additional weeks for those enrolled in the OLE).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Vineland™-II Adaptive Behavior Scale Two Domain Composite (2DC) Score at Week 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | Vineland™-II Adaptive Behavior Scales 2-Domain Composite (2DC) Score is defined as mean of the Communication domain standard score & Socialization domain standard score. If any of the 2 individual domain standard scores is missing 2DC score is not computed. Vineland™-II is an instrument that measures communication, daily living skills, socialization, motor skills and maladaptive behavior of individuals with developmental disabilities. Survey Interview Form will be administered to a subject's reliable caregiver in this study, during which the rater or clinician will ask to the caregiver open ended questions relating to the subject's activities and behavior. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. Mixed model with repeated measures (MMRM) was used for analysis with assessments at baseline, week 12 and week 24. | Baseline, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Vineland™-II Composite Standard Score After 12 Weeks and 24 Weeks of Treatment for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | The Vineland™-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable caregiver in this study, during which the rater or clinician will ask to the caregiver open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. | Baseline, Weeks 12 and 24 | 
| Change From Baseline in Vineland™-II Adaptive Behavior Scale Communication, Socialization, and Daily Living Skills Domain Standard Scores at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | The Vineland™-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable caregiver in this study, during which the rater or clinician will ask to the caregiver open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, and Daily Living Skills. Standardized scores on the domains range from 20-160 with higher scores indicating better functioning. Measure Type is Adjusted least-squares means. | Baseline, Weeks 12 and 24 | 
| Proportion of Subjects With >=6 Points Improvement in the Vineland-II 2DC Score for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | Vineland™-II Adaptive Behavior Scales 2-Domain Composite (2DC) Score is defined as mean of the Communication domain standard score & Socialization domain standard score. If any of the 2 individual domain standard scores is missing 2DC score is not computed. Vineland™-II is an instrument that measures communication, daily living skills, socialization, motor skills and maladaptive behavior of individuals with developmental disabilities. Survey Interview Form will be administered to a subject's reliable caregiver in this study, during which the rater or clinician will ask to the caregiver open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills and used to calculate the Vineland™-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. | Baseline, Weeks 12 and 24 | 
| Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 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. | Baseline, Weeks 12 and 24 | 
| Change From Baseline in Ohio Autism Clinical Impressions Scale-Severity (OACIS-S) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | The OACIS-S is a 10-item, clinician-completed measures based upon interview and/or observation. The OACIS-S assess severity and improvement, respectively, in social interaction, aberrant behavior, repetitive or ritualistic behavior, verbal communication, nonverbal communication skills, hyperactivity and inattention, anxiety and fearfulness, sensory sensitivities, restricted and narrow interests, and a global rating of autism. Each item of the OACIS-S is rated on a 7-point scale ranging from no symptoms (1) to very severe symptoms (7). Changes in CGI-S score were calculated as increase or decrease in absolute CGI-S scores between Baseline and Weeks 12 and 24. | Baseline, Weeks 12 and 24 | 
| Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | The CGI rating scales are tools used to evaluate both the severity of illness and change from baseline. The CGI-I is used to assess the clinical change as compared to symptoms at baseline using a 7-point scale, ranging from very much improved (1) to very much worse (7). For this study modified versions will be used. | Weeks 12 and 24 | 
| Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | The OACIS-I is a 10-item, clinician-completed measures based upon interview and/or observation. The OACIS-I assess severity and improvement, respectively, in social interaction, aberrant behavior, repetitive or ritualistic behavior, verbal communication, nonverbal communication skills, hyperactivity and inattention, anxiety and fearfulness, sensory sensitivities, restricted and narrow interests, and a global rating of autism. The OACIS-I is used to assess the clinical change as compared to symptoms at baseline using a 7-point scale, ranging from very much improved (1) to very much worse (7). | Weeks 12 and 24 | 
| Change From Baseline in Patient-Reported Pediatric Quality of Life (PedsQL) v4.0 Generic Core Scale After 12 Weeks and 24 Weeks of Treatment for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | The Pediatric Quality of Life Inventory PedsQL™4.0 Generic Core Scale assessment consists of a 23 item questionnaire encompassing 4 core scale domains: Physical Functioning (8 items); Emotional Functioning (5 items); Social Functioning (5 items); and School Functioning (5 items). For children aged 8 years and above, the PedsQL items are scored on a 5 point Likert-type response scale (0=never a problem; 1=almost never a problem; 2=sometimes a problem; 3=often a problem; and 4=almost always a problem). For children aged 5-7 years, scoring is based on a three-point scale (0=Not at all, 2=Sometimes, 4=A lot). Once scored, items will be reverse scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better health-related quality of life. | Baseline, Weeks 12 and 24 | 
| Change From Baseline in Vineland-II Composite Standard Score in Adolescents and Children Independently at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable caregiver in this study, during which the rater or clinician will ask to the caregiver open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. | Baseline, Weeks 12 and 24 | 
| Change From Baseline in Vineland-II Adaptive Behavior Scale 2DC Score at Week 12 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable caregiver in this study, during which the rater or clinician will ask to the caregiver open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. Mixed model with repeated measures (MMRM) was used for analysis. | Baseline, Week 12 | 
| Percentage of Participants With Adverse Events for Treatment With Balovaptan | PK review revealed that age-adjusted doses of 4 and 10 mg in 5-17 year olds were not equivalent to target exposure. For the Main Study Part, data was summarised by exposure ranges (tertiles) based on individual participants PK exposure at Week 12, estimated as the average plasma concentration since treatment start. To allow clear analysis by exposure tertiles, participants with dose adjustment were excluded from analysis by tertiles. | Baseline to Week 24 and up to Week 76 |