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

• ClinicalTrials.gov Identifier: NCT02901431
• Recruitment Status: Terminated
• First Posted: September 15, 2016
• Results First Posted: February 8, 2021
• Last Update Posted: February 8, 2021
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: September 12, 2016
• First Posted Date: September 15, 2016
• Results First Submitted Date: December 7, 2020
• Results First Posted Date: February 8, 2021
• Last Update Posted Date: February 8, 2021
• Actual Study Start Date: November 21, 2016
• Actual Primary Completion Date: April 15, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 14, 2021)

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 [ Time Frame: Baseline, 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 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.

Original Primary Outcome Measures (submitted: September 12, 2016)

• Change From Baseline in Vineland-II Adaptive Behavior Scale Composite Standard Score at Week 24 [ Time Frame: Baseline, Week 24 ]
• Number of Participants With Adverse events [ Time Frame: Baseline to Week 30 ]

Current Secondary Outcome Measures (submitted: January 14, 2021)

• 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 [ Time Frame: 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 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.
• 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 [ Time Frame: 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 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.
• Proportion of Subjects With >=6 Points Improvement in the Vineland-II 2DC Score for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo [ Time Frame: Baseline, Weeks 12 and 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 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.
• 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 [ Time Frame: Baseline, 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.
• 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 [ Time Frame: Baseline, Weeks 12 and 24 ]
  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.
• Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo [ Time Frame: Weeks 12 and 24 ]
  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.
• Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo [ Time Frame: Weeks 12 and 24 ]
  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).
• 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 [ Time Frame: Baseline, 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). 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.
• 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 [ Time Frame: 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 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.
• Change From Baseline in Vineland-II Adaptive Behavior Scale 2DC Score at Week 12 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo [ Time Frame: Baseline, Week 12 ]
  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.
• Percentage of Participants With Adverse Events for Treatment With Balovaptan [ Time Frame: Baseline to Week 24 and up to Week 76 ]
  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.

Original Secondary Outcome Measures (submitted: September 12, 2016)

• Change From Baseline in Vineland-II Adaptive Behavior Scale Communication, Socialization, and Daily Living Skills Domain Standard Scores at Weeks 12 and 24 [ Time Frame: Baseline, Weeks 12 and 24 ]
• Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Score at Weeks 12 and 24 [ Time Frame: Baseline, Weeks 12 and 24 ]
• Change From Baseline in Ohio Autism Clinical Impressions Scale-Severity (OACIS-S) Score at Weeks 12 and 24 [ Time Frame: Baseline, Weeks 12 and 24 ]
• Change From Baseline in Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 [ Time Frame: Baseline, Weeks 12 and 24 ]
• Change From Baseline in Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 [ Time Frame: Baseline, Weeks 12 and 24 ]
• Change From Baseline in Aberrant Behavior Checklist (ABC) Lethargy/ Social Withdrawal Subscale Score at Weeks 12 and 24 [ Time Frame: Baseline, Weeks 12 and 24 ]
• Change From Baseline in Repetitive Behavior Scale-Revised (RBS-R) Score at Weeks 12 and 24 [ Time Frame: Baseline, Weeks 12 and 24 ]
• Change From Baseline in Vineland-II Adaptive Behavior Scale Composite Standard Score in Adolescents and Children Independently at Weeks 12 and 24 [ Time Frame: Baseline, Weeks 12 and 24 ]
• Change From Baseline in Vineland-II Adaptive Behavior Scale Composite Standard Score at Week 12 [ Time Frame: Baseline, Week 12 ]
• Apparent Clearance (CL) of RO5285119 [ Time Frame: 4 hours (hrs) postdose on Day 1; predose (0 hrs) at Weeks 1, 3 and on Day 10; predose (0 hrs), 2, 4, 6 hrs postdose at Week 2; end of treatment(up to Week 24); 8-10 hrs postdose in evening at Week 10; predose (0 hrs), 2, 4 hrs postdose at Weeks 12 and 24 ]
• Volume of Distribution (VD) of RO5285119 [ Time Frame: 4 hrs postdose on Day 1; predose (0 hrs) at Weeks 1, 3 and on Day 10; predose (0 hrs), 2, 4, 6 hrs postdose at Week 2; end of treatment visit (up to Week 24); 8-10 hrs postdose in evening at Week 10; predose (0 hrs), 2, 4 hrs postdose at Weeks 12 and 24 ]
• Area Under the Concentration-time Curve of RO5285119 in Plasma at Steady State Over 24 Hours (AUC0-24,ss) [ Time Frame: 4 hrs postdose on Day 1; predose (0 hrs) at Weeks 1, 3 and on Day 10; predose (0 hrs), 2, 4, 6 hrs postdose at Week 2; end of treatment visit (up to Week 24); 8-10 hrs postdose in evening at Week 10; predose (0 hrs), 2, 4 hrs postdose at Weeks 12 and 24 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

Brief Summary

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Autism Spectrum Disorder

Intervention

• Drug: Placebo
  Participants received a matching placebo orally. Approximate treatment duration was up to 24 weeks.
• Drug: RO5285119
  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).

Study Arms

• Placebo Comparator: Placebo
  Participants received a matching placebo orally. Approximate treatment duration was up to 24 weeks.
  Intervention: Drug: Placebo
• Experimental: Balovaptan (RO5285119) 10 mg/d equivalent
  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).
  Intervention: Drug: RO5285119
• Experimental: Balovaptan (RO5285119) 4 mg/d equivalent
  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.
  Intervention: Drug: RO5285119

• Publications *: Hollander E, Jacob S, Jou R, McNamara N, Sikich L, Tobe R, Smith J, Sanders K, Squassante L, Murtagh L, Gleissl T, Wandel C, Veenstra-VanderWeele J. Balovaptan vs Placebo for Social Communication in Childhood Autism Spectrum Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2022 Aug 1;79(8):760-769. doi: 10.1001/jamapsychiatry.2022.1717.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: January 14, 2021): 339
• Original Estimated Enrollment (submitted: September 12, 2016): 300
• Actual Study Completion Date: June 30, 2020
• Actual Primary Completion Date: April 15, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 5 Years to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02901431
• Other Study ID Numbers: BP30153
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: January 2021