Autism Spectrum Disorder
Conditions
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.
Interventions
DRUGPlacebo
Participants received a matching placebo orally. Approximate treatment duration was up to 24 weeks.
DRUGRO5285119
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).
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
5 Years to 17 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 | 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 | 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 | 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 | 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. |
| 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 | 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 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 | 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 | 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 | 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 | 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. |
| Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 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). |
Countries
United States
Participant flow
Recruitment details
A total of 339 participants were enrolled from 44 sites in the United States.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| PK Part (Study Part 1) - Placebo Participants received a matching placebo orally. Approximate treatment duration was up to 8 weeks. | 12 |
| PK Part (Study Part 1) - Balovaptan (RO5285119) 4 mg/d Equivalent Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 8 weeks. | 11 |
| PK Part (Study Part 1) - Balovaptan (RO5285119) 10 mg/d Equivalent Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 10 mg/d of balovaptan (RO5285119). Approximate treatment duration was up to 8 weeks. | 15 |
| Main Study Part (Study Part 2) - Placebo Participants in the Main Study Part received a matching placebo orally. Approximate treatment duration was up to 24 weeks. | 112 |
| Main Study Part (Study Part 2) - Low Exposure Tertile Participants in the Main Study Part in the Low Exposure Tertile received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks. | 57 |
| Main Study Part (Study Part 2) - Medium Exposure Tertile Participants in the Main Study Part in the Medium Exposure Tertile received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks. | 66 |
| Main Study Part (Study Part 2) - High Exposure Tertile Participants in the Main Study Part in the High Exposure Tertile received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks. | 66 |
| Main Study Part (Study Part 2) - Dose-Adjusters Participants with dose adjustment who were excluded from the analysis by tertiles. Participants received age-adjusted total daily oral dose approximately equivalent to the adult dose of 4 or 10 milligrams per day (mg/d) of balovaptan (RO5285119). Approximate treatment duration was up to 24 weeks in Main Study Part. | 7 |
| Total | 346 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Main Treatment Part | Adverse Event | 0 | 0 | 0 | 3 | 3 | 4 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Main Treatment Part | Lack of Efficacy | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Main Treatment Part | Lost to Follow-up | 0 | 0 | 0 | 3 | 1 | 2 | 3 | 0 | 0 | 0 | 0 | 0 | 0 |
| Main Treatment Part | Physician Decision | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Main Treatment Part | Withdrawal by Caregiver | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Main Treatment Part | Withdrawal by Subject | 0 | 0 | 0 | 18 | 3 | 5 | 6 | 0 | 0 | 0 | 0 | 0 | 0 |
| Open Label Part | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 4 | 0 | 4 | 1 |
| Open Label Part | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 2 | 1 | 1 | 1 |
| Open Label Part | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 |
| Open Label Part | Study Terminated By Sponsor | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 35 | 12 | 21 | 31 | 0 |
| Open Label Part | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 6 | 5 | 7 | 3 | 1 |
| PK Part | 8 weeks of treatment ran out | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| PK Part | Adverse Event | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| PK Part | Discontinued per Sponsor | 0 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| PK Part | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| PK Part | Pending dose confirmation | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| PK Part | Pending IMC/SOC Dose Confirmation | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| PK Part | Stopped on Sponsor instruction pending dose confirmation | 1 | 0 | 4 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| PK Part | Stopped treatment after 8 weeks | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| PK Part | Withdrawal by Subject | 1 | 1 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | PK Part (Study Part 1) - Placebo | PK Part (Study Part 1) - Balovaptan (RO5285119) 4 mg/d Equivalent | PK Part (Study Part 1) - Balovaptan (RO5285119) 10 mg/d Equivalent | Main Study Part (Study Part 2) - Placebo | Main Study Part (Study Part 2) - Low Exposure Tertile | Main Study Part (Study Part 2) - Medium Exposure Tertile | Main Study Part (Study Part 2) - High Exposure Tertile | Main Study Part (Study Part 2) - Dose-Adjusters |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 9.8 Years STANDARD_DEVIATION 3.5 | 8.9 Years STANDARD_DEVIATION 3.8 | 9.9 Years STANDARD_DEVIATION 3.3 | 10.4 Years STANDARD_DEVIATION 3.5 | 12.5 Years STANDARD_DEVIATION 3 | 13.3 Years STANDARD_DEVIATION 2.3 | 12.6 Years STANDARD_DEVIATION 3 | 11.8 Years STANDARD_DEVIATION 3.3 | 12.6 Years STANDARD_DEVIATION 2.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 38 Participants | 0 Participants | 0 Participants | 0 Participants | 17 Participants | 7 Participants | 8 Participants | 6 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants | 0 Participants | 10 Participants | 11 Participants | 0 Participants | 0 Participants | 0 Participants | 59 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 18 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants | 3 Participants | 7 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 1 Participants | 4 Participants | 5 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 21 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 30 Participants | 0 Participants | 9 Participants | 10 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 45 Participants | 0 Participants | 1 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 263 Participants | 9 Participants | 10 Participants | 11 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 11 | 0 / 15 | 0 / 112 | 0 / 57 | 0 / 66 | 0 / 66 | 0 / 7 | 0 / 68 | 0 / 35 | 0 / 40 | 0 / 46 | 0 / 5 |
| other Total, other adverse events | 7 / 12 | 7 / 11 | 7 / 15 | 58 / 112 | 34 / 57 | 31 / 66 | 34 / 66 | 5 / 7 | 35 / 68 | 21 / 35 | 25 / 40 | 27 / 46 | 3 / 5 |
| serious Total, serious adverse events | 0 / 12 | 1 / 11 | 0 / 15 | 4 / 112 | 1 / 57 | 0 / 66 | 1 / 66 | 0 / 7 | 2 / 68 | 0 / 35 | 0 / 40 | 2 / 46 | 0 / 5 |
Outcome results
Primary
Change From Baseline in Vineland™-II Adaptive Behavior Scale Two Domain Composite (2DC) Score at Week 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo
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.
Time frame: Baseline, Week 24
Population: Efficacy Inferential Population included participants that were divided by randomized treatment and included participants taking balovaptan 10 mg equivalent dose and participants from the concurrently randomized placebo group in the corresponding randomization stage. Participants with dose adjustments or interruptions, or who were on a different dose than the final dose for their age group, were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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 | 2.34 Score on a scale | Standard Error 1.15 |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | 2.17 Score on a scale | Standard Error 1.11 |
p-value: 0.91190% CI: [-2.56, 2.23]Mixed Models Analysis
Secondary
Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo
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.
Time frame: Baseline, Weeks 12 and 24
Population: Efficacy Inferential Population included participants that were divided by randomized treatment and included participants taking balovaptan 10 mg equivalent dose and participants from the concurrently randomized placebo group in the corresponding randomization stage. Participants with dose adjustments or interruptions, or who were on a different dose than the final dose for their age group, were excluded.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | 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 | -3 (Very much improved), Week 12 | 1.5 Percentage of participants |
| Placebo | 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 | -2 (Much improved), Week 12 | 1.5 Percentage of participants |
| Placebo | 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 | -1 (Minimally improved), Week 12 | 31.3 Percentage of participants |
| Placebo | 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 | 0 (No change), Week 12 | 65.7 Percentage of participants |
| Placebo | 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 | +1 (Minimally worse), Week 12 | 0 Percentage of participants |
| Placebo | 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 | +2 (Much worse), Week 12 | 0 Percentage of participants |
| Placebo | 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 | +3 (Very Much worse), Week 12 | 0 Percentage of participants |
| Placebo | 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 | -3 (Very much improved), Week 24 | 1.6 Percentage of participants |
| Placebo | 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 | -2 (Much improved), Week 24 | 6.5 Percentage of participants |
| Placebo | 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 | -1 (Minimally improved), Week 24 | 32.3 Percentage of participants |
| Placebo | 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 | 0 (No change), Week 24 | 59.7 Percentage of participants |
| Placebo | 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 | +1 (Minimally worse), Week 24 | 0 Percentage of participants |
| Placebo | 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 | +2 (Much worse), Week 24 | 0 Percentage of participants |
| Placebo | 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 | +3 (Very much worse), Week 24 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | 0 (No change), Week 24 | 63.8 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | -3 (Very much improved), Week 12 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | -3 (Very much improved), Week 24 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | -2 (Much improved), Week 12 | 2.7 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | +2 (Much worse), Week 24 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | -1 (Minimally improved), Week 12 | 31.1 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | -2 (Much improved), Week 24 | 4.3 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | 0 (No change), Week 12 | 63.5 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | +1 (Minimally worse), Week 24 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | +1 (Minimally worse), Week 12 | 2.7 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | -1 (Minimally improved), Week 24 | 31.9 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | +2 (Much worse), Week 12 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | +3 (Very much worse), Week 24 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | +3 (Very Much worse), Week 12 | 0 Percentage of participants |
Secondary
Change From Baseline in Ohio Autism Clinical Impressions Scale-Severity (OACIS-S) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo
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.
Time frame: Baseline, Weeks 12 and 24
Population: Efficacy Inferential Population included participants that were divided by randomized treatment and included participants taking balovaptan 10 mg equivalent dose and participants from the concurrently randomized placebo group in the corresponding randomization stage. Participants with dose adjustments or interruptions, or who were on a different dose than the final dose for their age group, were excluded.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | 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 | -3 (Very much improved), Week 12 | 3.0 Percentage of participants |
| Placebo | 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 | -2 (Much improved), Week 12 | 6.0 Percentage of participants |
| Placebo | 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 | -1 (Minimally improved), Week 12 | 28.4 Percentage of participants |
| Placebo | 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 | 0 (No change), Week 12 | 59.7 Percentage of participants |
| Placebo | 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 | +1 (Minimally worse), Week 12 | 3.0 Percentage of participants |
| Placebo | 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 | +2 (Much worse), Week 12 | 0 Percentage of participants |
| Placebo | 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 | +3 (Very much worse), Week 12 | 0 Percentage of participants |
| Placebo | 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 | -3 (Very much improved), Week 24 | 6.5 Percentage of participants |
| Placebo | 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 | -2 (Much improved), Week 24 | 8.1 Percentage of participants |
| Placebo | 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 | -1 (Minimally improved), Week 24 | 33.9 Percentage of participants |
| Placebo | 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 | 0 (No change), Week 24 | 48.4 Percentage of participants |
| Placebo | 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 | +1 (Minimally worse), Week 24 | 3.2 Percentage of participants |
| Placebo | 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 | +2 (Much worse), Week 24 | 0 Percentage of participants |
| Placebo | 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 | +3 (Very much worse), Week 24 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | 0 (No change), Week 24 | 61.2 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | -3 (Very much improved), Week 12 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | -3 (Very much improved), Week 24 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | -2 (Much improved), Week 12 | 6.8 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | +2 (Much worse), Week 24 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | -1 (Minimally improved), Week 12 | 34.2 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | -2 (Much improved), Week 24 | 7.5 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | 0 (No change), Week 12 | 57.5 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | +1 (Minimally worse), Week 24 | 3.0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | +1 (Minimally worse), Week 12 | 1.4 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | -1 (Minimally improved), Week 24 | 28.4 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | +2 (Much worse), Week 12 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | +3 (Very much worse), Week 24 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | +3 (Very much worse), Week 12 | 0 Percentage of participants |
Secondary
Change From Baseline in Patient-Reported Pediatric Quality of Life (PedsQL) v4.0 Generic Core Scale After 12 Weeks and 24 Weeks of Treatment for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo
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.
Time frame: Baseline, Weeks 12 and 24
Population: Efficacy Inferential Population included participants that were divided by randomized treatment and included participants taking balovaptan 10 mg equivalent dose and participants from the concurrently randomized placebo group in the corresponding randomization stage. Participants with dose adjustments or interruptions, or who were on a different dose than the final dose for their age group, were excluded.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 | Change from Baseline at Week 12 | 2.42 Score on scale | Standard Error 1.49 |
| Placebo | 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 | Change from Baseline at Week 24 | 3.70 Score on scale | Standard Error 1.5 |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | Change from Baseline at Week 12 | 6.16 Score on scale | Standard Error 1.41 |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | Change from Baseline at Week 24 | 5.98 Score on scale | Standard Error 1.44 |
Comparison: Week 1290% CI: [0.78, 6.7]Mixed Models Analysis
Comparison: Week 2490% CI: [-0.73, 5.29]
Secondary
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.
Time frame: Baseline, Week 12
Population: Efficacy Inferential Population included participants that were divided by randomized treatment and included participants taking balovaptan 10 mg equivalent dose and participants from the concurrently randomized placebo group in the corresponding randomization stage. Participants with dose adjustments or interruptions, or who were on a different dose than the final dose for their age group, were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Vineland-II Adaptive Behavior Scale 2DC Score at Week 12 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 1.87 Score on scale | Standard Error 1 |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Change From Baseline in Vineland-II Adaptive Behavior Scale 2DC Score at Week 12 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 1.88 Score on scale | Standard Error 0.97 |
p-value: 0.99290% CI: [-1.99, 2.01]Mixed Models Analysis
Secondary
Change From Baseline in Vineland™-II Adaptive Behavior Scale Communication, Socialization, and Daily Living Skills Domain Standard Scores at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo
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.
Time frame: Baseline, Weeks 12 and 24
Population: Efficacy Inferential Population included participants that were divided by randomized treatment and included participants taking balovaptan 10 mg equivalent dose and participants from the concurrently randomized placebo group in the corresponding randomization stage. Participants with dose adjustments or interruptions, or who were on a different dose than the final dose for their age group, were excluded.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 | Communication Domain Standard Score, Week 12 | 1.86 Score on a scale | Standard Error 1.06 |
| Placebo | 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 | Communication Domain Standard Score, Week 24 | 1.51 Score on a scale | Standard Error 1.13 |
| Placebo | 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 | Socialization Domain Standard Score, Week 12 | 1.69 Score on a scale | Standard Error 1.31 |
| Placebo | 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 | Socialization Domain Standard Score, Week 24 | 2.87 Score on a scale | Standard Error 1.5 |
| Placebo | 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 | Daily Living Skills Domain Standard Score, Week 12 | -0.01 Score on a scale | Standard Error 1.38 |
| Placebo | 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 | Daily Living Skills Domain Standard Score, Week 24 | 1.44 Score on a scale | Standard Error 1.49 |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | Daily Living Skills Domain Standard Score, Week 12 | 2.13 Score on a scale | Standard Error 1.35 |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | Communication Domain Standard Score, Week 12 | 1.64 Score on a scale | Standard Error 1.03 |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | Socialization Domain Standard Score, Week 24 | 2.26 Score on a scale | Standard Error 1.45 |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | Communication Domain Standard Score, Week 24 | 2.21 Score on a scale | Standard Error 1.09 |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | Daily Living Skills Domain Standard Score, Week 24 | 1.61 Score on a scale | Standard Error 1.45 |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | Socialization Domain Standard Score, Week 12 | 2.20 Score on a scale | Standard Error 1.26 |
90% CI: [-0.63, 4.9]
Comparison: Communication Domain Standard Score, Week 1290% CI: [-2.36, 1.92]
Comparison: Communication Domain Standard Score, Week 2490% CI: [-1.6, 3.02]
Comparison: Socialization Domain Standard Score, Week 1290% CI: [-2.1, 3.12]
90% CI: [-3.74, 2.51]
90% CI: [-2.87, 3.22]
Secondary
Change From Baseline in Vineland™-II Composite Standard Score After 12 Weeks and 24 Weeks of Treatment for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo
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.
Time frame: Baseline, Weeks 12 and 24
Population: Efficacy Inferential Population included participants that were divided by randomized treatment and included participants taking balovaptan 10 mg equivalent dose and participants from the concurrently randomized placebo group in the corresponding randomization stage. Participants with dose adjustments or interruptions, or who were on a different dose than the final dose for their age group, were excluded.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 | Week 12 | 1.45 Score on a scale | Standard Error 1.07 |
| Placebo | 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 | Week 24 | 2.20 Score on a scale | Standard Error 1.19 |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | Week 12 | 1.74 Score on a scale | Standard Error 1.04 |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | Week 24 | 1.97 Score on a scale | Standard Error 1.15 |
Comparison: Week 1290% CI: [-1.85, 2.43]
Comparison: Week 2490% CI: [-2.67, 2.22]
Secondary
Change From Baseline in Vineland-II Composite Standard Score in Adolescents and Children Independently at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo
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.
Time frame: Baseline, Weeks 12 and 24
Population: Efficacy Inferential Population included participants that were divided by randomized treatment and included participants taking balovaptan 10 mg equivalent dose and participants from the concurrently randomized placebo group in the corresponding randomization stage. Participants with dose adjustments or interruptions, or who were on a different dose than the final dose for their age group, were excluded.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 | 5-12 Years Age Group, Absolute Value at Baseline | 73.9 Score on scale | Standard Deviation 9.7 |
| Placebo | 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 | 5-12 Years Age Group, Change From Baseline at Week 12 | 3.6 Score on scale | Standard Deviation 8.4 |
| Placebo | 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 | 5-12 Years Age Group, Change From Baseline at Week 24 | 4.8 Score on scale | Standard Deviation 9.1 |
| Placebo | 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 | 13-17 Years Age Group, Absolute Baseline Value | 71.0 Score on scale | Standard Deviation 10.3 |
| Placebo | 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 | 13-17 Years Age Group, Change From Baseline at Week 12 | 1.8 Score on scale | Standard Deviation 4.8 |
| Placebo | 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 | 13-17 Years Age Group, Change From Baseline at Week 24 | 2.7 Score on scale | Standard Deviation 8.6 |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | 13-17 Years Age Group, Change From Baseline at Week 12 | 3.7 Score on scale | Standard Deviation 9.4 |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | 5-12 Years Age Group, Absolute Value at Baseline | 77.3 Score on scale | Standard Deviation 10.9 |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | 13-17 Years Age Group, Absolute Baseline Value | 73.5 Score on scale | Standard Deviation 8.9 |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | 5-12 Years Age Group, Change From Baseline at Week 12 | 1.2 Score on scale | Standard Deviation 7.8 |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | 13-17 Years Age Group, Change From Baseline at Week 24 | 3.3 Score on scale | Standard Deviation 8.7 |
| Balovaptan (RO5285119) 10 mg/d Equivalent | 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 | 5-12 Years Age Group, Change From Baseline at Week 24 | 1.0 Score on scale | Standard Deviation 8.4 |
Secondary
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.
Time frame: Weeks 12 and 24
Population: Efficacy Inferential Population included participants that were divided by randomized treatment and included participants taking balovaptan 10 mg equivalent dose and participants from the concurrently randomized placebo group in the corresponding randomization stage. Participants with dose adjustments or interruptions, or who were on a different dose than the final dose for their age group, were excluded.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 1 - Very much improved, Week 12 | 0 Percentage of participants |
| Placebo | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 2 - Much improved, Week 12 | 22.4 Percentage of participants |
| Placebo | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 3 - Minimally improved, Week 12 | 49.3 Percentage of participants |
| Placebo | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 4 - No change, Week 12 | 22.4 Percentage of participants |
| Placebo | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 5 - Minimally worse, Week 12 | 6.0 Percentage of participants |
| Placebo | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 6 - Much worse, Week 12 | 0 Percentage of participants |
| Placebo | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 7 - Very much worse, Week 12 | 0 Percentage of participants |
| Placebo | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 1 - Very much improved, Week 24 | 0 Percentage of participants |
| Placebo | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 2 - Much improved, Week 24 | 30.6 Percentage of participants |
| Placebo | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 3 - Minimally improved, Week 24 | 48.4 Percentage of participants |
| Placebo | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 4 - No change, Week 24 | 19.4 Percentage of participants |
| Placebo | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 5 - Minimally worse, Week 24 | 1.6 Percentage of participants |
| Placebo | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 6 - Much worse, Week 24 | 0 Percentage of participants |
| Placebo | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 7 - Very much worse, Week 24 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 4 - No change, Week 24 | 36.8 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 1 - Very much improved, Week 12 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 1 - Very much improved, Week 24 | 4.4 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 2 - Much improved, Week 12 | 21.6 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 6 - Much worse, Week 24 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 3 - Minimally improved, Week 12 | 35.1 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 2 - Much improved, Week 24 | 26.5 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 4 - No change, Week 12 | 43.2 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 5 - Minimally worse, Week 24 | 1.5 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 5 - Minimally worse, Week 12 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 3 - Minimally improved, Week 24 | 30.9 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 6 - Much worse, Week 12 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 7 - Very much worse, Week 24 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 7 - Very much worse, Week 12 | 0 Percentage of participants |
Secondary
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).
Time frame: Weeks 12 and 24
Population: Efficacy Inferential Population included participants that were divided by randomized treatment and included participants taking balovaptan 10 mg equivalent dose and participants from the concurrently randomized placebo group in the corresponding randomization stage. Participants with dose adjustments or interruptions, or who were on a different dose than the final dose for their age group, were excluded.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 1 - Very much improved, Week 12 | 1.5 Percentage of participants |
| Placebo | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 2 - Much improved, Week 12 | 16.4 Percentage of participants |
| Placebo | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 3 - Minimally improved, Week 12 | 38.8 Percentage of participants |
| Placebo | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 4 - No change, Week 12 | 40.3 Percentage of participants |
| Placebo | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 5 - Minimally worse, Week 12 | 3.0 Percentage of participants |
| Placebo | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 6 - Much worse, Week 12 | 0 Percentage of participants |
| Placebo | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 7 - Very much worse, Week 12 | 0 Percentage of participants |
| Placebo | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 1 - Very much improved, Week 24 | 0 Percentage of participants |
| Placebo | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 2 - Much improved, Week 24 | 25.8 Percentage of participants |
| Placebo | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 3 - Minimally improved, Week 24 | 46.8 Percentage of participants |
| Placebo | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 4 - No change, Week 24 | 25.8 Percentage of participants |
| Placebo | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 5 - Minimally worse, Week 24 | 1.6 Percentage of participants |
| Placebo | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 6 - Much worse, Week 24 | 0 Percentage of participants |
| Placebo | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 7 - Very much worse, Week 24 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 4 - No change, Week 24 | 50.0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 1 - Very much improved, Week 12 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 1 - Very much improved, Week 24 | 2.9 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 2 - Much improved, Week 12 | 20.3 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 6 - Much worse, Week 24 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 3 - Minimally improved, Week 12 | 25.7 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 2 - Much improved, Week 24 | 22.1 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 4 - No change, Week 12 | 54.1 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 5 - Minimally worse, Week 24 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 5 - Minimally worse, Week 12 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 3 - Minimally improved, Week 24 | 25.0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 6 - Much worse, Week 12 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 7 - Very much worse, Week 24 | 0 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24 for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | 7 - Very much worse, Week 12 | 0 Percentage of participants |
Secondary
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.
Time frame: Baseline to Week 24 and up to Week 76
Population: Safety Population consisted of all participants who received a least one dose of study medication; Used for safety analyses and divided by exposure tertiles.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Adverse Events for Treatment With Balovaptan | 77.2 Percentage of Participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Percentage of Participants With Adverse Events for Treatment With Balovaptan | 71.2 Percentage of Participants |
| Main Study Part, High Exposure Tertile | Percentage of Participants With Adverse Events for Treatment With Balovaptan | 66.7 Percentage of Participants |
| Main Study Part (Study Part 2) - All Treated | Percentage of Participants With Adverse Events for Treatment With Balovaptan | 71.4 Percentage of Participants |
| Open Label Extension Part, Low Exposure Tertile | Percentage of Participants With Adverse Events for Treatment With Balovaptan | 68.6 Percentage of Participants |
| Open Label Extension Part, Medium Exposure Tertile | Percentage of Participants With Adverse Events for Treatment With Balovaptan | 70.0 Percentage of Participants |
| Open Label Extension Part, High Exposure Tertile | Percentage of Participants With Adverse Events for Treatment With Balovaptan | 78.3 Percentage of Participants |
| Open Label Extension Part, All Treated | Percentage of Participants With Adverse Events for Treatment With Balovaptan | 72.2 Percentage of Participants |
Secondary
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.
Time frame: Baseline, Weeks 12 and 24
Population: Efficacy Inferential Population included participants that were divided by randomized treatment and included participants taking balovaptan 10 mg equivalent dose and participants from the concurrently randomized placebo group in the corresponding randomization stage. Participants with dose adjustments or interruptions, or who were on a different dose than the final dose for their age group, were excluded.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Proportion of Subjects With >=6 Points Improvement in the Vineland-II 2DC Score for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | Week 12 | 30.3 Percentage of participants |
| Placebo | Proportion of Subjects With >=6 Points Improvement in the Vineland-II 2DC Score for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | Week 24 | 34.4 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Proportion of Subjects With >=6 Points Improvement in the Vineland-II 2DC Score for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | Week 12 | 27.1 Percentage of participants |
| Balovaptan (RO5285119) 10 mg/d Equivalent | Proportion of Subjects With >=6 Points Improvement in the Vineland-II 2DC Score for Balovaptan (R05285119) 10 mg Equivalent Compared to Placebo | Week 24 | 32.8 Percentage of participants |