Autism Spectrum Disorder
Conditions
Brief summary
This study will evaluate the efficacy, safety, and pharmacokinetics of 10 mg of oral administration balovaptan once a day (QD) compared with matching placebo in adults (18 years and older) with autism spectrum disorder (ASD).
Interventions
DRUGBalovaptan
Participants will receive 10 mg of oral administration balovaptan once a day (QD).
DRUGPlacebo
Participants will receive matching placebo.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject meets the DSM-5 criteria for ASD for an autism diagnosis and is confirmed using ADOS-2 criteria * SRS-2, proxy version, total t-score \>=66 at screening * A full scale IQ score \>=70 on the WASI®-II * Subject has an appropriate study partner, in the opinion of the investigator * For women of childbearing potential: agreement to remain abstinent or use a contraceptive method with a failure rate of \<1% per year during the treatment period and for at least 28 days after the last dose of study drug * Treatment with permitted medications (at a stable dose for 12 weeks before screening) and behavioral therapy regimens (regimens stable for 6 weeks before screening), with the intent that such treatments remain stable throughout the study and with no expected changes before the Week 24 visit
Exclusion criteria
* Pregnancy or breastfeeding, or intention to become pregnant during the study * Previous initiation of new or major change in psychosocial intervention within 6 weeks prior to screening * Unstable or uncontrolled clinically significant affective or psychotic disorders and/or neurologic disorder that may interfere with the assessment of safety or efficacy endpoints * Substance use disorders during the last 12 months * Significant risk for suicidal behavior, in the opinion of the investigator * Epilepsy or seizure disorder considered not well controlled within the past 6 months or changes in anticonvulsive therapy within the last 6 months * Clinical diagnosis of peripheral neuropathy * Within the last 2 years, unstable or clinically significant cardiovascular disease * Uncontrolled hypertension * Unexplained syncopal episode within the last 12 months * Confirmed elevation above upper limit of normal of CK-MB, high sensitivity cardiac troponin T, cardiac troponin I, and/or N-terminal pro B-type natriuretic peptide * Positive serology results for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV) 1 or 2 * History of coagulopathies, bleeding disorders, blood dyscrasias, hematological malignancies, myelosuppression (including iatrogenic), or current major bleeding event * Concomitant disease or condition that could interfere with, or treatment of which might interfere with, the conduct of the study, or what would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study * Confirmed clinically significant abnormality in parameters of hematology * Confirmed clinically significant abnormality in parameters of clinical chemistry, coagulation, or urinalysis * Medical history of malignancy, if not considered cured
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Week 24 on the Vineland Adaptive Behavior Scales (Vineland-II) Two-domain Composite (2DC) Score. | Week 24 | Vineland™-II Adaptive Behavior Scales 2-Domain Composite (2DC) Score is defined as mean of the Communication domain standard score & Socialization domain standard score. If any of the 2 individual domain standard scores is missing 2DC score is not computed. Vineland™-II is an instrument that measures communication, daily living skills, socialization, motor skills and maladaptive behavior of individuals with developmental disabilities. Survey Interview Form will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on Summary and Total Scores | Weeks 12 and 24 | The Pediatric Quality of Life Inventory PedsQL™4.0 Generic Core Scale assessment consists of a 23 item questionnaire encompassing 4 core scale domains: Physical Functioning (8 items); Emotional Functioning (5 items); Social Functioning (5 items); and School Functioning (5 items). Items are scored on a 5 point Likert-type response scale (0=never a problem; 1=almost never a problem; 2=sometimes a problem; 3=often a problem; and 4=almost always a problem). Once scored, items will be reverse scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better health-related quality of life. |
| Change From Baseline at Weeks 12 and 24 in the Vineland-II Adaptive Behavior Composite Standard Score | Weeks 12 and 24 | The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. Only descriptive statistics presented instead of the planned estimated due to the early discontinuation of the study due to futility. |
| Change From Baseline at Week 12 and 24 on the Vineland-II Socialization Domain Standard Score | Baseline, Weeks 12 and 24 | The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. Only descriptive statistics presented instead of the planned estimand due to the early discontinuation of the study due to futility. |
| Change From Baseline at Weeks 12 and 24 on the Vineland-II Communication Domain Standard Score | Weeks 12 and 24 | The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. |
| Change From Baseline at Weeks 12 and 24 on the Vineland-II Daily Living Skills Domain Standard Score | Weeks 12 and 24 | The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. Only descriptive statistics presented instead of the planned estimated due to the early discontinuation of the study due to futility. |
| Change From Baseline at Week 12 on the Vineland-II 2DC Score | Week 12 | Vineland™-II Adaptive Behavior Scales 2-Domain Composite (2DC) Score is defined as mean of the Communication domain standard score & Socialization domain standard score. If any of the 2 individual domain standard scores is missing 2DC score is not computed. Vineland™-II is an instrument that measures communication, daily living skills, socialization, motor skills and maladaptive behavior of individuals with developmental disabilities. Survey Interview Form will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. |
| Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Weeks 12 and 24 | This is a 7-point Likert scale that assesses improvement of the patient's condition. Scores range from the worst score of 7 (Very much worse) to the best score of 1 (Very much improved). Lower scores are better on this scale, and indicate greater improvement. Percentage of participants reported for each score. |
| Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores | Weeks 12 and 24 | The HAM-A is a 14-item, rater administered interview, assessing the severity of anxiety symptoms during the past 7 days. Seven items assess psychic anxiety and seven assess somatic anxiety. Each item utilizes a 5-point symptom severity response scale, ranging from none (0) to very severe (4). A total score is calculated that ranges from 0 to 56; higher scores are indicative of more severe anxiety. |
| Proportion of Subjects With a >=6-point Improvement in Vineland-II 2DC Score | Weeks 12 and 24 | The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning All participants who have an improvement of at least 6 points are included in the \>=6 score threshold |
| Percentage of Participants With Adverse Events | Week 24 and Up to Approximately 2 Years | According to the ICH guideline for Good Clinical Practice, an adverse event is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The Blinded Treatment Period continued for 24 weeks, Open Label Extension (OLE) Treatment Period continued up to 2 years. The study was pre-maturely terminated, therefore did not reach the planned end date. |
| Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Weeks 12 and 24 | The CGI-S reflects the rater's impression of the subject's current autism severity on a 7-point scale ranging from no symptoms (1) to very severe symptoms (7). Changes in CGI-S score were calculated as increase or decrease in absolute CGI-S scores between Baseline and Weeks 12 and 24. Percentage of participants reported for each change in score from baseline. |
Countries
Canada, France, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
322 Participants were randomized. 1 Participants did not receive the treatment and in the ITT Population, 321 participants received at least one dose of the study treatment. The Study was discontinued early before the planned sample size was reached.
Pre-assignment details
Participants received matching placebo in Blinded Treatment Period for 24 Weeks and 10 mg of oral administration balovaptan once a day (QD) during the Open Label Extension Treatment Period.
Participants by arm
| Arm | Count |
|---|---|
| Balovaptan Participants received 10 mg of oral administration balovaptan once a day (QD). | 163 |
| Placebo Participants received matching placebo. | 158 |
| Total | 321 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Blinded Treatment Period | Adverse Event | 4 | 4 |
| Blinded Treatment Period | Lack of Efficacy | 1 | 1 |
| Blinded Treatment Period | Lost to Follow-up | 1 | 4 |
| Blinded Treatment Period | Non-compliance with study drug | 0 | 1 |
| Blinded Treatment Period | Physician Decision | 1 | 0 |
| Blinded Treatment Period | Protocol Violation | 1 | 0 |
| Blinded Treatment Period | Study terminated by sponsor | 39 | 34 |
| Blinded Treatment Period | Unable due to leaving the study site, non-interest, withdrawal, and a partner inability | 1 | 3 |
| Blinded Treatment Period | Withdrawal by Subject | 12 | 9 |
| Open Label Extension Treatment Period | Adverse Event | 7 | 0 |
| Open Label Extension Treatment Period | Lack of Efficacy | 3 | 1 |
| Open Label Extension Treatment Period | Lost to Follow-up | 1 | 4 |
| Open Label Extension Treatment Period | Non-compliance with study drug | 0 | 1 |
| Open Label Extension Treatment Period | Study terminated by sponsor | 81 | 88 |
| Open Label Extension Treatment Period | The participant left the study site | 0 | 1 |
| Open Label Extension Treatment Period | Withdrawal by Subject | 8 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | Balovaptan |
|---|---|---|---|
| Age, Continuous | 27.6 Years STANDARD_DEVIATION 9.8 | 27.6 Years STANDARD_DEVIATION 9.7 | 27.6 Years STANDARD_DEVIATION 9.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 28 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 142 Participants | 287 Participants | 145 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 8 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 15 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 9 Participants | 5 Participants |
| Race (NIH/OMB) White | 140 Participants | 283 Participants | 143 Participants |
| Sex: Female, Male Female | 30 Participants | 65 Participants | 35 Participants |
| Sex: Female, Male Male | 128 Participants | 256 Participants | 128 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 163 | 1 / 158 | 0 / 100 | 0 / 97 |
| other Total, other adverse events | 49 / 163 | 59 / 158 | 28 / 100 | 30 / 97 |
| serious Total, serious adverse events | 2 / 163 | 5 / 158 | 0 / 100 | 2 / 97 |
Outcome results
Primary
Change From Baseline at Week 24 on the Vineland Adaptive Behavior Scales (Vineland-II) Two-domain Composite (2DC) Score.
Vineland™-II Adaptive Behavior Scales 2-Domain Composite (2DC) Score is defined as mean of the Communication domain standard score & Socialization domain standard score. If any of the 2 individual domain standard scores is missing 2DC score is not computed. Vineland™-II is an instrument that measures communication, daily living skills, socialization, motor skills and maladaptive behavior of individuals with developmental disabilities. Survey Interview Form will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning.
Time frame: Week 24
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Balovaptan | Change From Baseline at Week 24 on the Vineland Adaptive Behavior Scales (Vineland-II) Two-domain Composite (2DC) Score. | 4.56 Score | Standard Deviation 10.85 |
| Placebo | Change From Baseline at Week 24 on the Vineland Adaptive Behavior Scales (Vineland-II) Two-domain Composite (2DC) Score. | 6.83 Score | Standard Deviation 12.18 |
Secondary
Change From Baseline at Week 12 and 24 on the Vineland-II Socialization Domain Standard Score
The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. Only descriptive statistics presented instead of the planned estimand due to the early discontinuation of the study due to futility.
Time frame: Baseline, Weeks 12 and 24
Population: ITT Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Balovaptan | Change From Baseline at Week 12 and 24 on the Vineland-II Socialization Domain Standard Score | 12 Week | 3.63 Score | Standard Deviation 11.58 |
| Balovaptan | Change From Baseline at Week 12 and 24 on the Vineland-II Socialization Domain Standard Score | 24 Week | 5.54 Score | Standard Deviation 13.54 |
| Placebo | Change From Baseline at Week 12 and 24 on the Vineland-II Socialization Domain Standard Score | 12 Week | 5.26 Score | Standard Deviation 12.71 |
| Placebo | Change From Baseline at Week 12 and 24 on the Vineland-II Socialization Domain Standard Score | 24 Week | 6.86 Score | Standard Deviation 11.75 |
Secondary
Change From Baseline at Week 12 on the Vineland-II 2DC Score
Vineland™-II Adaptive Behavior Scales 2-Domain Composite (2DC) Score is defined as mean of the Communication domain standard score & Socialization domain standard score. If any of the 2 individual domain standard scores is missing 2DC score is not computed. Vineland™-II is an instrument that measures communication, daily living skills, socialization, motor skills and maladaptive behavior of individuals with developmental disabilities. Survey Interview Form will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning.
Time frame: Week 12
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Balovaptan | Change From Baseline at Week 12 on the Vineland-II 2DC Score | 3.47 Score | Standard Deviation 10 |
| Placebo | Change From Baseline at Week 12 on the Vineland-II 2DC Score | 4.85 Score | Standard Deviation 12.64 |
Secondary
Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores
The HAM-A is a 14-item, rater administered interview, assessing the severity of anxiety symptoms during the past 7 days. Seven items assess psychic anxiety and seven assess somatic anxiety. Each item utilizes a 5-point symptom severity response scale, ranging from none (0) to very severe (4). A total score is calculated that ranges from 0 to 56; higher scores are indicative of more severe anxiety.
Time frame: Weeks 12 and 24
Population: ITT Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Balovaptan | Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores | Week 24 Total | -2.7 Score | Standard Deviation 4.5 |
| Balovaptan | Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores | Week 12 Psychic Anxiety Subscale | -1.3 Score | Standard Deviation 3.5 |
| Balovaptan | Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores | Week 24 Psychic Anxiety Subscale | -2.1 Score | Standard Deviation 3.4 |
| Balovaptan | Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores | Week 12 Total | -1.7 Score | Standard Deviation 4.9 |
| Balovaptan | Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores | Week 24 Somatic Anxiety Subscale | -0.6 Score | Standard Deviation 2.2 |
| Balovaptan | Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores | Week 12 Somatic Anxiety Subscale | -0.4 Score | Standard Deviation 2.4 |
| Placebo | Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores | Week 24 Somatic Anxiety Subscale | -0.1 Score | Standard Deviation 2.9 |
| Placebo | Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores | Week 12 Total | -2.8 Score | Standard Deviation 4.4 |
| Placebo | Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores | Week 12 Psychic Anxiety Subscale | -1.8 Score | Standard Deviation 3.2 |
| Placebo | Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores | Week 24 Total | -2.8 Score | Standard Deviation 5.7 |
| Placebo | Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores | Week 24 Psychic Anxiety Subscale | -1.8 Score | Standard Deviation 3.9 |
| Placebo | Change From Baseline at Weeks 12 and 24 in the Hamilton Anxiety Rating Scale (HAM-A) Total and Domain Scores | Week 12 Somatic Anxiety Subscale | -1.0 Score | Standard Deviation 2.5 |
Secondary
Change From Baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on Summary and Total Scores
The Pediatric Quality of Life Inventory PedsQL™4.0 Generic Core Scale assessment consists of a 23 item questionnaire encompassing 4 core scale domains: Physical Functioning (8 items); Emotional Functioning (5 items); Social Functioning (5 items); and School Functioning (5 items). Items are scored on a 5 point Likert-type response scale (0=never a problem; 1=almost never a problem; 2=sometimes a problem; 3=often a problem; and 4=almost always a problem). Once scored, items will be reverse scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better health-related quality of life.
Time frame: Weeks 12 and 24
Population: ITT Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Balovaptan | Change From Baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on Summary and Total Scores | Total Score at Week 12 | 4.1 Score | Standard Deviation 11.2 |
| Balovaptan | Change From Baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on Summary and Total Scores | Psychosocial Health Summary Score at Week 12 | 4.9 Score | Standard Deviation 13.2 |
| Balovaptan | Change From Baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on Summary and Total Scores | Physical Health Summary Score at Week 12 | 2.5 Score | Standard Deviation 13.3 |
| Balovaptan | Change From Baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on Summary and Total Scores | Total Score at Week 24 | 8.0 Score | Standard Deviation 13.7 |
| Balovaptan | Change From Baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on Summary and Total Scores | Psychosocial Health Summary Score at Week 24 | 10.0 Score | Standard Deviation 15.4 |
| Balovaptan | Change From Baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on Summary and Total Scores | Physical Health Summary Score at Week 24 | 4.3 Score | Standard Deviation 15.5 |
| Placebo | Change From Baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on Summary and Total Scores | Psychosocial Health Summary Score at Week 24 | 6.9 Score | Standard Deviation 14.1 |
| Placebo | Change From Baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on Summary and Total Scores | Total Score at Week 12 | 5.0 Score | Standard Deviation 10.2 |
| Placebo | Change From Baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on Summary and Total Scores | Total Score at Week 24 | 6.0 Score | Standard Deviation 11.6 |
| Placebo | Change From Baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on Summary and Total Scores | Psychosocial Health Summary Score at Week 12 | 5.5 Score | Standard Deviation 12.7 |
| Placebo | Change From Baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on Summary and Total Scores | Physical Health Summary Score at Week 24 | 4.4 Score | Standard Deviation 14.5 |
| Placebo | Change From Baseline at Weeks 12 and 24 in the Pediatric Quality of Life (PedsQL) Inventory Generic Core Scales, Version 4.0, on Summary and Total Scores | Physical Health Summary Score at Week 12 | 4.3 Score | Standard Deviation 12.3 |
Secondary
Change From Baseline at Weeks 12 and 24 in the Vineland-II Adaptive Behavior Composite Standard Score
The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. Only descriptive statistics presented instead of the planned estimated due to the early discontinuation of the study due to futility.
Time frame: Weeks 12 and 24
Population: ITT Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Balovaptan | Change From Baseline at Weeks 12 and 24 in the Vineland-II Adaptive Behavior Composite Standard Score | Week 12 | 2.87 Score | Standard Deviation 6.99 |
| Balovaptan | Change From Baseline at Weeks 12 and 24 in the Vineland-II Adaptive Behavior Composite Standard Score | Week 24 | 4.32 Score | Standard Deviation 8.43 |
| Placebo | Change From Baseline at Weeks 12 and 24 in the Vineland-II Adaptive Behavior Composite Standard Score | Week 12 | 3.99 Score | Standard Deviation 10.01 |
| Placebo | Change From Baseline at Weeks 12 and 24 in the Vineland-II Adaptive Behavior Composite Standard Score | Week 24 | 5.26 Score | Standard Deviation 9.69 |
Secondary
Change From Baseline at Weeks 12 and 24 on the Vineland-II Communication Domain Standard Score
The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning.
Time frame: Weeks 12 and 24
Population: ITT Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Balovaptan | Change From Baseline at Weeks 12 and 24 on the Vineland-II Communication Domain Standard Score | Week 12 | 3.30 Score | Standard Deviation 13.74 |
| Balovaptan | Change From Baseline at Weeks 12 and 24 on the Vineland-II Communication Domain Standard Score | Week 24 | 3.59 Score | Standard Deviation 16.3 |
| Placebo | Change From Baseline at Weeks 12 and 24 on the Vineland-II Communication Domain Standard Score | Week 12 | 4.44 Score | Standard Deviation 16.58 |
| Placebo | Change From Baseline at Weeks 12 and 24 on the Vineland-II Communication Domain Standard Score | Week 24 | 6.81 Score | Standard Deviation 17.5 |
Secondary
Change From Baseline at Weeks 12 and 24 on the Vineland-II Daily Living Skills Domain Standard Score
The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning. Only descriptive statistics presented instead of the planned estimated due to the early discontinuation of the study due to futility.
Time frame: Weeks 12 and 24
Population: ITT Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Balovaptan | Change From Baseline at Weeks 12 and 24 on the Vineland-II Daily Living Skills Domain Standard Score | Week 12 | 2.93 Score | Standard Deviation 8.44 |
| Balovaptan | Change From Baseline at Weeks 12 and 24 on the Vineland-II Daily Living Skills Domain Standard Score | Week 24 | 5.14 Score | Standard Deviation 9.34 |
| Placebo | Change From Baseline at Weeks 12 and 24 on the Vineland-II Daily Living Skills Domain Standard Score | Week 12 | 2.74 Score | Standard Deviation 9.2 |
| Placebo | Change From Baseline at Weeks 12 and 24 on the Vineland-II Daily Living Skills Domain Standard Score | Week 24 | 3.02 Score | Standard Deviation 9.04 |
Secondary
Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S)
The CGI-S reflects the rater's impression of the subject's current autism severity on a 7-point scale ranging from no symptoms (1) to very severe symptoms (7). Changes in CGI-S score were calculated as increase or decrease in absolute CGI-S scores between Baseline and Weeks 12 and 24. Percentage of participants reported for each change in score from baseline.
Time frame: Weeks 12 and 24
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Balovaptan | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 12 -3 | 0 Percentage of Participants |
| Balovaptan | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 12 -2 | 2.0 Percentage of Participants |
| Balovaptan | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 12 -1 | 21.8 Percentage of Participants |
| Balovaptan | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 12 0 | 74.8 Percentage of Participants |
| Balovaptan | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 12 +1 | 0.7 Percentage of Participants |
| Balovaptan | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 12 +2 | 0.7 Percentage of Participants |
| Balovaptan | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 12 +3 | 0 Percentage of Participants |
| Balovaptan | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 24 -3 | 0 Percentage of Participants |
| Balovaptan | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 24 -2 | 5.5 Percentage of Participants |
| Balovaptan | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 24 -1 | 27.5 Percentage of Participants |
| Balovaptan | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 24 0 | 66.1 Percentage of Participants |
| Balovaptan | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 24 +1 | 0.9 Percentage of Participants |
| Balovaptan | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 24 +2 | 0 Percentage of Participants |
| Balovaptan | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 24 +3 | 0 Percentage of Participants |
| Placebo | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 24 0 | 68.0 Percentage of Participants |
| Placebo | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 12 -3 | 0 Percentage of Participants |
| Placebo | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 24 -3 | 1.0 Percentage of Participants |
| Placebo | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 12 -2 | 2.2 Percentage of Participants |
| Placebo | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 24 +2 | 0 Percentage of Participants |
| Placebo | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 12 -1 | 25.0 Percentage of Participants |
| Placebo | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 24 -2 | 10.0 Percentage of Participants |
| Placebo | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 12 0 | 72.1 Percentage of Participants |
| Placebo | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 24 +1 | 1.0 Percentage of Participants |
| Placebo | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 12 +1 | 0.7 Percentage of Participants |
| Placebo | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 24 -1 | 20.0 Percentage of Participants |
| Placebo | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 12 +2 | 0 Percentage of Participants |
| Placebo | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 24 +3 | 0 Percentage of Participants |
| Placebo | Change From Baseline in Severity of Clinical Impressions as Measured by Clinical Global Impression-Severity (CGI-S) | Week 12 +3 | 0 Percentage of Participants |
Secondary
Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I)
This is a 7-point Likert scale that assesses improvement of the patient's condition. Scores range from the worst score of 7 (Very much worse) to the best score of 1 (Very much improved). Lower scores are better on this scale, and indicate greater improvement. Percentage of participants reported for each score.
Time frame: Weeks 12 and 24
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Balovaptan | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 12 1 | 0 Percentage of Participants |
| Balovaptan | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 12 2 | 10.1 Percentage of Participants |
| Balovaptan | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 12 3 | 36.5 Percentage of Participants |
| Balovaptan | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 12 4 | 50.0 Percentage of Participants |
| Balovaptan | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 12 5 | 3.4 Percentage of Participants |
| Balovaptan | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 12 6 | 0 Percentage of Participants |
| Balovaptan | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 12 7 | 0 Percentage of Participants |
| Balovaptan | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 24 1 | 0 Percentage of Participants |
| Balovaptan | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 24 2 | 15.6 Percentage of Participants |
| Balovaptan | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 24 3 | 44.0 Percentage of Participants |
| Balovaptan | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 24 4 | 38.5 Percentage of Participants |
| Balovaptan | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 24 5 | 0.9 Percentage of Participants |
| Balovaptan | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 24 6 | 0.9 Percentage of Participants |
| Balovaptan | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 24 7 | 0 Percentage of Participants |
| Placebo | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 24 4 | 33.0 Percentage of Participants |
| Placebo | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 12 1 | 0 Percentage of Participants |
| Placebo | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 24 1 | 2.0 Percentage of Participants |
| Placebo | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 12 2 | 14.7 Percentage of Participants |
| Placebo | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 24 6 | 0 Percentage of Participants |
| Placebo | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 12 3 | 43.4 Percentage of Participants |
| Placebo | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 24 2 | 24.0 Percentage of Participants |
| Placebo | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 12 4 | 41.2 Percentage of Participants |
| Placebo | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 24 5 | 1.0 Percentage of Participants |
| Placebo | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 12 5 | 0.7 Percentage of Participants |
| Placebo | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 24 3 | 40.0 Percentage of Participants |
| Placebo | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 12 6 | 0 Percentage of Participants |
| Placebo | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 24 7 | 0 Percentage of Participants |
| Placebo | Improvements in Clinical Impressions, as Measured by Clinical Global Impression-Improvement (CGI-I) | Week 12 7 | 0 Percentage of Participants |
Secondary
Percentage of Participants With Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The Blinded Treatment Period continued for 24 weeks, Open Label Extension (OLE) Treatment Period continued up to 2 years. The study was pre-maturely terminated, therefore did not reach the planned end date.
Time frame: Week 24 and Up to Approximately 2 Years
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Balovaptan | Percentage of Participants With Adverse Events | 60.1 Percentage of Participants |
| Placebo | Percentage of Participants With Adverse Events | 65.8 Percentage of Participants |
| Balovaptan OLE | Percentage of Participants With Adverse Events | 59.0 Percentage of Participants |
| Placebo OLE | Percentage of Participants With Adverse Events | 55.7 Percentage of Participants |
Secondary
Proportion of Subjects With a >=6-point Improvement in Vineland-II 2DC Score
The Vineland-II is an instrument that measures communication, daily living skills, socialization, motor skills (only in children up to 6 years) and maladaptive (not assessed in this study) behavior of individuals with developmental disabilities. The Survey Interview Form (i.e., semi -structured interview) will be administered to a subject's reliable study partner in this study, during which the rater or clinician will ask to the study partner open ended questions relating to the subject's activities and behavior. Domain scores will be obtained for the individual domains of Socialization, Communication, Daily Living Skills, and motor skills (up to 6 years only) and used to calculate the Vineland-II Adaptive Behavior Composite score. Standardized scores on the Adaptive behavior composite range from 20-160 with higher scores indicating better functioning All participants who have an improvement of at least 6 points are included in the \>=6 score threshold
Time frame: Weeks 12 and 24
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Balovaptan | Proportion of Subjects With a >=6-point Improvement in Vineland-II 2DC Score | Week 12 >=6 | 34.4 Percentage of Participants |
| Balovaptan | Proportion of Subjects With a >=6-point Improvement in Vineland-II 2DC Score | Week 24 >=6 | 43 Percentage of Participants |
| Placebo | Proportion of Subjects With a >=6-point Improvement in Vineland-II 2DC Score | Week 12 >=6 | 42.1 Percentage of Participants |
| Placebo | Proportion of Subjects With a >=6-point Improvement in Vineland-II 2DC Score | Week 24 >=6 | 48.4 Percentage of Participants |