E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
ASD is a neurodevelopmental disorder that impairs the ability to communicate and interact |
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E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of 24-week treatment with balovaptan (RO5285119) compared to placebo as measured by the change from baseline on the Vineland-II Adaptive Behavior Scales, second edition (Vineland-II) Two Domain Composite (2DC) (average of Communication and Socialization domains).
To evaluate the safety and tolerability of 24-week treatment with balovaptan.
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E.2.2 | Secondary objectives of the trial |
Change from baseline on Vineland-II Composite standard score after 12 weeks & 24 weeks of treatment;Change from baseline in Vineland-II Communication, Socialization,&Daily Living Skills domain standard scores after 12 weeks&24 weeks of treatment;Proportion of subjects with ≥6-point improvement in Vineland-II 2DC score to evaluate clinically meaningful response;Change from baseline in severity of clinical impressions as measured by CGI-S & OACIS-S after 12 weeks & 24 weeks of treatment;Improvements in clinical impressions as measured by CGI-I & OACIS-I after 12 weeks & 24 weeks of treatment; PedsQL v 4.0 Generic Core Scale after 12 weeks & 24 weeks of treatment;Change from baseline in Vineland-II)Composite standard score in adolescents & children independently after 12 weeks & 24 weeks of treatment;Change from baseline on Vineland-II Adaptive Behavior Scales,2nd edition 2DC score after 12 weeks of treatment;To evaluate safety and tolerability of 76 weeks treatment with balovaptan |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 |
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E.4 | Principal 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) |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Change From Baseline in Vineland-II Adaptive Behavior Scale Two Domain Composite (2DC) Score at Week 24 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Change from Baseline in Vineland-II Composite Standard Score After 12 Weeks and 24 Weeks of Treatment
2. Change From Baseline in Vineland-II Adaptive Behavior Scale Communication, Socialization, and Daily Living Skills Domain Standard Scores at Weeks 12 and 24
3. Proportion of Subjects with >=6 Points Improvement in the Vineland-II 2DC Score
4. Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Score at Weeks 12 and 24
5. Change From Baseline in Ohio Autism Clinical Impressions Scale-Severity (OACIS-S) Score at Weeks 12 and 24
6. Change From Baseline in Clinical Global Impressions- Improvement (CGI-I) Score at Weeks 12 and 24
7. Change From Baseline in Ohio Autism Clinical Impressions Scale- Improvement (OACIS-I) Score at Weeks 12 and 24
8. Patient-Reported Pediatric Quality of Life (PedsQL) v4.0 Generic Core Scale after 12 Weeks and 24 Weeks of Treatment
9. Change From Baseline in Vineland-II Adaptive Behavior Scale Composite Standard Score in Adolescents and Children
10. Change From Baseline in Vineland-II Adaptive Behavior Scale Composite Standard Score at Week 12
11. Apparent Clearance (CL) of Balovaptan (RO5285119)
12. Volume of Distribution (VD) of Balovaptan (RO5285119)
13. Area Under the Concentration-time Curve of Balovaptan (RO5285119) in Plasma at Steady State Over 24 Hours (AUC0-24,ss)
14. Number of Participants With Adverse Events |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-2, 4-7, 9: Baseline, Weeks 12 and 24
3: Baseline to Week 30
8: Weeks 12 and 24
10: Baseline, Week 12
11-13: 4 hours (hrs) postdose on Day 1; predose (0 hrs) at Weeks 1, 3 and on Day 10; predose (0 hrs), 2, 4, 6 hrs postdose at Week 2; end of treatment(up to Week 24); 8-10 hrs postdose in evening at Week 10; predose (0 hrs), 2, 4 hrs postdose at Weeks 12 and 24
14: Baseline to Week 30
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
Will this trial be conducted at a single site globally?
| No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 9 |