Table 2.
List of study measures.
| Name of measure | Measure details |
|---|---|
| Primary outcome | |
| Socialization domain of the Vineland Adaptive Behavior Scales, 3rd edition (VABS−3) (26) | The Socialization Domain of the VABS−3 measures social function and behavior, covering interpersonal relationships, play and leisure and coping skills. The informant (parent/carer) is required to reside with the participant. The same informant and interviewer will be used at both timepoints, and any change will be reported as a protocol deviation, and wherever possible the interviewer will be blind to other study assessments. Interviewers administering the VABS−3 will be required to achieve 90% reliability with a gold standard rater in order to administer it for the trial. Regular reliability meetings will be scheduled for VABS−3 gold standard raters and interviewers across study sites to maintain reliability. |
| Key secondary outcomes | |
| Clinical Global Impression – Severity (CGI–S) scale (28, 29) | The CGI–S will assess the severity of impairment in global functioning, including but not limited to social engagement, internalizing and externalizing problems. It is rated on a 7-point scale ranging from 1 (normal, not at all impaired) to 7 (among the most extremely impaired) by a treating clinician. A CGI-S score of 3 (mildly impaired) will be the anchor applied to all participants meeting diagnostic criteria for ASD, with higher scores indicating significant co-occurring problems. |
| Clinical Global Impression – Improvement (CGI–I) scale (28, 29) | The Clinical Global Impression – Improvement (CGI–I) scale will measure improvement in global functioning during the previous week since treatment initiation. It will be rated by a treating clinician on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), with 4 representing no change. All available information will be used to inform clinical judgement. The CGI–I scores will also be used to assess safety, with participants who have CGI–I scores of 6 or more (much or very much worse) for two or more consecutive visits being discontinued from the trial. |
| Other secondary outcomes | |
| Communication and Daily Living Skills domain of the Vineland Adaptive Behavior Scales, 3rd edition (VABS−3) (26). | The Communication and Daily Living Skills domains of the VABS-3 (described in primary outcome above) will be administered to assess these areas of adaptive behavior. |
| Brief Observation of Social Communication Change (BOSCC) (30) | The BOSCC is a brief, 12-min observation of a semi-structured social interaction between the participant and an examiner. The interaction is video-recorded, and autism symptoms are coded using an algorithm. |
| Social Responsiveness Scale, 2nd edition (SRS−2) (31) | The SRS−2 is a 65-item measure identifying the presence and severity of autistic symptoms. Items are rated on a 4-point scale with higher scores reflecting more severe autism. It will be completed by parents/carers and teachers. The teacher completing this measure should spend at least 10 h per week in direct contact with the participant. |
| Autism Impact Measure (AIM) (32) | The AIM will be completed by the parent/carer to assess symptoms of autism. It consists of 41 items measuring both the frequency and impact of autism symptoms using a 5-point scale. |
| Aberrant Behavior Checklist - Community version (ABC-C) (24) | The ABC-C will also be completed by the parent/carer to measure irritability, lethargy/social withdrawal, stereotypic behavior, hyperactivity/non-compliance, and inappropriate speech displayed by the participant. Fifty-eight items are rated on a 4-point scale, with higher scores indicating more severe problem behaviors. The ABC-C will be completed by the parent/carer. |
| Child Behavior Checklist (CBCL) (33) | The CBCL will be used to measure emotional and behavioral problems. Items are rated on a 3-point scale with higher scores indicating more problems. Two different versions will be administered to parents of 5-year olds (1–5-year version) and 6–17-year olds (6–18-year version). |
| Pediatric Quality of Life Inventory (PedsQL) (34) | The PedsQL measures health related quality of life in children and adolescents. The Generic Core Scales, consisting of 23 items rated on a 5-point scale, will be used to measure physical and psychosocial health. Parents/carers will complete one of three different versions dependent on the participant's chronological age (5–7; 8–12; 13–18 years). |
| Exploratory measures | |
| Electrophysiology and sensory processing | Electrophysiology and sensory processing will be measured using electroencephalograms (EEG). Computer tasks chosen specifically for the trial will be completed whilst the EEG is being conducted to measure resting state, response to social and non-social stimuli, auditory processing and habituation response. The tasks take about 1 h to complete. |
| DNA acquisition | DNA samples (using 6 mls EDTA tubes) will be obtained from patient, and both parents when possible. This will help us to explore the genetics of those responders to the drug, vs. non-responders. |
| Digital Biomarkers | Digital biomarker (dBM) technology allows the remote measurement of the signs and symptoms of ASD, which can potentially reduce the burden of site visits and allow frequent/daily tracking in an ecologically valid environment. Patients will be asked to complete some tasks on a pre-set mobile phone and wear a smart wrist watch during the time of the study. Bluetooth beacons will be used to estimate the frequency of social interactions at home. |
| Safety assessments | |
| Medical checks | Vital signs (pulse, temperature and non-supine blood pressure) will be checked by a treating clinician. Physical examinations and electrocardiograms will be performed, and height and weight will be recorded with all outer wear and shoes removed. Safety blood tests checking complete blood count, liver enzymes, renal function and non-fasting glucose will be performed. Pregnancy testing will be performed for female participants of childbearing potential. Drug testing will also be performed on urine samples. |
| Safety Monitoring Uniform Report Form (SMURF) (35) | The SMURF will be administered by a treating clinician to record possible adverse events of psychotropic medication. Where appropriate, the participant and their parent/carer will be interviewed together and events since the last visit will be sought. |
| Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) (36) | The ESS-CHAD will be administered by a treating clinician to measure daytime sleepiness and sedation in the past week. It consists of 8 items tapping into different situations which are rated on a 4-point scale with higher scores indicating greater chance of sleepiness. |
| Columbia-Suicide Severity Rating Scale (C-SSRS) (37) | Suicidality assessments will be completed by a treating clinician using the C-SSRS to measure the presence and intensity of suicidal ideation and behavior. The “baseline” version will be administered at week 0 and the “since last time” version thereafter. Two different versions will be administered depending on the chronological age of the participant. |
| Screening/characterization assessments | |
| Autism Diagnostic Observation Schedule−2 (ADOS−2) (27) | The ADOS−2 modules 3 or 4 will be administered to enable characterization of autism symptoms and severity. If a reliable ADOS−2 assessment has been administered in the 24 months prior to screening, with family consent, the scores from the previous assessments will be used an administration of these assessment will not be required. |
| Wechsler Scales | The appropriate Wechsler Scales according to age will be administered to enable characterization of the cognitive functioning of the sample. If a reliable standardized cognitive assessment has been administered in the 24 months prior to screening, with family consent, the scores from the previous assessments will be used an administration of these measures will not be required. |
| Social Communication Questionnaire-Lifetime version (SCQ) (38) | The SCQ is a 40-item yes-no measure of autism symptoms and severity and will be completed by the parent/carer. Scores of 15 or greater indicate a possible ASD. |
| Repetitive Behavior Scale-Revised (RBS-R) (39) | This questionnaire is part of the digital biomarkers optional sub-study and only completed if opted in. The RBS-R is an empirically-derived comprehensive survey of the entire spectrum of repetitive behaviors clinically observed and referred to in the DSM-IV (3) diagnostic description of Autistic Disorder. Parents or caregivers rate 43 behaviors on a scale of 0–3, where 0 indicates the behavior does not occur and 3 indicates the behavior does occur and is a severe problem. |