Handen 2015.

Study characteristics
Methods	Parallel trial of atomoxetine versus placebo
Participants	Inclusion criteria: aged 5‐14 years minimum mental age of 24 months meet criteria for an ASD (autistic disorder, Asperger’s disorder, PDD‐NOS), based upon the ADI‐R and expert clinical evaluation using a DSM‐4‐TR interview exhibit significant symptoms of overactivity and/or inattention at both home and school, based on a mean item score of at least 1.50 on the parent and teacher SNAP scales and a CGI–S score of ≥ 4 free of psychotropic medications for 2 weeks before randomisation (except stable doses of melatonin or low‐dose clonidine for sleep and anticonvulsant for seizure control) Exclusion criteria: Rett disorder, childhood disintegrative disorder, diagnosis of schizophrenia or other psychotic disorder, bipolar disorder, current diagnosis of major depression or obsessive‐compulsive disorder significant medical conditions or abnormalities on routine laboratory tests or ECG prior trial of atomoxetine for ≥ 4 weeks, within the last 2 years regular usage of b‐adrenergic blocking agents, asthma medicine prior involvement in a highly structured parent training programme Location/setting: University of Pittsburgh Medical Centre, Ohio State University, and University of Rochester, USA Sample size: atomoxetine 32, placebo 32 Number of withdrawals/dropouts: inadequate improvement (2 placebo group); behavioural AEs especially irritability 2 atomoxetine group, 3 placebo group; physical AE 2 placebo group; LTFU 1 from each group; other LTFU/unknown 3 placebo group Gender: atomoxetine 26/32 boys; placebo 24/32 boys Mean age: atomoxetine 8.6 years; 8.2 years placebo IQ: atomoxetine group: 78.7; placebo group: 86.7 Baseline ABC‐I or other BoC: ABC‐I atomoxetine group: 16.00; placebo group 16.97 Concomitant medications: “a single anticonvulsant for seizure control was allowed, provided that stable doses and seizure‐free status had been 6 months or more”. History of previous medications: details not reported
Interventions	Intervention (atomoxetine) for 10 weeks: the initial dose was 0.3 mg/kg/day (rounded to the nearest 5 mg) with weekly escalations by 0.3 mg/kg/day, unless there were limiting side effects or no further improvement, to a target dose of 1.2 mg/kg/day, but could be increased to a maximum of 1.8 mg/kg/day. Mean final dose of atomoxetine was 1.38 mg/kg/day. Comparator (placebo) for 10 weeks: sugar pill administered twice daily
Outcomes	Primary outcomes: irritability, measured using parent‐reported ABC‐I subscale (Aman 1985) AEs Secondary outcomes: tolerability Timing of outcome assessment: “study visits occurred weekly to assess medication response, to monitor adverse events (AEs), and to adjust doses. Final dose adjustments were made at week 6, with subsequent monitoring visits at weeks 8 and 10"
Notes	Study start date: October 2008 Study end date: April 2014 Source of funding: grants from the National Institute of Mental Health to Ohio State University (5R01MH079080), University of Pittsburgh (5R01MH079082‐05), and University of Rochester (5R01 MH083247), by Eli Lilly and Co, who provided atomoxetine and placebo, and by the University of Rochester CTSA (UL1 RR024160) and Ohio State University CTSA (UL1TR001070) from the National Center for Research Resources and the National Center for Advancing Translational Sciences of the National Institutes of Health Conflicts of interest: none declared Trial registry: NCT00844753
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The study biostatistician generated the randomisation sequence using a computer algorithm"
Allocation concealment (selection bias)	Low risk	Quote: "a designated team member at each site obtained the assignment for each participant via a Web portal maintained by the data centre"
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "ATX [atomoxetine] assignment was double‐blinded"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"ATX [atomoxetine] assignment was double‐blinded". Independent evaluators blinded to treatment assignment until completion of the study rated participants on the CGI scale.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	High LTFU across groups 29/128 although data were estimated from Missing At Random models and sensitivity tested using LOCF.
Selective reporting (reporting bias)	Unclear risk	Protocol and archived versions available NCT00844753
Other bias	Unclear risk	More than twice as many (72%) in special education compared to placebo group (34%)