Handen 2011.

Study characteristics
Methods	Parallel trial of donepezil versus placebo
Participants	Inclusion criteria: children and adolescents aged 8‐17 years IQ > 75 diagnosed with ASD using ADI‐R and ADOS score at least one SD lower than the mean on the Card Sorting test, verbal fluency, or Executive Function tests Exclusion criteria: not reported Location/setting: not reported Sample size: 34 (donepezil 18, placebo 16) Number of withdrawals/dropouts: "one subject terminated due to an increase in aggression and irritability. Two other subjects were unable to tolerate the 10mg/day dose and were maintained on a 5mg/day dose". Gender: details not provided Mean age: treatment group 8 years 7 months, placebo group 9 years 7 months IQ: mean 96.8 (treatment group), 96.7 (placebo group) Baseline ABC‐I or other BoC: baseline CBCL (aggression) 9.72; RFRLRS (affectual responses i.e. irritability) 0.90 Concurrent medications: concurrent psychotropic medications allowed provided the dose levels are maintained during the trial. 5 participants were taking SSRIs, 4 were taking stimulants and 2 were taking atomoxetine. History of previous medications: not reported
Interventions	Intervention ‐ donepezil max 5 mg/day for 4 weeks followed by donepezil maximum 10 mg/day for 4 weeks if tolerated. Participants began on 2.5 mg/day increasing to 5 mg/day after 1 week. After 4 weeks at 5 mg/day doses were increased to 7.5 mg/day for 1 week, up to a maximum of 10 mg/day for the remaining for 4 weeks (for 16/18 who could tolerate higher doses). Comparator (placebo) for 10 weeks: equivalent placebo
Outcomes	Primary outcomes: aggression, measured using the CBCL (Achenbach 2000) irritability, measured using the RFRLRS Affectual Responses subscale (Freeman 1986) Secondary outcomes: none reported Timing of outcome assessments: "following randomisation, subjects were seen for a total of 4 clinic visits (following one week on 2.5mg/day, following four weeks on 5.0mg/day, one week on 7.5mg/day, and four weeks at 10mg/day".
Notes	Study start date: not reported Study end date: not reported Source of funding: NIMH Grant 5R21 MH64941‐03 as well as a gift by Pfizer and Eisai Pharmaceutical companies Conflicts of interest: none declared Trial registry: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "The study pharmacist conducted the randomization for each subject"
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not described though study authors stated the trial was double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not described
Incomplete outcome data (attrition bias) All outcomes	Low risk	LOCF analysis used for the one of 34 randomised participants who did not complete the trial
Selective reporting (reporting bias)	Low risk	All outcome data appear to have been reported
Other bias	High risk	A gift was given by Pfizer and Eisai Pharmaceutical companies (who also provided the medication and placebo for this trial). The placebo group were one year older (9 years 7 months) compared to the donepezil group (8 years 7 months). Baseline scores for aggression (9.72 vs 7.47) and irritability (0.90 vs 0.80) were also higher for the donepezil group.