Hardan 2012.

Study characteristics
Methods	Parallel trial of N‐acetylcysteine versus placebo
Participants	Inclusion criteria: outpatients 3‐12 years physically healthy male and female diagnosis of autism based on the DSM‐4‐TR criteria CGI‐S rating of ≥ 4 stable concomitant medications and biomedical treatments for at least 2 weeks before enrolment no planned changes in psychosocial interventions during the trial Exclusion criteria: DSM‐4 diagnosis of schizophrenia, schizoaffective disorder or psychotic disorder not otherwise specified prior adequate trial of N‐acetylcysteine active medical conditions, unstable seizures or significant physical illness pregnant or sexually active female participants taking antioxidant agents and glutathione prodrugs, except where they have been off these compounds for at least 4 weeks Setting/location: autism clinic at Stanford University, USA Sample size: 33 (15 randomised to NAC and 18 to placebo) Number of withdrawals/dropouts: 2 from NAC group (1 AE, 1 dislike taste); 6 from placebo group (3 dislike the taste, 2 withdrawal, 1 LTFU) Gender: 31 male, 2 female Mean age: NAC group 7.0 years, placebo 7.2 years IQ: details not provided Baseline ABC‐I or other BoC: NAC group ABC‐I 16.9, repetitive behaviour scale (Scales of Independent Behaviour) 3.9; placebo group ABC‐I 14.8, Repetitive Behaviour Scale (Scales of Independent Behaviour) 3.4 Concomitant medications: "14 subjects were on at least on psychotropic medication with three being on more than one. The most commonly prescribed classes of medication were second generation antipsychotics and SSRIs". History of previous medications: details not provided
Interventions	Intervention (N‐Acetylcysteine) for 12 weeks: NAC was initiated at 900 mg/day for the first 4 weeks, then 900 mg twice/day for 4 weeks, then 900 mg 3 times/day for 4 weeks (or matching placebo) Comparator (placebo) for 12 weeks: sugar pill
Outcomes	Primary outcomes: irritability, measured using the ABC‐I (Aman 1985) self‐injurious behavior, measured with the Repetitive Behaviour Scale ‐ Scales of Independent Behaviour (Bodfish 2000) AEs Secondary outcomes: tolerability Timing of outcome assessment: baseline, 4, 8 and 12 weeks
Notes	Study start date: March 2009 Study end date: September 2010 Source of funding: "grant from the Escher Family Fund at the Silicon Valley Community Foundation to AYH. Dr AY Hardan has received research support from the companies: Bristol‐Myers Squibb Company and Forest Pharmaceuticals. Dr Frazier has received research support from, acted as a consultant to, or received travel support from Shire Development, Inc. and Bristol‐Myers Squibb Company. Dr LA Herzenberg and Dr R Tirouvanziam are listed as inventors on two patents licensed by Bioadvantex, Inc, the supplier of the N‐acetylcysteine and placebo for this study, covering the use of N‐acetylcysteine in cystic fibrosis". 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: "randomisation was done by the Stanford pharmacist using www.randomization.com, which randomises each subject by using the method of randomly permuted blocks"
Allocation concealment (selection bias)	Low risk	Quote: "each participant received a supply of the compound (NAC or placebo) labeled with a reference number"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Parents and investigators involved in the study were blinded to participant status". "The study coordinator was not involved in randomisation and clinical ratings, received information about the group assignments and distribute the compound to the parents"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "investigators involved in the study were blinded to participants' status"
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Participants did not complete intervention after randomisation ‐ unclear if ITT analysis or other approach was used to account for these losses.
Selective reporting (reporting bias)	Unclear risk	Without knowing what was in the trial protocol, it is difficult to know if outcomes and measures originally undertaken were reported
Other bias	High risk	Pharmaceutical company provided both active treatment and placebo for study. 2 study authors are inventors of two patents listed with this same company.