Klaiman 2013.

Study characteristics
Methods	Parallel trial of tetrahydrobiopterin versus placebo
Participants	Inclusion criteria: meet the DSM‐4‐TR diagnostic criteria for an ASD aged 3‐7 years of age at the start of the study developmental quotient > 50 as assessed by the Vineland Adaptive Behaviour Scale not taken any psychoactive medications other than supplements, anticonvulsants, melatonin, or diphenhydramine for sleep or seizures within the 6 months prior to enroling in the study Exclusion criteria: taken any psychoactive medications other than supplements, anticonvulsants, melatonin, or diphenhydramine for sleep or seizures within the 6 months prior to enroling in the study Location/setting: Children’s Health Council in Palo Alto, California, USA Sample size: 46 (23 in both groups) Number of withdrawals/dropouts: tetrahydrobiopterin (BH4) AEs (2) and lack of efficacy (1), placebo lack of efficacy (1) Gender: tetrahydrobiopterin (BH4) 20 male, 3 female, 18 male, 5 female Mean age: 5 years IQ: not reported Baseline ABC‐I or other BoC: ABC‐I BH4 11.1, placebo 11.9 Concomitant medications: participants could not have been taking psychotropic drugs in 6 months prior to trial and not start any new medications during the trial. History of previous medications: not reported
Interventions	Intervention (tetrahydrobiopterin) for 16 weeks: "individual doses of BH4 were prescribed in tablet form at 20mg/kg of body weight and taken once daily. The form of BH4 prescribed was given as tetrahydrobiopterin dihydrochloride. "The mean dose of BH4 at endpoint was 385mg/day or 19mg/kg/day" Comparator (placebo) for 16 weeks: matching placebo
Outcomes	Primary outcomes: irritability, measured using the ABC‐I subscale (Aman 1985) AEs Secondary outcomes: tolerability Timing of outcome assessments: baseline, week 8 and week 16 (endpoint)
Notes	Study start date: not reported Study end date: not reported Source of funding: "study drugs and matching placebo were provided by BioMarin Pharmaceutical, Inc" Conflicts of interest: none declared Trial registry: NCT00850070
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Group assignment was generated by a randomization program on Microsoft Excel"
Allocation concealment (selection bias)	Low risk	One member of the research team (LH) was responsible for all randomisation; randomisation records were kept on a password‐protected computer in a locked office.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	BH4 and placebo were supplied by the pharmacist as matching pills in identical packaging. "Participants, parents, and evaluators (GRE and CK) responsible for assessing the children all were blind to assignment; they remained blind until the final participant completed the trial."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Participants, parents, and evaluators (GRE and CK) responsible for assessing the children all were blind to assignment; they remained blind until the final participant completed the trial."
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants were included in the analysis and an ITT analysis was used, including using LOCF. All outcomes were reported in full.
Selective reporting (reporting bias)	Low risk	All measures were reported in full.
Other bias	High risk	This research was funded by BioMarin Pharmaceutical, Inc. as an investigator‐initiated study (#CHC0901).