Dean 2019.

Study characteristics
Methods	24‐week trial of N‐acetyl cysteine (NAC) versus placebo
Participants	Inclusion criteria: "diagnosis of Autistic Disorder according to DSM‐4‐TR (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) criteria (American Psychiatric Association, 2000) and were aged between 3 and 9 years, inclusive". Exclusion criteria: "had a known or suspected clinically relevant systemic medical disorder or known genetic or metabolic cause of developmental delay, such as fragile X or Rett syndrome; had a prior sensitivity or allergy to NAC were considered likely to be unable to comply with the treatment protocol, e.g., having a highly restricted diet leading to refusal to take NAC; had parents/guardians who were non‐fluent in English; had a history of asthma or epilepsy, as these are equivocally influenced by NAC, or were already receiving any treatment containing NAC, glutathione or their precursors". Location/setting: Australia Sample size: ITT sample was 98: NAC 48; placebo 50 Reason for dropouts/withdrawals: NAC: 6 withdrew between baseline and week 4 (2 parents withdrew consent, 3 protocol violations, and 1 withdrew due to behavioural changes); 4 withdrew between week 4 and week 12 (1 parent withdrew consent, 1 protocol violation, 1 withdrew because of behavioural changes, and 1 withdrew for health reasons); 3 withdrew between week 12 and week 24 (2 LTFU and 1 protocol violation) Placebo: 6 withdrew between baseline and week 4 (2 parents withdrew consent, 2 protocol violations, 1 serious AE, 1 withdrew for health reasons); 3 withdrew between between week 4 and week 12 (1 parent withdrew consent, 1 protocol violation, 1 LTFU); 4 LTFU between week 12 and 24 Mean age: 6.4 years Mean IQ: 73 Gender: 79 male, 19 female Baseline ABC‐Irritability scores: Repetitive Behaviour Scale (self‐injury) 2.2 (2.9) in intervention group, 1.7 (2.6) in placebo group Current or previous medications: "children undergoing any pharmacological treatment for autistic disorder were allowed to continue with that treatment, as usual". Not specified per group but outlined 26.5% on a psychotropic medication (most commonly; melatonin 12/2% and risperidone 5.1%). Other medications included health supplements (most commonly fish oil 19.4%), anti‐allergy medication (total use 5.1%), skin medication (total use 4.1%) and 9.1% of children were on a range of other medications (e.g. paracetamol).
Interventions	Intervention: fixed dose 500 mg once daily of N‐acetyl cysteine Comparator: equivalent placebo
Outcomes	Primary outcomes: self‐injurious behaviour, measured with the Repetitive Behaviour Scale (Bodfish 2000); AEs Secondary outcomes: tolerability Timing of outcome assessments: baseline, week 4, 12 and 24
Notes	Study start date: details not provided Study end date: details not provided Funding: "This work was supported by the Simons Foundation Autism Research Initiative (SFARI) [Grant 201473]. A pilot award and scholarship support for Kristi‐Ann Villagonzalo was obtained from Australian Rotary Health. Michael Berk is supported by an NHMRC Senior Principal Research Fellowship (1059660)". Conflicts of interest: "No potential conflict of interest was reported by the authors". Trial registry: ACTRN12610000635066
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Participants were randomised sequentially into either the NAC or placebo groups using a computer program designed for clinical trial randomisation (randomization.com)". "An independent researcher, who had no contact with any participants, coordinated the computer‐generated randomisation codes"
Allocation concealment (selection bias)	Unclear risk	Details not provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants, their parents/guardians, trial staff and the statistician were blind to treatment arm allocation for the duration of the study.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Participants, their parents/guardians, trial staff and the statistician were blind to treatment arm allocation for the duration of the study
Incomplete outcome data (attrition bias) All outcomes	High risk	Large amount of attrition by 6 months (> 25% in both groups). Not clear if AEs is for all participants or just those at 6 months' follow‐up
Selective reporting (reporting bias)	Unclear risk	Outcomes have not been listed on the clinical trials registry and so it is difficult to know if all outcomes have been reported.
Other bias	Unclear risk	The study medication was gifted by BioMedica