Sikich 2021.

Study characteristics
Methods	24‐week parallel trial of oxytocin versus placebo
Participants	Inclusion criteria: aged 3 years‐17 years 11 months diagnosed ASD, Asperger's syndrome, or PDD‐NOS using DSM‐5‐TR criteria clinical diagnosis of ASD confirmed using the ADOS and ADI‐R; must be within 1 point of autism criteria on both social and communication domains of the ADI or meet autism criteria in one of these ADI domains and come within 2 points of autism criteria in the other guardian or participant able to provide informed consent Exclusion criteria: Participants could not have received a diagnosis of the Rett syndrome or childhood disintegrative disorder, deafness or blindness, active cardiovascular or renal disease, or uncontrolled epilepsy or be pregnant, lactating, or sexually active without contraception Previous daily treatment with intranasal oxytocin for more than 30 days Changes in neuropsychiatric medications were not allowed within 1 month before randomisation; changes in nonmedication therapies for autism spectrum disorder were not allowed within 2 months before randomisation Location/setting: USA Sample size: oxytocin 146; placebo 144 Reasons for withdraws/dropouts: oxytocin 21 (AEs (5), clinical worsening (3), LTFU (3), participant withdrew (2), physician decision (1), did not have baseline ABC‐SW (2), did not have a postbaseline ABC SW (5)); placebo 19 (AEs (2), clinical worsening (2), LTFU (3), participant withdrew (4), physician decision (2), did not have a postbaseline ABC SW (6)) Gender: 242 male, 35 female Mean age: approximately 10.5 years across both groups IQ: details not provided Baseline ABC‐I or other BoC scale (mean and SD): oxytocin ABC‐Irritability 10.9 (SD7.83); placebo 12.6 (8.94) Concomitant medications: participants must be on stable psychotropic medication in the month prior to and during the study. Anticonvulsants and stimulants were allowed. Previous medications: details not provided
Interventions	Intervention (oxytocin) for 24 weeks: "Each insufflation will deliver 8 IU or 24 IU of oxytocin. A maximum of 3 insufflations at a time will be required. Dosing will be flexible between 8 IU/day and 80 IU/day, typically in two divided doses delivered in the morning and in the afternoon. Doses will typically increase by 8 IU twice daily (BID) at week 2 and weeks 4 and 8 until achieving the target dose of 24 IU BID at week 8. Subsequently doses may be increased in 8 IU BID increments ONLY at each visit until a maximum dose of 40 IU BID is achieved.Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking". Comparator (placebo) for 24 weeks: "This nasal spray will contain all of the ingredients that are in the active oxytocin spray in the same quantities, except oxytocin will NOT be added to the solution. It will be packaged using the same container system as the active oxytocin nasal spray. Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. Dose titration will occur using exactly the same criteria and procedures as for active study drug."
Outcomes	Primary outcomes: irritability (measured using the ABC‐I subscale (Aman 1985) AEs Secondary outcomes: none reported Timing of outcome assessments: endpoint (24 weeks)
Notes	Study start date: August 2014 Study end date: June 2017 Funding: “Supported by a grant (U01HD073984) from the Eunice Ken[1]nedy Shriver National Institute of Child Health and Human Development through the Autism Centers of Excellence Program and the Department of Psychiatry and Behavioral Sciences at Duke University. The data and safety monitoring board was funded by a grant (UL1TR002489) from the National Center for Advancing Translational Sciences.” Conflicts of interest: details not provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomly assigned in a 1:1 ratio, by means of a centralised randomisation table
Allocation concealment (selection bias)	Unclear risk	Participants were randomly assigned in a 1:1 ratio, by means of a centralised randomisation table
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind; "the trial physician, who was unaware of the participant’s trial‐group assignment, completed a physical examination, systematically elicited a history of adverse events, verified concomitant treatments, and, at visits after the baseline visit, assessed current symptoms of autism spectrum disorder using the Clinical Global Impressions" "Scale of Improvement. Parents or guardians completed the Aberrant Behavior Checklist (ABC) and the Pervasive Developmental Disorders Behavior Inventory–Screening Version (PDDBI‐SV) at each visit..."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double‐blind; "the trial physician, who was unaware of the participant’s trial‐group assignment, completed a physical examination, systematically elicited a history of adverse events, verified concomitant treatments, and, at visits after the baseline visit, assessed current symptoms of autism spectrum disorder using the Clinical Global Impressions" "Scale of Improvement. Parents or guardians completed the Aberrant Behavior Checklist (ABC) and the Pervasive Developmental Disorders Behavior Inventory–Screening Version (PDDBI‐SV) at each visit..."
Incomplete outcome data (attrition bias) All outcomes	High risk	Several exclusions for "not having data" e.g. "2 Had no baseline ABC‐mSW data"
Selective reporting (reporting bias)	High risk	At least one of the outcomes on trials registry was not reported in the paper (CGI)
Other bias	Low risk	Nothing else identified