Levy 2003.

Study characteristics
Methods	Cross‐over trial of single‐dose secretin versus single‐dose placebo
Participants	Inclusion criteria: diagnosis of ASD confirmed using the ADI‐R. No other inclusion criteria outlined Exclusion criteria: significant hearing or vision loss other neurological disorders, e.g. cerebral palsy, phenylketonuria, tuberous sclerosis, neurofibromatosis, seizure disorders; genetic disorders prematurity (< 32 weeks gestation) diagnosis of coeliac disease or other gastrointestinal disease associated with malabsorption previous treatment with secretin anaemia lead poisoning Location/setting: Children's Hospital of Philadelphia, USA Sample size: 62 total (31 in each group) Number of withdrawals/dropouts: 2 participants dropped out post‐randomisation however reasons were not provided Gender: all participants were male Mean age: secretin 6.4 years; placebo 5.9 years. IQ: not reported Baseline ABC‐I or other behaviours of concern: RFRLRS (subscale3) 0.74 (secretin), 0.64 (placebo). Concomitant medications: 7/31 (secretin) were on either prozac (1), Adderall (2), guanfacine (2), methylphenidate (2). Placebo: either prozac, guanfacine or risperidone with 1 child taking prozac and guanfacine History of previous medications: not reported
Interventions	Intervention (single‐dose secretin)with 6‐week washout before placebo (or vice versa): single intravenous dose of human secretin (2 CU/kg). Initially, a test dose of 0.2 uh was given and if no reaction was noted after 1 min, the remaining dose of 2 CU/kg up to a maximum of 75 CU was injected slowly over 1 min Comparator (placebo): single intravenous dose of saline placebo (2 CU/kg)
Outcomes	Primary outcomes: irritability, measured using the RFRLRS Affectual Responses subscale (Freeman 1986); adverse effects although data were not reported for both groups and so could not be included. Secondary outcomes: none reported Timing of outcome assessments: baseline, 2 and 4 weeks postinfusion
Notes	Study start date: not reported Study end date: not reported Source of funding: ChiRhoClin Corporation donated the human secretin used for the study. Otherwise, sponsorship was through research grants. Conflicts of interest: none declared Trial registry: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "the 62 subjects were randomly assigned to two groups using a computerised randomisation assignment"
Allocation concealment (selection bias)	Unclear risk	Details were not provided on how the placebo was administered.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Each participant was separated from his or her parents during the infusion (since secretin may cause a transient skin rash—the presence of which may unblind the parent to the treatment condition).
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "All personnel involved in clinical and neurodevelopmental assessments were blinded to subject's allocation"
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	2 participants did not complete both phases of the trial (1 in each group) however reasons were not provided and information not given if an ITT analysis was used or LOCF
Selective reporting (reporting bias)	Low risk	The outcome measures were the Global Behavior Rating Scale, Communication and Symbolic Behavior Scale and the Real Life Ritvo Behavior Scale. All outcomes were reported at baseline and at the end of each phase of the cross‐over trial.
Other bias	Unclear risk	"ChiRhoClin Corporation donated the human synthetic secretin used for the study". Only a single dose of secretin was used