Stein 1996.

Study characteristics
Methods	5‐week, triple‐blind, placebo‐controlled, cross‐over trial with 4 interventions: MPH twice daily MPH 3 times daily MPH titration placebo
Participants	Number of participants screened: not stated Number of participants included: 25 (all boys) Number of participants followed up: 24 Number of withdrawals: 1 Diagnosis of ADHD: DSM‐III‐R (combined (88%), inattentive (12 %)) Age: mean 8.0 years (range 6‐12) IQ: not stated MPH‐naive: 44% Ethnicity: white (96%), Hispanic (4%) Country: USA Setting: outpatient clinic Comorbidity: ODD (28%), CD (12%) Comedication: no Other sociodemographics: Hollingshead socioeconomic status category I: 8 (33%), II: 8 (33%), III: 3 (12.5%), IV: 5 (20.8%) Inclusion criteria DSM‐III‐R ADHD diagnosis from parent interview using Disruptive Behavior Disorders module of the NIMH DISC Parent version Clinically significant ratings on CPRS for Impulsivity/Hyperactivity factor (T > 65) or on CBCL (parent form) Attention factor (T > 65) Teacher ratings < 20th percentile for attention or hyperactivity problems on the ADD‐H Teacher Rating Scale (ACTeRS) Exclusion criteria History of significant developmental delay (indicated by IQ testing or special educational services) Diagnosis of pervasive developmental disorder Unwillingness of parents or school personnel to meet trial requirements
Interventions	Participants were randomly assigned to 1 of 4 possible drug condition orders of MPH and placebo Mean MPH dosage: 8.8 mg, 0.3 mg/kg/dose Administration schedule: twice/3 times daily: 8:00 am, 12:00 pm (and 2:00 pm) Duration of each medication condition: 1 week Washout before trial initiation: ≥ 5 days Medication‐free period between interventions: none Titration period: initiated after randomisation Treatment compliance: "there was generally good compliance, with a mean of 1.5 missed doses per child over the 5‐week course of the study"
Outcomes	ADHD symptoms CPRS, 48 items; factors include Conduct Problem, Learning Problem, Psychosomatic Problems, Impulsivity/Hyperactivity and Anxiety. Collected on a weekly basis for 5 consecutive weeks, including baseline assessment ACTeRS: collected on a weekly basis for 5 consecutive weeks, including baseline assessment Serious AEs None observed Non‐serious AEs Stimulant Side Effects Rating Scale (SSERS): collected on a weekly basis for 5 consecutive weeks, including baseline assessment Sleep log: parents completed a sleep log to record the time when the child was sent to bed and fell asleep, as well as total sleep duration ActiGraph: for 2 consecutive 18‐h periods during each week, children wore an ActiGraph wrist monitor from 4:00 pm to 8:00 am to record activity level, latency to sleep onset (time sent to bed to first minute of sleep), duration of sleep and number and duration of awakenings
Notes	Sample calculation: no Ethics approval: approved by the Institutional Review Board of the University of Chicago Comments from trial authors "Analysis revealed no significant effects of order on any of the measures of ADHD symptoms, sleep variables and side effects" "Our sample size and resultant statistical power were moderate, limiting our ability to detect mild or subtle effects" Key conclusions of trial authors For many children with ADHD, 3 times/d dosing may be optimal Few differences in acute side effects have been noted between twice/d and 3 times/d MPH dosing Dosing schedule should be selected according to severity and time course of ADHD symptoms, rather than in anticipation of dosing schedule‐related side effects Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: no Any withdrawals due to AEs: yes; 1 Funding source: the work was supported by the Smart Family Foundation Email correspondence with trial authors: July 2014. Supplemental information regarding randomisation and whether all planned outcomes were measured and reported was received from trial authors. Unfortunately, trial authors no longer had access to the dataset; therefore it has not been possible to receive supplemental data
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomly assigned to 1 of 4 different orders of drug administration. The research pharmacist used a random numbers table to assign participants to different orders of administration
Allocation concealment (selection bias)	Low risk	"All medication and placebos were prepared by the study pharmacist and placed in opaque gelatin capsules" In addition to the pharmacist, 1 investigator had access to the dosage code in the event of a medical emergency that necessitated breaking the blind
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Triple‐blinded: participants always took 3 capsules daily during the trial. "Active drug phase (b.i.d. or three t.i.d. [two or three times/day]) was always preceded by a titration phase. The purpose of the titration phase was to introduce a typical dose of MPH gradually, so that any observation of side effects during the b.i.d. and t.i.d. dosing phases could not be attributed to rapid introduction of MPH"; "All medication and placebos were prepared by the study pharmacist and placed in opaque gelatin capsules"; "In addition to the pharmacist, one investigator had access to the dosage code in the event of a medical emergency that necessitated breaking the blind"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Triple‐blinded: in addition to the pharmacist, one investigator had access to the dosage code in the event of a medical emergency that necessitated breaking the blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	One dropout. Data collected on this participant were used in the descriptive information for baseline, 3 times/d and titration phases Selection bias (e.g. titration after randomisation → exclusion): no
Selective reporting (reporting bias)	Low risk	All planned outcomes were measured and reported