Wigal 2004.

Study characteristics
Methods	4‐week, randomised, double‐blind, placebo‐controlled, ITT, parallel multicentre trial with 3 arms: d‐MPH Dex,I‐MPH placebo
Participants	Number of participants screened: 174 Number of participants included: 132 (116 boys, 16 girls) Number of participants followed up: 119 (d‐MPH 42, dex,l‐MPH 40, placebo 37) Number of withdrawals: 13 (d‐MPH 2, dex,l‐MPH 6, placebo 5) Diagnosis of ADHD: DSM‐IV (combined (64%), hyperactive‐impulsive (1%), inattentive (35%)) Age: mean 9.8 years (range 6‐17) IQ: not stated. No mental disability MPH‐naive: 95 (72%) Ethnicity: white (78%), African American (14%), other (8%) Country: USA Setting: outpatient clinic Comorbidity: no Comedication: no Other sociodemographics: no significant differences in baseline demographics were noted between the 2 groups Inclusion criteria Enrolled in elementary school Within 30% of normal body weight Anticipated as available for the entire length of the trial Female participants were required to be pre‐menarche Exclusion criteria History or evidence of cardiovascular, renal, respiratory (other than asthma/allergy), endocrine or immune system disease History of substance abuse Hypersensitivity to dex,l‐MPH or other stimulants Treatment with any investigational drug within 30 days of screening Any other significant CNS disorders such as mental disability, Tourette’s or chronic tic disorder, psychosis, pervasive developmental disorder, eating disorders, OCD, impulse control disorder or sleep disorders requiring medication, major depressive disorder or generalised anxiety disorder Treatment with antidepressants (tricyclic antidepressants, SSRIs and MAOIs), sedative/hypnotics (e.g. barbiturates, benzodiazepine), neuroleptic/antipsychotics, mood stabilisers; anticonvulsants, beta‐blockers, α2‐agonists, thyroid medications and long‐term oral steroids
Interventions	Participants were randomly assigned to IR‐MPH (dex‐MPH, dex,l‐ MPH) or placebo No of participants randomised to each group: d‐MPH 44, dex,l‐MPH 46, placebo 42 Mean MPH dosage: d‐MPH 18.25 mg/d, dex, l‐MPH 32.14 mg/d Administration schedule: twice daily in the morning (7:00 am‐8:00 am) and at noon (11:30 am‐2:30 pm) Duration of intervention: 4 weeks Titration period: maximum 3 weeks initiated after randomisation, included in the 4 weeks of intervention Treatment compliance: not stated
Outcomes	ADHD symptoms SNAP ADHD‐RS ‐ Teacher Version: teacher‐rated, at baseline and twice weekly for 4 weeks, in the afternoon SNAP ADHD‐RS ‐ Parent Version: parent‐rated, at baseline and daily on the weekend for 4 weeks, at 3:00 pm and 6:00 pm Non‐serious AEs Occurrence and severity, monitored by investigator, at weekly visits Laboratory tests, physical examination findings and vital signs
Notes	Sample calculation: yes Ethics approval: yes; approved by the institutional review board at each centre Comments from trial authors Post hoc contrasts of small differences between d‐MPH and dex,l‐MPH conditions were not statistically significant in this between‐participant design 3 participants who did not meet the criteria set for a placebo response during the lead‐in period were inadvertently entered into the double‐blind phase (2 randomly assigned to dex,l‐MPH, 1 to placebo), which was a violation of the protocol Key conclusions of trial authors For treatment of ADHD, an average titrated dose of 18.25 mg/d of d‐MPH is as efficacious and safe as an average titrated dose of 32.14 mg/d of dex,l‐MPH Both active treatments have large effect sizes. Thus, d‐MPH and dex,l‐MPH appear to provide similar efficacy Comment from review authors We have not used these data, as reported data could not be used in our meta‐analyses Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: yes, see exclusion criteria Any withdrawals due to AEs: yes. “parental consent was withdrawn for one patient due to deterioration of behavior on placebo”, and “AEs (two patients each in the d,l‐MPH and placebo groups)” Funding source: Celgene Corporation Email correspondence with trial authors: January 2014. Not possible to obtain data from trial authors
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomised"
Allocation concealment (selection bias)	Unclear risk	No information
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Drug (d‐MPH and dex,l‐MPH) and placebo were identical in appearance
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double‐blind
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Sample size calculations were based on a clinically meaningful effect size of 0.75 in the change in score over 4 weeks on the teacher‐rated SNAP between d‐MPH and placebo groups. Efficacy parameters were performed on the ITT sample, which included participants who received medication, had a baseline efficacy evaluation and had ≥ 1 post‐baseline efficacy evaluation Selection bias (e.g. titration after randomisation → exclusion): no
Selective reporting (reporting bias)	Unclear risk	No protocol published