Silva 2005a.

Study characteristics
Methods	6‐week, randomised, single‐blind, placebo‐controlled, cross‐over trial with 5 interventions: ER‐MPH 20 mg ER‐MPH 40 mg OROS‐MPH 18 mg OROS‐MPH 36 mg Placebo
Participants	Number of participants screened: not stated Number of participants included: 54 (34 boys, 20 girls) Number of participants followed up: 53 Number of withdrawals: 1 Diagnosis of ADHD: DSM‐IV (combined (70.4%), hyperactive‐impulsive (1.9%), inattentive (27.8%)) Age: mean 9.4 years (range 6‐12) IQ: > 80 MPH‐naive: 0% Ethnicity: white (63.0%), African American (14.8%), Asian (0%), other (22.2%) Country: USA Setting: laboratory classroom Comorbidity: not stated Comedication: not stated Other sociodemographics: none Inclusion criteria Children 6‐12 years old Meeting DSM‐IV criteria for primary diagnosis of ADHD Written consent from parents Treated and stabilised on total daily dose of 20 mg‐40 mg MPH for ≥ 2 weeks before enrolment Girls are required to be pre‐menarchal, sexually abstinent or using an approved method of contraception Girls of childbearing potential are required to have a negative pregnancy test before enrolment Exclusion criteria IQ level ≤ 80 Diagnosed with Tourette's syndrome or a tic disorder Deemed by investigator to be unable to comply with trial instructions Significant concurrent medical or psychiatric illness or substance abuse disorder History of sensitivity to MPH History of substance abuse Currently taking atomoxetine Have taken, or is currently taking or planning to take, any investigational drug within 30 days of trial start date
Interventions	Participants were randomly assigned to 1 of 10 possible drug condition orders of 20 mg ER‐MPH, 40 mg ER‐MPH, 18 mg OROS‐MPH, 36 mg OROS‐MPH and placebo Mean MPH dosage: not stated Administration schedule: once Duration of each medication condition: 1 day Washout before trial initiation: 1 day Medication‐free period between interventions: participants were instructed to continue to take their regularly prescribed medication Sundays through Thursdays between trial days; no medication was administered on Fridays to avoid possible carry‐over effects during the Saturday treatment period Titration period: none Treatment compliance: not stated
Outcomes	ADHD symptoms SKAMP: by blinded raters, −0.5, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 h post‐dose. Primary analysis time point was 2 h post‐dose Non‐serious AEs AEs were assessed throughout the classroom period day Only 1 AE was considered to be drug‐related
Notes	Sample calculation: yes; 46 Ethics approval: approved by an independent investigational review board Comments from trial authors As available formulations of ER‐MPH contain 11% more MPH than their OROS‐MPH counterparts, outcomes might appear to be biased toward ER‐MPH OROS‐MPH releases a third bolus of active drug between 8 and 12 h after dosing, whereas ER‐MPH releases its last bolus at 4 h post dose. Hence, outcomes during the last 4 h of the day might, theoretically, be biased towards OROS‐MPH Study was conducted in a controlled laboratory classroom These results are representative of participants who are known responders to MPH All participants had been previously stabilised on ADHD medication, so they may have been able to detect a difference between active treatment and placebo Key conclusions of trial authors Efficacy of ER‐MPH 20 mg is similar to that of OROS‐MPH 18 mg and 36 mg during the first 8 h post‐dose Statistically greater benefits are observed with extended‐release MPH 40 mg than with OROS‐MPH 36 mg and persist through h 8 Active treatments show comparable efficacy from 8‐12 h post‐dose Both doses of each MPH formulation are well tolerated Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: yes Any withdrawals due to AEs: no Funding source: Novartis Pharmaceuticals Corporation Email correspondence with trial authors: April 2014. Sent an email to trial authors to ask for additional data but have not receive a reply
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	All trial personnel, with the exception of the nurse, pharmacist or physician dispensing medication, were blinded Trial medications were administered in an opaque container with a small aperture, so participants could not see them during administration
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The SKAMP was completed by blinded raters
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	1 participant received ER‐MPH 20 and 40 mg before discontinuing the trial. Reason not stated Selection bias (e.g. titration after randomisation → exclusion): no
Selective reporting (reporting bias)	Unclear risk	No protocol found