Greenhill 2002.

Study characteristics
Methods	3‐week, randomised, double‐blind, 32‐site, parallel trial with 2 arms: MR‐MPH placebo
Participants	Number of participants screened: 507 Number of participants included: 321 (257 boys, 57 girls) Number of participants followed up: MPH 141, placebo 135 Number of withdrawals: MPH 17, placebo 28 Diagnosis of ADHD: DSM‐IV (combined subtype or predominantly hyperactive‐impulsive subtype) Age: mean 9 years (range 6‐15) IQ: > 80 ADHD treatment‐naive: 36% Ethnicity: white (71%), African American (15%), Hispanic (10%), other (4%) Country: USA Setting: outpatient clinic Comorbidity: none Comedication: concomitant use of clonidine, anticonvulsant drugs and medications known to affect BP and heart rate was not allowed Other sociodemographics: no significant differences in baseline demographics were noted between the 2 groups Inclusion criteria 6‐16 years of age Primary diagnosis of ADHD, combined subtype or predominantly hyperactive‐impulsive subtype, as defined in DSM‐IV Did not respond to placebo with a reduction of ADHD symptoms during washout period First‐grade or higher school setting in which a single teacher could assess behaviour BP, heart rate and oral temperature had to be within normal range Exclusion criteria Comorbid psychiatric diagnosis History of seizure or tic disorder Family history of Tourette’s syndrome IQ < 80 Inability to follow or understand trial instructions Female patient who had undergone menarche Use of amphetamines, pemoline or an investigational drug within 30 days of trial entry Concomitant use of clonidine, anticonvulsant drugs or medications known to affect BP, heart rate or CNS function Hyperthyroidism or glaucoma Concurrent chronic or acute illness (e.g. allergic rhinitis, severe cold) or disability that could confound trial results Failed a previous trial of stimulants for ADHD Requiring a third daily dose in the afternoon or evening Documented allergy or intolerance to MPH Living with anyone who currently had substance abuse disorder (excluding dependency)
Interventions	Participants were randomly assigned to MR‐MPH or placebo Number randomised to each group: MPH 158, placebo 163 Mean MPH dosage: 40.7 mg/d (1.28 mg/kg/d) Administration schedule: once daily Duration of intervention: 3 weeks Titration period: none Treatment compliance: medication counts showed satisfactory adherence in both groups
Outcomes	General behaviour CGI ‐ teacher version: rated twice daily (morning and afternoon), 3 times a week CGI ‐ parent version, 1 day of each weekend during the morning, afternoon and evening Non‐serious AEs Pittsburgh (11‐item) Side Effects Questionnaire: parent‐ and teacher‐rated weekly Teachers completed a similar side effect questionnaire
Notes	Sample calculation: no Ethics approval: yes; probably approved by an institutional review board Comments from trial authors "Because no dose‐response curves were collected on children in the trial, we could not determine whether effects of modified‐release methylphenidate were dose‐related." Trial inclusion and exclusion criteria were selected for milder cases of ADHD Lower scores in this trial mean that findings may not be generalisable 3‐week duration of the trial did not allow investigators to determine whether dual‐phase effects of MR‐MPH persist with long‐term treatment Trial design limited generalisability of the results because it excluded acute placebo responders and those who had failed to respond to any MPH treatment before the start of the trial Parents were aware that researchers had the option of stepping up the "dose" of placebo each week Key conclusion of trial authors MR‐MPH administered once daily in the morning was well tolerated and was significantly more effective in a double‐blind comparison with placebo in controlling ADHD symptoms throughout the school day Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: yes; participants with a documented allergy or intolerance to MPH were excluded Any withdrawals due to AEs: yes, 2 Funding source: Celltech Pharmaceuticals Incorporated Email correspondence with trial authors: November and December 2013: not possible to get supplemental information regarding the trial through personal email correspondence with trial authors
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated "randomised". Stratification based on previous treatment before randomisation ensured equal distribution across the 2 treatment groups
Allocation concealment (selection bias)	Unclear risk	No information
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Identical appearing MR‐MPH and placebo capsules were packaged in blister cards
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Stated "double‐blinded"
Incomplete outcome data (attrition bias) All outcomes	Low risk	316 were included in the safety population, and 314 in the ITT efficacy population. All statistical summaries and analyses were conducted for the ITT population using the LOCF approach for children who withdrew prematurely Selection bias (e.g. titration after randomisation → exclusion): yes; exclusion of placebo responders
Selective reporting (reporting bias)	Unclear risk	No protocol available