Wolraich 2001.

Study characteristics
Methods	28‐day, randomised, parallel, double‐blind clinical trial with 3 arms: OROS‐MPH IR‐MPH placebo
Participants	Number of participants screened: 405 Number of participants included: 312 (233 boys, 49 girls) Number of participants followed up: 206 (OROS‐MPH 79, IR‐MPH 81, placebo 46) Number of withdrawals: 71 (OROS‐MPH 15, IR‐MPH 13, placebo 43) Diagnosis of ADHD: DSM‐IV (combined (73.4%), hyperactive‐impulsive (7.1%), inattentive (19.5%)) Age: mean 9.0 years (range 6‐12) IQ: > 70 MPH‐naive: 20.2% Ethnicity: white (84.4%), African American (7.4%), Asian (0.4%), Hispanic (3.5%), other (4.3%) Country: USA Setting: outpatient clinic Comorbidity: ODD (41.8%), CD (11.3%), tic disorder (5.3%), anxiety disorder (1.4%), depression (0.7%) Comedication: not stated Other sociodemographics: none Inclusion criteria 6‐12 years of age Clinical diagnosis of any subtype of ADHD ‐ had to be confirmed by the DISC‐4, administered by a trained interviewer Patients who were taking MPH or had taken it in the past had to have been on a total daily dose of MPH (IR‐or a combination of IR/ER) of ≥ 10 mg but ≤ 60 mg Patients had to agree to take the supplied trial drug as the only medication for ADHD during the 4‐week trial period IQ > 70 Exclusion criteria Acute or serious chronic disease Hypersensitivity to MPH Significant adverse experiences from MPH Taking a medication that would interfere with safe administration of MPH Glaucoma, Tourette’s syndrome, ongoing seizure disorder or psychotic disorder Girls who had reached menarche During the course of the trial, participants were allowed to receive behavioural interventions as long as the interventions had been initiated before the start of the trial and did not change during the trial. New behavioural therapy was not allowed during the course of the trial
Interventions	Average total daily dose: IR‐MPH 29.5 mg/d (0.90.4 mg/kg/d ), OROS‐MPH 34.3 mg/d (1.1 to 0.5 mg/kg/d ) No. of participants randomised to each group: OROS‐MPH 94, IR‐MPH 94, placebo 89 Administration schedule: 3 times/d Duration of intervention: 4 weeks Titration period: 4‐week titration period before randomisation (open‐label) for trial participants who had not received MPH for ADHD from their own practitioner in the 4 weeks before trial entry. Participants who had taken MPH during the 4 weeks before trial entry were assigned to a dose level based on their pre‐trial therapeutic dose and regimen Treatment compliance: not stated
Outcomes	ADHD symptoms IOWA CRS: teacher‐ and parent‐rated on day 27 SNAP, 4th Edition: teacher‐ and parent‐rated, week 4 Quality of life CGAS
Notes	Sample size calculation: yes Ethics approval: yes Key conclusion of trial authors Results of this study show that OROS methylphenidate administered once a day and immediate‐release methylphenidate administered 3 times a day were significantly better than placebo and were not significantly different from each other for the primary efficacy measure, teacher IOWA Conners' Rating Scale, Inattention‐Impulsivity‐Overactivity subscale score, which evaluated attention and behaviour at school. Furthermore, significant improvement in attention and behaviour was seen in the first week for participants who were taking OROS methylphenidate qd or immediate‐release methylphenidate three times a day compared with placebo, and this improvement was maintained throughout the 4 weeks of the study. These results were consistent across settings (home and school), raters (parents, teachers, clinical investigators) and measures (IOWA Conners' Rating Scale; Swanson, Nolan and Pelham, Fourth Edition; Peer Interaction; Global Assessments; Parent Satisfaction) and were statistically significant Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: yes; 111 who had not received MPH before the study initially were enrolled into a dose‐titration study. One of these did not enrol in the randomised study because the 54‐mg dose was found to be ineffective Any withdrawals due to AEs: yes; 3 Funding source: ALZA Corporation Comments from review authors in July 2013: corresponded with first trial author, Wolraich, who answered all of our questions (Krogh 2013c [pers comm]).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Within each dose level, participants were randomly assigned equally to OROS‐MPH once/d, IR‐MPH (over‐encapsulated Ritalin) 3 times/d or placebo in a 3‐group parallel design. Stratified randomisation was conducted centrally at ALZA Corporation
Allocation concealment (selection bias)	Low risk	Double‐dummy
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind; double‐dummy
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double‐blind; double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	LOCF Selection bias (e.g. titration after randomisation → exclusion): no, but 59 discontinued due to lack of efficacy.
Selective reporting (reporting bias)	Unclear risk	Not able to get trial protocol