Greenhill 2006.

Study characteristics
Methods	7‐week multi‐centre, randomised, double‐blind, placebo‐controlled, parallel trial with 2 arms: ER‐d‐MPH placebo To compare the efficacy and safety of ER‐d‐MPH vs placebo in paediatric patients with ADHD Pre‐randomisation phase of up to 2 weeks followed by double‐blind treatment phase for 7 weeks (5 weeks of dose titration followed by 1 week of optimal constant dose)
Participants	Number of participants screened: not stated Number of participants included: 103 (66 boys, 37 girls) Number of participants followed up: MPH 48, placebo 37 (ITT analyses: MPH 52, placebo 45) Number of withdrawals: MPH 5, placebo 13 Diagnosis of ADHD: DSM‐IV (combined (83%), hyperactive‐impulsive (1.9%), inattentive (15.1%)) Age: mean MPH 9.6 years, placebo 10.4 years (range 6‐17) IQ: > 70 (age‐appropriate functioning levels academically) MPH‐naive: 40 Ethnicity: white (60%), African American (23.3%), other (16.5%) Country: USA Setting: classroom setting Comorbidity: no psychiatric comorbidity Comedication: not stated Other sociodemographics: no significant difference in baseline demographics was noted between the 2 groups. See Tables 1 and 2 Inclusion criteria ADHD diagnosis as per DSM‐IV Baseline age of 6‐17 years Conners' ADHD/DSM‐IV Scales ‐ Teacher, for boys 6‐8 years ≥ 27, 9‐11 years ≥ 24, 12‐14 years ≥ 19, 15‐17 years ≥ 14 Conners' ADHD/DSM‐IV Scales ‐ Teacher, for girls 6‐8 years ≥ 16, 9‐11 years ≥ 13, 12‐14 years ≥ 12; 15‐17 years ≥ 6 Age‐appropriate functioning levels academically Negative pregnancy test and adequate contraception Exclusion criteria Clinically significant abnormalities in vital signs, physical examination findings or laboratory test results History of seizures or use of anticonvulsant medication Comorbid psychiatric conditions (obtained by clinical interview) Any medical condition that could interfere with trial participation or assessments, or that may pose danger with administration of MPH Psychotropic medications Initiation of psychotherapy within the past 3 months Positive urine drug screen History of poor response or intolerance to MPH Pregnant or nursing Any other investigational drug within 30 d of trial entry
Interventions	Participants were randomly assigned to an ER formulation of d‐MPH or placebo. Permitted doses were 5 mg/d for the 1st week; 5 or 10 mg/d for the 2nd week; 5 mg/d, 10 mg/d or 15 mg/d for the 3rd week; 5 mg/d, 10 mg/d, 15 mg/d or 20 mg/d for the 4th week; and 5 mg/d, 10 mg/d, 15 mg/d, 20 mg/d or 30 mg/d for the 5th through 7th weeks Number randomised to each group: MPH 53, placebo 50 Mean final MPH dosage: 24.0 ± 7.1 mg/d Administration schedule: once daily in the mornings Duration of intervention: 5‐week titration period plus 2 weeks at a constant dose Titration period: initiated after randomisation Treatment compliance: at each trial visit, compliance was assessed by investigator and trial staff on the basis of pill count and participant report
Outcomes	ADHD symptoms Conners' ADHD/DSM‐IV Scales ‐ Teacher: rated weekly by teachers Conners' ADHD/DSM‐IV Scales ‐ Parent: rated weekly by parents Serious AEs Spontaneous reporting recorded weekly: no deaths or serious AEs Quality of life Child Health Questionnaire, Parent Form 50: parent‐rated at final visit Non‐serious AEs Vital signs were rated weekly Spontaneously reported AEs were recorded weekly
Notes	Sample calculation: assumptions for sample size and power included treatment difference of 9.0 and SD of 13.5 Ethics approval: no information provided Comments from trial authors "It is of interest that no participant who received extended‐release dexmethylphenidate discontinued the trial because of an AE. This may result in part from the fact that more than one‐third of participants in each treatment group had prior experience with ADHD medications (mainly methylphenidate and dexmethylphenidate) and in part from the flexible‐dose design of the trial" "Another possible limitation is that patients with previous methylphenidate or dexmethylphenidate experience were enrolled only if they had not experienced moderate to severe adverse reactions. By excluding patients who could not tolerate methylphenidate or dexmethylphenidate, investigators may have inflated the apparent safety and tolerability of extended‐release dexmethylphenidate. However, only about one‐fourth of the participants in each treatment group had prior experience with methylphenidate or dexmethylphenidate, so this factor probably had little impact on AE rates during the trial" Key conclusions of trial authors "In conclusion, results of this trial indicate that extended‐release dexmethylphenidate administered once daily in doses of 5 mg to 30 mg is safe and effective for treatment of paediatric patients with ADHD symptoms, as reflected by its significant superiority over placebo on Conners' ADHD/DSM‐IV Scales ‐ Teacher, Conners' ADHD/DSM‐IV Scales ‐ Parent, CGI ‐ Improvement Scale and CGI ‐ Severity Scale, and in the Child Health Questionnaire Psychosocial Component score." "Extended‐release dexmethylphenidate was well tolerated and had a safety profile consistent with those of other methylphenidate or dexmethylphenidate formulations, resulting in appetite reduction and reduced weight in some patients." Comments from review authors Statistically significant treatment by centre interaction in primary efficacy analysis Trial authors defined baseline scores on Conners' ADHD/DSM‐IV Scales ‐ Teacher (to be included) as different scores for different age groups, but they informed efficacy as the difference from baseline to endpoint in all medicated individuals As precise information on dose (mg/kg/d) was lacking, it is difficult to evaluate whether 24 mg/d was enough for participants in this age range (6‐17 years) Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: yes; participants with history of poor response or intolerance to MPH were excluded Withdrawals due to AEs: MPH 0, placebo 1 Funding source: Novartis Email correspondence: July 2014. Wrote to Novartis to request additional information but have not received a reply
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomised, no further description provided
Allocation concealment (selection bias)	Unclear risk	No description provided
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Double‐blind, no further description provided
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Double‐blind, no further description provided
Incomplete outcome data (attrition bias) All outcomes	Low risk	Trial used an ITT analysis. LOCF analysis was used to impute missing values for all final visit analyses Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): no
Selective reporting (reporting bias)	High risk	Trial authors defined baseline scores on Conners' ADHD/DSM‐IV Scales ‐ teacher‐rated, as inclusion criteria (different scores for age groups), but they informed efficacy as the difference from baseline to endpoint for all medicated individuals