Silva 2008.

Study characteristics
Methods	Randomised, multi‐centre, double‐blind, placebo‐controlled, cross‐over design with 2 interventions: ER‐d‐MPH placebo
Participants	Number of participants screened: 68 (45 boys, 23 girls) Number of participants included: 68 Number of participants followed up: 67 Number of withdrawals: 1 (from the placebo group) Diagnosis of ADHD: DSM‐IV (combined (82.4%), hyperactive‐impulsive (0%), inattentive (17.6 %)) Age: mean 9.5 years (range 6‐12) IQ: > 70 MPH‐naive: none Ethnicity: white (50%), African American (22.1%), Asian (0%), Hispanic (19.1%), other (8.8%) Country: USA Setting: outpatient clinic Comorbidity: not stated Comedication: not stated Other sociodemographics: none Inclusion criteria 6‐12 years of age DSM‐IV diagnosis of ADHD Participants had to be clinically and behaviourally stable in the opinion of the referring physician and the site's principal investigator Have taken their current dose of medication without adjustment for ≥ 2 weeks (this was required to be a total daily dose or nearest equivalent of MPH 40 mg or IR‐d‐MPG 20 mg (Concerta 36 mg was allowed)) Parents and/or guardians had to provide informed consent Female participants were required to be pre‐menarchal or sexually abstinent, or had to be using an adequate and reliable contraceptive method (e.g. double‐barrier method), which was documented in the medical record. Girls who were sexually active were required to have a negative result on a urine pregnancy screening test Exclusion criteria Children were excluded if they or their parents/guardians were unable to understand or follow instructions necessary to participate in the trial If they were deemed by the investigator to have below‐normal cognitive capacity, or if they were home schooled Diagnosed with Tourette's disorder or a tic disorder, or had a history of, or concurrent, significant medical or psychiatric illness or substance abuse disorder Children taking an antidepressant medication, those who initiated psychotherapy within the 3 months preceding screening and those with a positive urine drug screen Also excluded were children with poor response or intolerance to MPH, who were currently taking other medications for ADHD or were taking or planning to take any other investigational drug within 30 days of trial start or who had previously participated in ER‐d‐MPH studies
Interventions	Participants were randomly assigned to ER‐d‐MPH or placebo Mean MPH dosage: 20 mg/d Administration schedule: once daily, in the morning Duration of each medication condition: 7 days Washout before trial initiation: 2 days Titration period: none Treatment compliance: not stated
Outcomes	ADHD symptoms Combined score on the SKAMP: measured at time points 1, 3, 4, 5, 7, 9, 10, 11 and 12 h post‐dose by independent blinded raters. Rated at practice day (0), period 1 (visit day 7) and period 2 (visit day 14), and at final visit (visit day 15) Attention and deportment scores on the SKAMP, obtained from 0.5 h up to 12 h by independent blinded raters. Rated at practice day (0), period 1 (visit day 7) and period 2 (visit day 14), and at final visit (visit day 15) Combined score on the SKAMP, measured at time point 0.5 by independent raters. Rated at practice day (0), period 1 (visit day 7) and period 2 (visit day 14), and at final visit (15) Non‐serious AEs Vital signs obtained at practice day (0), period 1 (visit day 7) and period 2 (visit day 14), and at final visit (15) Recording of spontaneously reported AEs
Notes	Sample calculation: no Ethics approval: yes Comment from trial authors Unequal carry‐over effects: as a result of the design used in this trial, a test for carry‐over effects could not be performed. Instead, tests of sequence effects in the analysis of the co‐variance model were examined. If tests on sequence factors among time points were statistically significant (P = 0.05), analyses were performed by each period Limitations Each participant took ER‐d‐MPH for only 1 week Only 1 dose (20 mg/d) was used, meaning that results may not be generalisable to other doses Trial was confined to school‐aged children, so applicability of results to pre‐school children, adolescents or adults is unknown All participants in this trial had been previously shown to respond to and tolerate MPH or d‐MPH Children who received placebo during the week before the laboratory classroom day showed statistically better pre‐dose performance than children who received active medication on all measures except the Swanson, Kotkit, Agler, M‐Flynn and Pelham Scale Key conclusions of trial authors In this study, once‐daily ER‐d‐MPH 20 mg was effective in treating both inattentive and behavioural symptoms in paediatric patients over a 12‐h laboratory classroom day Primary efficacy variable ‐ combined score on the SKAMP ‐ showed significant superiority over placebo at all time points from 1‐12 h Secondary efficacy variables indicated that onset of effect was rapid (0.5 h) and duration of effect was relatively long (12 h post dose) In this sample, the drug was safe and well tolerated Changes in vital signs were comparable with those of placebo Inclusion of MPH responders only/exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: yes Any withdrawals due to AEs; yes Funding source: Novartis Email correspondence with trial authors: October 2013. We received supplemental information from trial authors regarding ethics approval and data. We were not able to obtain first period data
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random assignment
Allocation concealment (selection bias)	Unclear risk	No information
Blinding of participants and personnel (performance bias) All outcomes	Low risk	All trial medications were identical in appearance for blinding purposes; double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double‐blind
Incomplete outcome data (attrition bias) All outcomes	Low risk	Safety population consisted of all participants who took ≥ 1 dose of trial medication. Efficacy population included all randomly assigned participants who provided valid efficacy measurements for both treatment periods. Selection bias (e.g. titration after randomisation → exclusion): no
Selective reporting (reporting bias)	Low risk	Outcomes according to protocol