Wilens 2008.

Study characteristics
Methods	Open‐label, 5‐week, dose‐optimisation period. This dose was maintained during the subsequent 3 weeks of the trial, except for 1 d/week of 3‐way cross‐over assessment. Randomised, double‐blind, 8‐centre, 3‐way, 3‐week, cross‐over trial with 3 interventions: MPH transdermal patch (4 h) MPH transdermal patch (6 h) placebo
Participants	Number of participants screened: 148 Number of participants included: 128 in open‐label, dose‐titration; 117 entered the blinded, randomised trial Number followed up: 127 for safety and 117 for efficacy Number of withdrawals: 2 (both withdrew from the analogue classroom phase but were included in the ITT efficacy analysis) Characteristics of the 127 followed up for safety Sex: 84 boys, 42 girls Diagnosis of ADHD: DSM‐IV (combined or hyperactive‐impulsive (92.1%) inattentive (not stated)) Age: mean 8.8 years (SD 1.84; range 6‐12) IQ: > 80 MPH‐naive: not stated Ethnicity: white (63.2%), African American (15.4%), Asian (not stated) Country: USA Comorbidity: not allowed Comedication: not stated Other sociodemographics: none Characteristics of the 117 followed up for efficacy Sex: 75 boys, 42 girls Diagnosis of ADHD: DSM‐IV (type not stated) Age: mean 8.8 years (range 6‐ 12) IQ: > 80 MPH‐naive: not stated Ethnicity: white (63.2%), African American (15.4%), Asian (0%), other (21.4%) Country: USA Setting: outpatient clinic (analogue class room) Comorbidity: not allowed Comedication: not stated Sociodemographics: not stated Inclusion criteria Diagnosed with ADHD according to DSM‐IV‐T Minimum IQ score of 80 Exclusion criteria CD or comorbid illnesses that contraindicated or could confound MPH transdermal system treatment History of failing to respond to psychostimulant treatment Taken another investigational product within 30 days of screening or participated in other research trials involving drug treatment during the course of the trial Safety population consisted of 127 participants, who received ≥ 1 dose of trial medication 11 participants discontinued before the double‐blind randomisation phase, resulting in an ITT population of 117 participants 7 participants discontinued before the double‐blind randomisation phase, 3 were randomly assigned but did not undergo MPH transdermal system treatment 2 participants did not complete the analogue classroom phase of the trial: 1 because of an application site reaction, and 1 because of an AE (conjunctivitis), resulting in a total of 115 trial completers
Interventions	Participants were randomly assigned to 1 of 3 possible drug orders of MPH (4 and 6 h) and placebo Mean MPH dosage: 10 mg patch (n = 15), 15 mg patch (n = 34), 20 mg patch (n = 32) and 30 mg patch (n = 36) Administration schedule: once daily in the morning; patch worn for 9 h daily, and for 4 or 6 h for cross‐over assessments Duration of each medication condition: 1 day Participants were kept on their optimised dose between classroom sessions Washout before trial initiation: none; in‐between treatment with optimal dose of MPH Titration period: 5 weeks before randomisation Treatment compliance: not stated
Outcomes	ADHD symptoms SKAMP: teacher‐rated at randomisation (week 5) and 2 h after patch application at end of treatment (week 6, 7, 8) Quality of life ADHD Impact Module‐Child ‐ Child Impact Scale and Family Impact Scale: rated at baseline, at randomisation (week 5) and at end of trial (week 8) Non‐serious AEs Vital signs were evaluated at screening, at baseline and at weeks 1‐8 Erythema, oedema, papules and vesicles, discomfort, haematology, urinalysis and ECG measures were completed at screening, at baseline and at weeks 5 and 8 No clinically meaningful changes from baseline were observed in vital signs, ECG, urinalysis and haematological results or physical examinations. AEs were recorded from the time informed consent was signed until 30 days (week 12) after the last drug treatment
Notes	Sample calculation: yes; assuming a mean difference in SKAMP deportment score of 2.0 between active treatment and placebo, an SD of 5.0, a between correlation of 0.2, 90% power and a probability level of.05 (2‐sided), it was estimated that approximately 102 participants were needed to complete the double‐blind, cross‐over phase of the trial Ethics approval: yes; institutional review board at each site approved the trial Comments from trial authors Important to note that participants who failed to respond to psychostimulants in the past and those with CD were excluded from the study. Therefore, results of this study should not be extrapolated to these patient populations From Manos in Wilens 2008: "Lack of placebo comparison has the potential to confound the findings of this study. The relatively short study duration (about 2 months) may not be sufficient to capture some emerging changes in health‐related quality of life" Key conclusion of trial authors All efficacy measures indicated that 4‐ and 6‐h wear times improved ADHD symptoms Comments from review authors Treatment period is 1 day, 1 week apart for the 3 phases, and all participants are treated with MPH at optimal titrated dose in‐between Quality‐of‐life assessments are aggregated for all (not possible to assess MPH vs placebo) Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: yes; participants with a history of failing to respond to psychostimulant treatment were also excluded Any withdrawals due to AEs: yes; 1 (conjunctivitis) Funding: Shire Development Incorporated Email correspondence with trial authors in April‐June 2014. Emailed trial authors twice to ask for additional data but never received a response
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Single randomisation schedule prepared by an independent statistician using computer software that generated random numbers
Allocation concealment (selection bias)	Unclear risk	No information
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Each participant wore 2 patches prepared by an unblinded pharmacist to maintain treatment blind
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias) All outcomes	Low risk	There were only 2 withdrawals during the double blind phase Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): no
Selective reporting (reporting bias)	Low risk	No indication of selective reporting, outcomes according to protocol