Findling 2008.

Study characteristics
Methods	7‐week randomised, phase III, double‐blind, multi‐centre, parallel‐group, placebo‐controlled, naturalistic home and school trial with 3 arms: MPH transdermal system patch + placebo capsule OROS‐MPH capsule + placebo patch placebo capsule + placebo patch 5‐week titration phase, 2‐week maintenance phase
Participants	Number of participants screened: not stated Number of participants included: 282 (187 boys, 95 girls) Number of participants randomly assigned (and administered ≥ 1 dose of trial medication): MPH transdermal system 100, OROS‐MPH 94, placebo 88 Number of participants followed up: MPH transdermal system 71, OROS‐MPH 66, placebo 32 Number of withdrawals: MPH transdermal system 27, OROS‐MPH 25, placebo 53 Diagnosis of ADHD: DSM‐IV‐TR (combined (80.5%), hyperactive‐impulsive (1.4%), inattentive (17.0%), unclassified (1.1%)) Age: mean 8.8 years (range 6‐12). MPH transdermal system 8.9, OROS‐MPH 8.8, placebo 8.5 IQ: ≥ 80 MPH‐naive: 86% Ethnicity: white (77.3%), African American (14.5%), Asian (0.7%), Hispanic (not stated), other (7.4%) Country: USA Setting: outpatient clinic Comorbidity: not stated Comedication: not stated Other sociodemographics: no significant differences in baseline demographics (age, sex, ethnicity, ADHD subtype, prior ADHD medication use) among the 3 groups Inclusion criteria 6‐12 years of age, inclusive ADHD, DSM‐IV‐TR Stimulant‐naive or known to be stimulant‐responsive IQ ≥ 80 Total score of 26 on ADHD‐RS‐IV, while unmedicated Normal laboratory parameters and vital signs, including ECG Female patients of childbearing potential must have a negative serum HCG pregnancy test at screening and a negative urine pregnancy test at baseline Exclusion criteria Comorbid psychiatric diagnosis (except ODD) History of seizures during the past 2 years Tic disorder Any concurrent illness or skin disorder that might compromise safety or trial assessments Ingestion of clonidine, atomoxetine, antidepressants, antihypertensives, investigational medications, hepatic or cytochrome (p 450) enzyme‐altering agents, medications with central nervous system effects, sedatives, antipsychotics or anxiolytics within the 30 days before trial entry Overweight (body mass index (BMI)‐for‐age > 90th percentile)
Interventions	Participants were randomly assigned to MPH patch, OROS‐MPH or placebo Titration period: 5 weeks (after randomisation) of optimisation to 1 of 4 total daily dosage strength. OROS‐MPH: 18 mg, 27 mg, 36 mg and 54 mg. MPH transdermal system and placebo transdermal system: 10 mg, 15 mg, 20 mg and 30 mg over a 9‐h period in patches of 12.5 cm², 18.75 cm², 25 cm² and 37.5 cm², respectively Administration schedule: treatments were administered at approximately 7:00 am each morning; patches were applied to the hip area and were worn for approximately 9 h daily, different hip each day Mean patch wear time: 8.70 (0.51) to 9.46 (0.53) h Duration of intervention: 7 weeks Washout before trial initiation: up to 28 days if applicable Treatment compliance: mean compliance 97% to 99% during both trial phases
Outcomes	ADHD symptoms ADHD‐RS‐IV: clinician‐rated, weekly CTRS: teacher‐rated, twice weekly CPRS: parent‐rated, twice weekly Non‐serious AEs Evaluations for safety were performed at the end of each week during both dose‐optimisation and dose‐maintenance phases. Furthermore, AEs were spontaneously reported as coded via MedDRA (7.0) Adverse Event Dictionary BP, pulse, oral temperature, weight: weekly Laboratory parameters: week 7 Sleep‐related behaviours rated by parents each week using Childrens' Sleep Habits Questionnaire Skin reactions due to the patch investigated each week; Dermal Response Scale ECG: final dose‐optimisation visit and final trial visit
Notes	Sample calculation: yes (258 participants) Ethics approval: yes   Comments from trial authors It is important to note, however, that effects reported are for baseline and endpoint reports of sleep problems; thus, these results may not generalise to the titration period. For example, sleep problems may have resulted in dosage adjustments and attenuation of sleep problems during titration Respondents did not enter the maintenance phase if spontaneously reported side effects could not be controlled by adjusting the dose. Thus, participants with extreme insomnia would not have entered the maintenance phase Rating scales for sleep problems may lack validity Key conclusions of trial authors Results of this trial suggest that the MPH transdermal system is an efficacious treatment option for children with ADHD "Results of our analysis suggest that emergence or worsening of sleep problems in response to treatment of ADHD symptoms with OROS methylphenidate or methylphenidate transdermal system generally should not be a major concern to clinicians, children with ADHD or their parents after titration to an optimal dose, as described for this protocol. However, these suggestions should be considered in the light of other research that supports an effect of MPH on insomnia and other sleep difficulties, especially when MPH will be administered to children with pre‐existing sleep difficulties. These findings should not be generalised to children who have not been titrated to an optimal dose." Inclusion of MPH responders only/exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: yes. An inclusion criterion is that participants are stimulant‐naive or stimulant‐responsive Any withdrawals due to AEs: yes; 11 Funding source: Shire Development Incorporated, Wayne, Pennsylvania Email correspondence with trial authors. June‐September 2013. We attempted to obtain supplemental efficacy and safety data from trial authors but without success
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random numbers schedule
Allocation concealment (selection bias)	Low risk	Computer‐generated random numbers schedule
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind, double‐dummy: participants received both a patch and a capsule to be administered each day. MPH and placebo capsules were over‐encapsulated to blind the identity of the capsule’s content
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Double‐blind
Incomplete outcome data (attrition bias) All outcomes	High risk	ITT, LOCF Selection bias: yes; non‐responders excluded during the trial. Participants who did not reach an acceptable condition by the final dose‐optimisation visit (week 5) were withdrawn from the trial
Selective reporting (reporting bias)	Low risk	Outcomes reported according to protocol