Findling 2010.

Study characteristics
Methods	Phase IIIB, randomised, double‐blind, parallel‐group, placebo‐controlled, multi‐centre, dose‐optimisation trial evaluating the efficacy and safety of the following in adolescents 13‐17 years of age with ADHD: MPH transdermal system (10 mg, 15 mg, 20 mg or 30 mg/9‐h patches) Placebo transdermal system Double‐blind RCT consisted of 4 experimental periods Screening and washout Dose optimisation (5 weekly visits) Dose maintenance (5 monthly visits) 7‐day post‐treatment follow‐up Open‐label extension follow‐up consisted of an open‐label extension trial conducted to evaluate the safety and efficacy of the MPH transdermal system (10 mg, 15 mg, 20 mg or 30 mg/9‐h patches) for participants who completed all required trial visits; consisted of 3 experimental periods
Participants	Double‐blind RCT Number of participants screened: not stated Number of participants included: 217 (162 boys, 55 girls) Number of participants randomly assigned: MPH 145, placebo 72 Number of participants followed up (ITT population): MPH 143, placebo 72 Number of withdrawals: MPH 2, placebo 0 Number that completed 7‐week dose‐optimisation/dose‐maintenance phase: MPH 95, placebo 72 Diagnosis of ADHD: DSM‐IV (types not stated) Age: mean 14.6 years (SD 1.3, range 13‐17) IQ: ≥ 80 MPH‐naive: 122 (56%) Ethnicity: white (77%), African American (18%), Asian (0.5%), other (4.5%) Country: USA Setting: outpatient clinic Comorbidity: 0% Comedication: not stated Other sociodemographics: no significant difference in baseline demographics were noted between the 2 groups Open‐label extension (safety measures) Number of participants included: 163 (previously taking MPH 110, placebo 53) Number of participants followed up: 162 (121 boys, 41 girls) Number of withdrawals: 1 Diagnosis of ADHD: DSM‐IV (types not stated) Age: 14.5 years (SD 1.24, range 13‐17) IQ: ≥ 80 MPH‐naive: 122 (56%) Ethnicity: white (78%), African American (17%), Asian (0.6%), other (4.4%) Country: USA Comorbidity: 0 % Comedication: not stated Other sociodemographics: none Inclusion criteria Male or female adolescents 13‐17 years of age Primary diagnosis of ADHD according to DSM‐IV IQ score > 80 Total score ≥ 26 on the ADHD‐RS‐IV, at baseline Participants were required to have ECG results within normal range or variants that were not clinically significant, as judged by investigators in conjunction with the central laboratory BP measurements within the 95th percentile for age, sex and height No current or past skin disease or other skin problems, including sensitive skin or signs of skin irritation Female patients must have a negative urine pregnancy test at entry and must agree to use acceptable contraceptives throughout the trial period and for 30 days the last dose of IP Participant and parent of legally authorised representative are able, willing and likely to fully comply with trial procedures and restrictions Open‐label extension (6 months): participants must have completed all required trial visits or a 5‐week dose‐optimisation period without achieving an acceptable condition (i.e. ≥ 25% decrease from baseline in a participant's ADHD‐RS‐IV, score with minimal side effects) Exclusion criteria CD or comorbid psychiatric illness (such as clinically significant OCD, depressive or anxiety disorder; PTSD; psychosis; bipolar illness; or pervasive developmental disorder); history of structural cardiac abnormality, cardiomyopathy, cardiac rhythm abnormalities or other serious cardiac problems; suicidal ideation; alcohol or other substance abuse (except caffeine or nicotine) within the past 6 months Seizures during the previous 2 years A history of being non‐responsive to psychostimulant treatment  Use of clonidine, atomoxetine, antidepressants, sedatives, antipsychotics, anxiolytics, P450 enzyme‐altering agents or other investigational medications within 30 days before screening Female participant who is pregnant or lactating Open‐label extension (6 months): Participants were not eligible to participate in the extension trial if they were discontinued from the antecedent trial because of a protocol violation (including non‐compliance) or had experienced an AE for which continued treatment would be medically contraindicated, or a serious AE Participants with considerable general medical illness (except mild, stable asthma) or an unstable medical condition, disability or other condition the investigator believed might interfere with or prevent completion of the trial
Interventions	Participants were randomly assigned to MPH transdermal (patches) or placebo Mean MPH dosage at week 7: 10 mg (4.2%), 15 mg (16.7%), 20 mg (24.0%), 30 mg (55.2%); median exposure time: 48 days (range 4‐57) Administration schedule: single patch in the morning, once daily for 9 h Duration of intervention: 7 weeks Titration period: 5 weeks, initiated after randomisation Treatment compliance: 124 fulfilled the protocol. However, it is not stated in the article how compliance regarding the medication had to be assessed to fulfil the protocol Mean MPH dosage at month 6: 10 mg (5.6%), 15 mg (7.9%), 20 mg (32.6%), 30 mg (53.9%); median exposure time: 168 days (range 3‐200) Administration schedule: single patch in the morning, once daily for 9 h Duration of intervention: 6 months Titration period: 5 weeks of the 6 months Treatment compliance: not stated. 88 fulfilled the protocol. However, it is not stated in the article how compliance regarding the medication had to be assessed to fulfil the protocol
Outcomes	7‐week parallel trial (Double‐blind RCT) ADHD symptoms ADHD‐RS, Clinicians: rated baseline and weekly for 7 weeks (each trial visit) CPRS‐R, Parents: rated baseline and weekly for 7 weeks (each trial visit) Serious AEs None Non‐serious AEs AEs monitored at each trial visit. All AEs were coded using the MedDRA, Version 7.0 Height measurements were performed at screening and at the final double‐blind trial visit Vital signs (SBP and DBP, pulse) and weight, at screening, at baseline and at each trial visit The investigator determined the clinical significance of any physical examination, height or vital sign measurement that was outside the normal range. Clinically significant deviations from measurements recorded at screening were reported as AEs. A 12‐lead ECG evaluation was obtained at screening, at baseline, at week 5 and at the final double‐blind trial visit. Dermal skin reaction: Dermal Scale was used to evaluate observed skin findings: range 0‐7, where 0 shows no evidence of irritation Regarding 6‐month open‐label extension: Dose optimisation (5 weekly visits); dose maintenance (5 monthly visits) AEs were monitored at each trial visit and were assessed by an open‐ended inquiry along with specific dermatological questions asked by an investigator or a qualified evaluator. AEs were considered treatment‐emergent if they began or worsened on or after application of the first patch, and occurred before or at the same time as application of the patch. AEs coded and defined using the MedDRA, Version 7.03, at 7‐day post‐treatment follow‐up Height: measured at month 6 visit by the investigator Weight: recorded at all visits (5) by the investigator Vital signs (SBP, DBP, pulse): measured at all trial visits by the investigator. 12‐Lead ECG performed at entry, week 4, month 3 and month 6 by the investigator Blood and urine samples collected at entry, week 4, month 4 and month 6 Dermal skin reaction: measured by Dermal Scale at each trial visit Sleep: measured by non‐validated Post‐Sleep Questionnaire. Measured at 6‐month visit Changes noted between evaluation data at trial entry and data obtained at schedule visits deemed to be clinically significant by the investigator were considered an AE
Notes	Sample calculation: yes. By using 85% power to detect an effect size of 0.5 between active treatment and placebo at the significance level of 5%, it was estimated that 112 participants were needed for MPH transdermal system groups and 56 for placebo transdermal system groups. Assuming a 20% dropout rate, ~ 210 participants (MPH transdermal system 140, placebo transdermal system 70) were required for the trial Ethics approval: yes Comments from trial authors Given the short duration of this trial, results do not characterise the long‐term effects of treatment with MPH transdermal system It is important to note that participants who failed to respond to psychostimulants in the past and those with CD and other psychiatric comorbidity were excluded from the trial Regarding the 6‐month trial: no clinically significant findings between laboratory evaluation parameters obtained post entry relative to screening values obtained at the antecedent trial Limitations: this trial used an open‐label design; thus tolerability and effectiveness assessments are susceptible to observer bias. Another way in which results of long‐term, open‐label continuation studies may be biased is that participants who enrol in a trial after participating in an antecedent trial may represent that subset of patients who have had improvement in ADHD symptoms and/or who did not experience substantial AEs in the antecedent trial Key conclusions of trial authors MPH transdermal system therapy was generally well tolerated and resulted in significantly greater improvement in ADHD symptoms among adolescents when compared with the placebo transdermal system Reported AEs included those typically observed for oral MPH, with the exception of generally mild application site erythema associated with transdermal delivery Regarding the 6‐month open‐label trial: MPH transdermal system was generally well tolerated, and AEs were generally typical of those associated with oral MPH, with the exception of application site reactions associated with transdermal delivery of MPH Comments from review authors As already stated, people who earlier had failed to respond to psychostimulants were not included in the trial. Therefore, results can be generalised only to responders Risk of bias table done only for the 7‐week parallel‐group trial Regarding the 6‐month open‐label trial: participants who had not reached an acceptable response by the end of week 5 were withdrawn from the trial Inclusion of MPH responders only/exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: yes, participants were excluded if they had a history of being non‐responsive to psychostimulant treatment Any withdrawals due to AEs: yes, 10 (2 in placebo group, 8 on MPH group) Fnding source: Shire Development Incorporated
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were allocated the next sequential randomisation number and received treatment that corresponded with that randomised number as given by an interactive voice response system
Allocation concealment (selection bias)	Low risk	Randomisation schedule was produced by computer software that incorporated a standard procedure for generating random numbers
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Double‐blind, but no information on MPH and placebo blinding
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Double‐blind
Incomplete outcome data (attrition bias) All outcomes	High risk	Efficacy analyses were performed on the ITT population, defined as all randomly assigned participants who received ≥ 1 dose of trial medicine and ≥ 1 post‐baseline primary efficacy assessment. Safety population was defined as all randomly assigned participants who received ≥ 1 dose of trial medicine. Selection bias (e.g. titration after randomisation → exclusion): yes. No further dose titration was permitted for any participant after week 5, and participants who had not reached an acceptable response by the end of week 5 were withdrawn from the trial
Selective reporting (reporting bias)	Low risk	No indication of selective reporting. Protocol registered 12 July 2007. First participant consent was obtained 29 August 2007 for the open‐label trial