Findling 2010.

Methods	This was a Phase IIIB, randomised, double‐blind, parallel‐group, placebo‐controlled, multicentre, dose‐optimisation study evaluating the efficacy and safety of Methylphenidate transdermal system (10‐, 15‐, 20‐, or 30‐mg/9‐hour patches) Placebo transdermal system The study consisted of 4 experimental periods: Screening and washout Dose optimisation (5 weekly visits) Dose maintenance (5 monthly visits) A 7‐day post‐treatment follow‐up. The follow‐up was an open‐label extension study for evaluating the safety and efficacy of methylphenidate transdermal system (10‐, 15‐, 20‐ or 30 mg/9‐hour patches) for participants who completed all required study visits and consisted of 3 experimental periods
Participants	For the open‐label extension: Number of participants screened: not stated Number of participants included: 163 (110 previously on MPH and 53 on PL) Number of participants followed up: 162 Number of withdrawals 1 Diagnosis of ADHD: DSM‐IV (subtype: not stated) Age: 14.5 (SD 1.24) years (range 13‐17) IQ: ≥80 Sex: 121 males, 41 females Methylphenidate‐naïve: 56% (122) Ethnicity: white (78%), African American (17%), Asian (0.6%), others (4.4%) Country: USA Comorbidity: none Comedication: not stated Sociodemographics; not stated Inclusion criteria Male or female adolescents 13‐17 years Primary diagnosis of ADHD according to DSM‐IV IQ score of > 80 A total score of ≥ 26 on the ADHD‐Rating Scale‐IV (ADHD‐RS‐IV) at baseline Participants were required to have electro‐cardiogram (ECG) results within normal range or variants that were not clinically significant as judged by investigators in conjunction with the central laboratory Blood pressure measurements within the 95th percentile for age, gender, and height No current or history of skin disease or other skin problems including sensitive skin or signs of skin irritation Females must have a negative urine pregnancy test at entry and agree to use acceptable contraceptives throughout the study 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 study procedures and restrictions Regarding the 6‐month open‐label study: participants must have completed all required study visits or completed a 5‐week dose‐optimisation period without achieving an acceptable condition (i.e. . ≥ 25% decrease from baseline in a participant's ADHD‐Rating Scale IV score with minimal side effects) Exclusion criteria Conduct disorder or comorbid psychiatric illnesses (such as clinically significant obsessive compulsive disorder, depressive, or anxiety disorders; posttraumatic stress disorder; psychosis; bipolar illness; or pervasive developmental disorder) A 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 last 6 months Seizures during the previous 2 years and those who had 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 prior to screening Female participants who are pregnant or lactating Regarding the 6‐month open‐label study: participants were not eligible to participate in the extension study if they were discontinued from the antecedent study due to protocol violation (including non‐compliance), an AE for which continued treatment would be medically contraindicated, or a serious adverse event (SAE). 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 if the study were also excluded
Interventions	Methylphenidate type: transdermal system Mean methylphenidate dosage at month 6: 10 mg (5.6.%), 15 mg (7.9%), 20 mg (32.6%), and 30 mg (53.9%); median exposure time: 168.0 days (range, 3‐200 days) Administration schedule: single patch in the morning, once daily for 9 hours Duration of intervention: 6 months Titration period: 5 weeks of the 6 months Treatment compliance: 88 fulfilled the protocol
Outcomes	Regarding the 6‐month open‐label study: Dose optimisation (5 weekly visits) versus dose maintenance (5 monthly visits): Adverse events were monitored at each study visit and assessed by an open‐ended inquiry along with specific dermatological questions asked by an investigator or 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) a 7‐day post‐treatment follow‐up. Height: measured at month 6 visit by the investigator Weight: recorded at all 5 visits by the investigator Vital signs (systolic blood pressure, diastolic blood pressure pulse), measured at all study visits, by the investigator. 12‐lead ECG performed at entry, week 4, month 3, month 6, by the investigator Blood and urine samples collected at entry, week 4, month 4, and month 6 Dermal skin reaction: measured by DRS at each study visit Sleep: measured by the non‐validated Post‐Sleep Questionnaire. Measured at the 6 month visit Any changes noted between evaluation data at study entry and data obtained at schedule visits deemed to be clinically significant by the investigator were considered an adverse event
Notes	Sample calculation: yes Ethics approval: yes Funding: this study was funded by Shire Development Inc., which was involved in the study design, conduct, and data analysis Vested interests/authors' affiliations: Dr Findling has received research support, acted as a consultant, and/or served on speakers' bureaus for Abbott, Addrenex, As‐ traZeneca, Biovail, Bristol‐Myers Squibb, Forest, GlaxoSmith Kline, KemPharm, Johnson & Johnson, Eli Lilly, Lundbeck, Neuropharm, Novartis, Organon, Otsuka, Pfizer, Sanofi‐Aventis, Sepracor, Schering‐Plough, Shire, Solvay, Supernus Pharmaceuticals, Validus, and Wyeth. Dr Katic has received research support, acted as a consultant, and/or served on speakers' bureaus for Forest, GlaxoSmithKline, Lundbeck, Merck, Novartis, Sanofi‐Aventis, Sepracor, Shire, Somerset, and Wyeth. Dr Rubin has received research support, acted as a consultant, and/or served on speakers' bureaus for Abbott, Addrenex, Cephalon, Eli Lilly, Johnson, Johnson, McNeal, Novartis, Shire, and UCB Celltech. Dr Moon received research support, acted as a consultant, and/or served on speakers' bureaus for Abbott, AstraZeneca, CNS Response, Eli Lilly, Johnson & Johnson, McNeil, Novartis, Pfizer, Sanofi‐ Aventis, Shire, Synosia Therapeutics, Takeda, and UCB Inc. Drs Civil and Li are employees of Shire Development Inc. Dr Civil is an employee of Shire Development, Inc. At the time of this study, Dr Li was an employee of Shire Development, Inc. Key conclusions of the study authors: regarding the 6 months open‐label study: methylphenidate transdermal system was generally well tolerated, and AEs were generally typical of those associated with oral methylphenidate, with the exception of application‐site reactions associated with transdermal delivery of methylphenidate Comments from the study authors: it is important to note that participants who failed to respond to psychostimulants in the past and those with conduct disorder and other psychiatric comorbidities were excluded from the study. Regarding the 6‐month study: no clinically significant findings between laboratory evaluation parameters obtained postentry relative to screening values obtained at the antecedent study Comments from the review authors: as already stated, people who earlier had failed to respond to psychostimulants were not included in the study. Therefore results can only be generalised to responders. Regarding the 6‐month open‐label study: participants who had not reached an acceptable response by the end of week 5 were withdrawn from the study Supplemental information requested from the study authors and Noven Pharmaceuticals with no reply