Wilens 2006b.

Study characteristics
Methods	2‐week, randomised, double‐blind, 15‐centre, parallel trial with 2 arms: OROS‐MPH placebo Phases: preceded by a 4‐week, open‐label, dose‐titration phase, and followed by an 8‐week, open‐label, follow‐up phase
Participants	Number of participants screened: 220 in the 4‐week dose‐titration phase Number of participants included: 177 (142 boys, 35 girls) Number of withdrawals: 44. MPH 16, placebo 28 Number of participants followed up: 171; number completing follow‐up: 135 Diagnosis of ADHD: DSM‐IV (subtype not stated) Age: mean 14.6 years (range 13‐18) IQ: not stated ADHD treatment‐naive: 24 Ethnicity: white (75.1%), African American (13.6%), other (11.3%) Country: USA Setting: outpatient clinic Comorbidity: not stated Comedication: not stated Other sociodemographics: the 2 groups were similar demographically, but the placebo group had a greater ratio of boys (P value < 0.04) Inclusion criteria Diagnosis of ADHD, as defined by DSM‐IV CGAS rating of 41‐70 at baseline (screening phase) Between 13 and 18 years of age Exclusion criteria Participants who are known to not respond to MPH Adverse experiences from MPH or hypersensitivity to Concerta or its components Marked anxiety, tension or agitation Psychiatric comorbidity requiring additional or different medication Glaucoma, ongoing seizure disorder, psychotic disorder, Tourette's disorder or family history of Tourette's disorder, bipolar disorder, an eating disorder Treatment with theophylline, coumarin, anticonvulsants Severe gastrointestinal narrowing SBP or DBP at ≥ 95th percentile for age, sex and height at screening
Interventions	Participants were randomly assigned to OROS‐MPH or placebo Number of participants randomised to each group:  MPH 87, placebo 90 Mean MPH dosage: 0.84 mg/kg Administration schedule: once daily Duration of intervention: 2 weeks Titration period: 4 weeks initiated before randomisation. All participants initiated therapy at 18 mg/d, and clinical response was measured after 1 week. If response to treatment was inadequate, as per the a priori trial definition, the dose was titrated upward (in 18‐mg increments) at 1‐week intervals for up to 4 weeks, with maximum dose of 72 mg/d Treatment compliance: not stated; 8‐week, open‐label follow‐up on individualised dosage
Outcomes	ADHD symptoms ADHD‐RS, clinician‐ and parent‐rated: completed at baseline and weekly during double‐blind phase Serious AEs Reported in only 1 participant during the open‐label dose‐titration phase of the trial. While being treated with OROS‐MPH 18 mg/d, a 16‐year‐old female participant with a history of depression and suicidal ideation threatened suicide on the 3rd day of medication use after an argument with her mother. Decision was made to discontinue trial medication, and symptoms resolved No serious AEs were reported during the double‐blind phase Non‐serious AEs Heart rate and BP, recorded by a clinician weekly throughout the whole trial ECG at screening and at end of double‐blind phase of the trial Spontaneous reports to the investigator of AEs recorded at weekly visits Safety assessments made at monthly visit and every 2 weeks between monthly visits during follow‐up Height and weight assessed at baseline and at weeks 4 and 8 in the follow‐up trial No participants experienced clinically important effects on ECG indexes, heart rate or BP during the trial
Notes	Sample calculation: yes Ethics approval: yes; trial was approved by the institutional review boards for all participating centres before the start of the trial Comments from trial authors "Exclusion criteria were significant and possibly limited the generalisability of results." "Participants may have had improved ADHD symptoms or psychosocial carry‐over effects as a consequence of participation in the study, medication titration and regular meeting with study personnel." "Our study was conducted partially during the summer, and this may have resulted in less stress on adolescents and overall improvement in both study groups. More sensitive measures of attention may be needed for adolescents with ADHD than for children." "Participants were titrated to their individualised dosage before the double‐blind phase of the study. This may have biased the results toward a positive response in the double‐blind phase." "The short duration of the double‐blind phase may have decreased the likelihood of detecting potential rare AEs." Rates of AEs reported for OROS‐MPH have been underestimated because participants entering this study phase were already stabilised on an affective tolerated dosage of medication. Key conclusions of trial authors In adolescents, once‐daily OROS‐MPH significantly reduced ADHD symptoms and was well tolerated at dosages up to 72 mg/d Adolescents required, on average, a higher absolute dose but a lower weight‐adjusted dose (mg/kg) of OROS‐MPH than was previously reported in children The incidence of AEs was not related to dose Inclusion of MPH responders only/exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: yes; criteria of response, defined as ≥ 30% improvement from baseline on the investigator‐scored ADHD‐RS. Participants who successfully completed the open‐label, dose‐titration phase were assigned a randomisation number Any withdrawals due to AEs: yes; 1 in the placebo group Funding source: McNeil Consumer and Specialty Pharmaceuticals Email correspondence with trial authors: December 2013 and Janurary 2014. Not able to make contact with trial authors
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomised, but method was not described
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Investigators were supplied with packages containing medication for each participant, as identified by randomisation number. Therefore, investigators and participants were blinded to whether a participant was receiving active medication or placebo
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Investigators were supplied with packages containing medication for each participant, as identified by randomisation number. Therefore, investigators and participants were blinded to whether a participant was receiving active medication or placebo
Incomplete outcome data (attrition bias) All outcomes	High risk	Non‐responders not included. LOCF technique was used for all assessments in the double‐blind phase. Of 182 (83%) participants who successfully achieved the criteria for improvement at the dose‐titration phase, only 177 were randomly assigned to the double‐blind phase, because 5 reached the criteria after the double‐blind phase was closed. Of 177 randomly assigned participants, 1 did not enter the double‐blind phase, and efficacy data were not collected for another participant. Therefore, 175 participants were included in the efficacy analysis of the double‐blind phase, but 177 were included in the dosage and safety analysis. Selection bias: yes, participants were excluded due to lack of efficacy during the double blind phase
Selective reporting (reporting bias)	Low risk	No indication of selective reporting, outcomes according to protocol