Schulz 2010.

Study characteristics
Methods	Double‐blind, randomised, multi‐centre, triple cross‐over design with 3 interventions: ER‐MPH (Ritalin) 20 mg once daily ER‐MPH (Medikinet Retard) 20 mg once daily Placebo
Participants	Number of patients screened: 147 Number of participants included: 147 (119 boys, 28 girls) Number of participants followed up: 139 Number of withdrawals: 1 Diagnosis of ADHD: DSM‐IV diagnosis (combined (55%), hyperactive‐impulsive (8%), inattentive (37%)) Age: mean 10.2 years (range 6‐14) IQ: not stated MPH‐naive: 0% Ethnicity: not stated Country: Germany Setting: outpatient clinic Comorbidity: 6.8% (disturbance in social behaviour (2.7%), initial insomnia (0.7%), ODD (1.36%), dysphaemia (0.68%), encopresis (0.68%)) Comedication: no Other sociodemographics: none Inclusion criteria DSM‐IV diagnosis of ADHD confirmed by K‐SADS in the German Version All children had to be on a stable and well‐tolerated dose of 20 mg‐equivalent MPH for ≥ 1 month before screening Exclusion criteria Patients with known previous non‐response to MPH Children with relevant somatic or psychiatric comorbidity requiring pharmacological treatment (e.g. psychosis, major depression) Patients with warnings as described in the prescribing information for ER‐MPH (Ritalin), including tic disorders
Interventions	Pre‐randomisation phase and 3 treatment periods of 7 days each. Participants were randomly assigned to 1 of 6 possible drug condition orders of 20 mg ER‐MPH (Ritalin), 20 mg ER‐MPH (Medikinet Retard) and placebo Number of participants: not stated Mean MPH dosage: 20 mg daily Administration schedule: once daily, morning Time points: 9:00 am Duration of each medication condition: 7 days Washout before trial initiation: none Medication‐free period between interventions: none Titration period: none Treatment compliance: not stated
Outcomes	ADHD symptoms SKAMP (Wigal 1998) by 3 treatment‐blinded observers: rated at 1.5, 3.0, 4.5, 6.0 and 7.5 h after drug intake at the end of each treatment week SeriousAEs One serious AE was reported: a case of acute appendicitis during treatment with ER‐MPH (Ritalin). This was judged to be not treatment‐related 4 events were reported as "severe" and drug‐related: placebo: 2× aggressive behaviour; placebo: 1× lack of attention; ER‐MPH (Medikinet) 1× aggressive behaviour General behaviour Nisonger Child Behavior Rating Form (NCBRF‐TIQ) to assess behaviour in children applied once at the end of each treatment period Non‐serious AEs Monitoring and recording of all AEs by "Non‐directive questioning" at every visit "Regular monitoring of vital signs" Participants were called by phone every midweek and were asked about AEs Clinical abnormality in BP defined as increase or decrease ≥ 20 mmHg from age‐dependent normal values (ages 6‐9: SBP 90 mmHg, DBP 60 mmHg; age > 10 years: SBP 110 mmHg, DBP 75 mmHg) Clinically notable increased values for SBP were recorded under all 3 treatments: 15% on placebo, 17% on ER‐MPH (Ritalin) and 18% on ER‐MPH (Medikinet). Abnormal increases in DBP were noted in 5% of participants taking placebo and LA MPH (Ritalin) and in 3% of participants given ER‐MPH (Medikinet). Abnormal values in SBP among participants who had normal values at screening and at baseline were recorded in only 7 participants (3 given placebo, 3 taking ER‐MPH (Medikinet) and 2 taking ER‐MPH (Ritalin) ‐ as reported in the article). Changes in vital signs were attributed to sympathomimetic effects of MPH and were not considered clinically relevant
Notes	Sample calculation: yes Ethics approval: yes Comments from trial authors Another factor to be considered a limitation is that all participants were known MPH responders. This decision was made to ensure that study objectives regarding efficacy were met. However, it might have led to overestimation of treatment effect and tolerability in the overall population, as no treatment‐naive participants were included in this trial Individual dose titration as a standard approach in everyday practice was not allowed during this trial; therefore treatment response might not have been optimal for all children Inclusion of many other children, all with ADHD, as well as other experimental factors might have influenced the behaviour of the individual child Encapsulation might have altered the pharmacokinetics of active substances Key conclusions of trial authors Compared with placebo, both ER‐MPH (Ritalin) and ER‐MPH (Medikinet Retard) demonstrated robust treatment effects on core inattentive and hyperactive symptoms for up to 7.5 h in children with ADHD in a laboratory classroom Treatment with ER‐MPH (Ritalin) and ER‐MPH (Medikinet Retard) was generally well tolerated No participant had to discontinue participation in the trial because of AEs Although almost every third participant was affected by ≥ 1 AE, almost all AEs were of mild intensity Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: yes; efficacy trial to prove non‐inferiority of ER‐MPH (Ritalin) vs ER‐MPH (Medikinet). Highly restrictive inclusion criterion ‐ responders only. Trial authors acknowledge "it might overestimate the treatment effect and the tolerability in the overall population, as no treatment naive patients have been included in this trial" Any withdrawals due to AEs: no Funding source: not declared. Trial aimed at showing efficacy of ER‐MPH (Ritalin) with purpose of obtaining marketing authorisation.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization was centrally generated with a validated system that automated the random assignment of treatment sequences to randomization numbers in a specified ratio"
Allocation concealment (selection bias)	Unclear risk	No information
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"All treating physicians, other site staff, and patients, as well as data analysts and Novartis in‐house personnel, remained blinded from the time of randomization until database lock. The raters also did not have access to information about adverse events to maintain the blind" "To ensure blinding of the study, all capsules were overencapsulated in an identical optical design"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"The scale was rated by three treatment‐blinded observers in the classroom who were specifically trained on the SKAMP scale"
Incomplete outcome data (attrition bias) All outcomes	Low risk	All randomly assigned participants were included in the ITT population. Missing values for the primary endpoints were replaced by the worst value observed in another participant under the same treatment at the same assessment time. For non‐inferiority comparisons, the per‐protocol (PP) population consisting of participants without major protocol violations was considered primary Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): no
Selective reporting (reporting bias)	Unclear risk	No protocol identified