Muniz 2008.

Study characteristics
Methods	Randomised, multi‐centre, double‐blind, 5‐period, cross‐over trial in a laboratory classroom setting with 3 interventions: ER‐d‐MPH ER‐d,l‐MPH placebo Phases: ER‐d‐MPH 20 mg/d, ER‐d‐MPH 30 mg/d, ER‐d,l‐MPH 36 mg/d, ER‐d,l‐MPH 54 mg/d and placebo
Participants	Number of participants screened: 84 Number of participants included: 84 (55 boys, 29 girls) Number of participants followed up: 81 Number of withdrawals: 3 Diagnosis of ADHD: DSM‐IV (combined (89.3%), inattentive (10.7%)) Age: mean 9.5 years (SD 1.7, range 6‐12) IQ: not stated MPH‐naive: 0% Ethnicity: white (42.9%), African American (27.4%), Hispanic (28.6%), other (1.2%) Country: USA Setting: outpatient clinic Comorbidity: no Comedication: no Other sociodemographics: none Inclusion criteria DSM‐IV diagnosis of ADHD using DISC On stabilised total daily dose or nearest equivalent dose of 40 mg‐60 mg of ER‐d,l‐MPH or 20 mg‐30 mg ER‐d‐MPH for ≥ 2 weeks before screening visit Exclusion criteria Tic disorder or Tourette’s syndrome History of a seizure disorder Psychiatric illness Substance abuse disorder Taking prohibited concomitant medications or ADHD medication other than MPH Taking antidepressant or psychotropic medications Had begun psychotherapy within 3 months before randomisation Home‐schooled children Girls of child‐bearing potential with positive urine pregnancy test before enrolment (or, if sexually active, not using adequate and reliable contraception)
Interventions	Participants were randomly assigned to 1 of 5 possible drug condition orders of ER‐d‐MPH 20 mg/d, 30 mg/d, 36 mg/d, 54 mg/d and placebo Mean MPH dosage: not stated Administration schedule: once daily. Morning dosing as 2 capsules Sunday to Saturday. 6 doses were administered at home (Sunday to Friday), and the Saturday dose was administered by research staff. This was repeated until all 5 treatments had been administered. Mean duration of exposure to trial medication was 7 days for all 5 treatments Washout before trial initiation: 6 days medication‐free Titration period: "On stabilized total daily dose or the nearest equivalent dose of 40 to 60 mg of d,l‐MPH or 20 to 30 mg d‐MPH for at least 2 weeks prior to the screening visit" initiated before randomisation Treatment compliance: not stated
Outcomes	ADHD symptoms Primary efficacy variable Change from pre‐dose SKAMP‐Combined score at 2 h post‐dose with ER‐d‐MPH 20 mg/d compared with ER‐d,l‐MPH 36 mg. This change was calculated by subtracting the pre‐dose value (hour 0 score) from the post‐dose value Secondary outcome measures Change from pre‐dose (0 hour) on Combined, Attention and Deportment subscores of the SKAMP, at specified intervals post‐dose (0.5, 1, 2, 3, 4, 6, 8, 10, 11 and 12 h), and area under the score vs time curve (AUC) of the change from pre‐dose in Combined score from hour 0 to hour 4 (AUC 0 to 4), and from hour 0 to hour 12 (AUC 0 to 12) Serious AEs Safety assessments consisted of monitoring and recording of all AEs General behaviour "The Conners’ Parent Rating Scale (CPRS), a 27‐item questionnaire designed to evaluate children’s behaviour (Conners 1998a), was completed by parents on the Practice Day to assess behaviour without medication and at each subsequent assessment day to rate the child’s behaviour during the previous week" Non‐serious AEs Safety assessments consisted of monitoring and recording all AEs and recording vital signs and body weight at each visit Laboratory parameters (including haematology, blood chemistry and urinalysis), ECGs and results of physical examinations were assessed for abnormalities at screening and final visits (no final visit assessments were carried out for ECGs and physical examinations)
Notes	Sample calculation: yes; "It was determined that approximately 90 patients were required to detect a 0.05‐level treatment difference at 84% power assuming a difference and standard deviation of 3.5 and 11 for SKAMP‐Combined score, at 2 h post‐dose using a paired t‐test" Ethics approval: no information Key conclusions of trial authors "The results of this study demonstrated that all active treatments generally provided significant improvement in ADHD symptoms over placebo over 11 to 12 hours post‐dose in children 6–12 years old" "The primary efficacy variable, adjusted mean change in SKAMP‐Combined score from pre‐dose to 2 hours post‐dose, was significantly greater during treatment with d‐MPH‐ER 20 mg/d than d,l‐MPH‐ER 36 mg/d (adjusted mean change 10.65 and 5.94, respectively; p 0.001). Similar results at 2 hours post‐dose were noted for the secondary measure of SKAMP‐Combined score comparing d‐MPH‐ER 30 mg/d with d,l‐MPH‐ER 54 mg/d (adjusted mean change 11.17 and 7.52, respectively; p0.001)." Comment from review authors We did not include the Swanson pencil and paper math test of "academic productivity" among ADHD outcome measures. This may be seen as an ADHD outcome measure, but it does not specifically measure the 3 key ADHD core signs of inattention, hyperactivity and impulsivity. Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: yes; "Children recruited for this study had been stabilized on a total daily dose or the nearest equivalent dose of 40 to 60 mg of d,l‐MPH or 20 to 30 mg d‐MPH for at least 2 weeks prior to the screening visit" ‐ so presumably non‐responders to MPH and those experiencing intolerable AEs while taking MPH were not included Any withdrawals due to AEs: no Funding source: "This study was funded by Novartis Pharmaceuticals Corporation and reports the following involvement: design and conduct of the study; collection, management, analysis, and interpretation of data; preparation, review, and approval of the manuscript" Email correspondence with trial authors: July 2014. Emailed trial authors to ask for additional information but have not received a reply
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"A total of 84 subjects were randomized to receive treatment and were included in the efficacy and safety analyses"
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"After the Practice Day, the first assigned treatment was dispensed to the parents as blinded capsules according to their child’s randomized sequence. To maintain blinding, all treatments were over‐encapsulated and the same number of capsules were given once daily for each sequence"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"The ratings were based on the frequency and quality of behaviours as observed by three independent, blinded raters in each class. To maintain consistency throughout the study, the blinded observers were responsible for observing and rating the same 6 children at specified intervals throughout the 12‐hour testing period at each center"
Incomplete outcome data (attrition bias) All outcomes	Low risk	"The intent‐to‐treat population included all randomized patients who took at least 1 dose of study medication and had at least 1 post‐dose efficacy measurement" Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): no
Selective reporting (reporting bias)	Low risk	No selective outcome reporting