Wigal 2014.

Study characteristics
Methods	Cross‐over trial with 2 interventions: MPH‐MLR placebo Phases: 4 Screening/washout period (< 4 weeks) Open‐label dose‐optimisation period Randomised, double‐blind, placebo‐controlled, cross‐over design 30‐day safety follow‐up period
Participants	Number of participants screened: 32 Number of participants included: 26 (in open‐label phase; 12 boys, 10 girls) Number of participants followed up: 20 Number of withdrawals: 6 Diagnosis of ADHD: DSM‐IV‐TR (combined (n = 11), hyperactive‐impulsive (n = 3), inattentive (n = 12)) Age: mean 8.7 years (range 6‐12) IQ: mean not stated (range 86‐133) MPH‐naive: none Ethnicity: white (82%), black (9%), Asian (5%), Hispanic or Latino (23%), other (5%) Country: USA Setting: outpatient clinic, laboratory classroom setting Comorbidity: 11; generalised anxiety disorder, enuresis, ODD, chronic motor or vocal tic disorder, transient tic disorder Comedication: no Other sociodemographics: none Inclusion criteria Children (male or female) 6‐12 years of age Any of the 3 subtypes of ADHD as defined by DSM‐IV‐TR, ADHD‐RS‐IV total or subscale score > 90th percentile relative to the general population of children by age and sex Naive to treatment for ADHD or inadequately managed on current treatment regimen Negative illicit drug and alcohol test results at screening and at each visit to the research site Exclusion criteria IQ > 80 Any severe psychiatric or significant comorbid condition Use of a MAOI or any psychotropic medication with CNS effects < 14 days of screening, or any experimental drug or medical device > 30 days of screening Clinically significant ECG, or any laboratory abnormality Any participant unable or unwilling to follow directions and complete trial assessments or take oral capsules
Interventions	Participants were randomly assigned to 1 of 2 possible drug condition orders of MPH (15 mg, 20 mg, 30 mg or 40 mg) and placebo Mean MPH dosage: 32 mg Administration schedule: once/d Time points: in the morning Duration of each medication condition: 1 week Washout before trial initiation: 2 days Medication‐free period between interventions: not stated Titration period: yes; 2‐4 weeks before randomisation Treatment compliance: yes; verified at scheduled trial visits by trial personnel who examined documentation of drug dispensed, drug consumed and remaining drug, and recorded the information on the drug reconciliation form Compliance was calculated to be > 82% throughout the trial
Outcomes	ADHD symptoms SKAMP: total scores, trained observers, post‐dose over time points 1.0, 2.0, 3.0, 4.5, 6.0, 7.5, 9.0, 10.5 and 12.0 h SKAMP: attention and deportment scores averaged over all post‐dose time points ADHD‐RS‐IV: clinician‐rated, 3.0 h post‐dose each laboratory day Non‐serious AEs Safety and tolerability assessments CSHQ There is not enough data on the CSHQ available for us to include it in the analysis.
Notes	Sample calculation: yes Ethics approval: yes Comment from trial authors Limitations of this study: study was slightly underpowered and produced a study population that may not be reflective of the general population of children and adolescents with ADHD Key conclusions of trial authors "In this study, methylphenidate‐MLR administered to children 6 to 12 years of age demonstrated a significant decrease in scores on the Swanson, Kotkit, Agler, M‐Flynn and Pelham Scale compared with placebo." "Onset of action in this population is 1 hour, and duration of efficacy is sustained to 12 hours post dose." "Future studies that include measurement of efficacy earlier than hour 1.0 and extend beyond hour 12.0 would add clarity to the precise onset and duration of clinical efficacy." Inclusion of MPH responders only/exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: yes; 2 withdrew during the open‐label phase as the result of lack of efficacy Any withdrawals due to AEs: yes (n = 1) Funding source: Rhodes Pharmaceuticals L.P. Email correspondence with trial authors: April 2015. Obtained supplemental information from trial authors. Trial authors were contacted regarding CSHQ data in November 2021, but no answer was received.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Randomisation was determined by using a table of random numbers. Randomisation tables were provided to the randomisation monitor, who created unblinding envelopes and packaged the drug with blinded labels.
Allocation concealment (selection bias)	High risk	One participant received placebo at 2 periods ‐ the method was not efficacious
Blinding of participants and personnel (performance bias) All outcomes	Low risk	All sponsor representatives, investigators, participants and independent raters remained blinded until after data were locked
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Yes; this has been done
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT were used Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo‐responders): no; no exclusion of MPH non‐responders after randomisation
Selective reporting (reporting bias)	Low risk	No indication of selective reporting