Stein 2003.

Study characteristics
Methods	4‐week, double‐blind, placebo‐controlled, cross‐over trial in which participants were randomly assigned to: 3 doses of MPH placebo
Participants	Number of participants screened: not stated Number of participants included: 47 (33 boys, 14 girls) Number of participants followed up: 39 Number of withdrawals: 8 Diagnosis of ADHD: DSM‐IV (combined (68%), hyperactive‐impulsive (0%), inattentive (32%)) Age: mean 9.02 years (range 5 years 11 months‐16 years) IQ: mean 106.8 Stimulant‐naive: 70% Ethnicity: white (89.4%), African American (4.3%), Hispanic (2.1%), other (4.3%) Country: USA Setting: outpatient clinic Comorbidity: ODD (17%), encopresis/enuresis (10.6%), tic disorder (2.1%) Comedication: no Other sociodemographics: predominantly mid to upper socioeconomic status referral base of the clinic Inclusion criteria DSM‐IV criteria for ADHD Exclusion criteria: Intellectual disability Severe mood disorders (requiring antidepressant or concurrent psychotropic medications) Tourette's syndrome, seizure disorders or other medical disorders associated with symptoms that may mimic ADHD (e.g. thyroid disorder) Children taking systemic medications
Interventions	Participants were randomly assigned to different orders of OROS‐MPH (18 mg, 36 mg, 54 mg) and placebo. No child could start with the 54‐mg dose, and 1 child who weighed < 40 kg did not receive the 54‐mg dose to minimise potential side effects in smaller children Administration schedule: once daily Duration of each medication condition: 7 days Washout before trial initiation: 2‐week washout period for children who took stimulant medication before trial start Medication‐free period between interventions: no Titration period: none Treatment compliance: 92% of all trial medications were given
Outcomes	ADHD symptoms ADHD‐RS‐IV: parent‐rated, at baseline and weekly during interventions ACTeRS: teacher‐rated at baseline and weekly during interventions Non‐serious AEs Side Effect Rating Scale (SERS; Barkley 1990): parent‐rated at baseline and weekly during interventions Vital signs (weight, height, BP, pulse and temperature): obtained weekly by clinical staff Children’s Sleep Questionnaire
Notes	Sample calculation: no Ethics approval: approved by the Institutional Review Boards of The University of Chicago, Children’s National Medical Center and the General Clinical Research Center Advisory Council Comments from trial authors Forced titration procedure deserves some comment The advantage of this procedure is increased potential to determine optimal response. However, this procedure is likely to result in increased reports of stimulant side effects compared with a more gradual titration procedure In interpreting the results, several limitations should be kept in mind Potential expectancy biases or placebo effects need to be considered because each medication differed in appearance, size and colour, and, in the case of the 54‐mg condition, number of capsules Other limitations include the short‐term nature of the study, the relatively small number of participants with ADHD predominantly inattentive subtype and the measures of ADHD symptoms used that were rating scales rather than behavioural observations or laboratory measures of attention Key conclusions of trial authors In children with ADHD combined subtype ‐ the most common subtype of ADHD ‐ increasing doses of stimulant medication were associated with increased improvement in inattention and hyperactivity symptoms In children with ADHD predominantly inattentive subtype, symptom improvement occurred at lower doses and less benefit was derived from higher doses In both ADHD subtypes, higher doses were associated with parent ratings of increased insomnia and decreased appetite Children who were homozygous for the less common, 9‐repeat DAT1 30‐UTR genotype displayed a distinct dose–response curve from that of other genotype groups, with absence of typical linear improvement when the dose was increased from 18 mg to 36 mg and 54 mg Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: no Any withdrawals due to AEs: yes; 8 Funding source: the NIMH, the General Clinical Research Center Program of the National Center for Research Resources, and the NIH, Department of Health and Human Services Correspondence with trial authors: August 2014. We contacted trial authors to request additional data. Trial authors no longer have access to the data
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Dosing schedules were assigned from a randomly ordered list of all dosing schedules
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	High risk	Each medication differed in appearance, size and colour and, in the case of the 54‐mg condition, number of capsules. The placebo capsule was slightly larger than the MPH preparations. Trial authors conducted several analyses to investigate the impact of these differences in appearance on the findings of the trial (almost no impact on the results) but still considered risk of bias to be high. Parents and clinicians who were blinded to genotype and medication status rated ADHD symptoms, impairment and stimulant side effects each week
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Parents and clinicians who were blinded to genotype and medication status rated ADHD symptoms, impairment and stimulant side effects each week
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Any child who could not complete a treatment phase was classified as a premature discontinuation. Their data were included for all phases that were completed. No description on how many participants the analyses were based on. Selection bias (e.g. titration after randomisation → exclusion): no
Selective reporting (reporting bias)	High risk	Data were included for all phases that were completed. There is no description that reveals how many people the analyses were based on. In the abstract belonging to the trial (Stein et al. 2004), researchers write that they will "prospectively evaluate the effects of different doses of stimulant medication on these and other sleep problems". This is not provided in any of the articles included in the Stein 2003 trial.