Gadow 2007.

Study characteristics
Methods	Double‐blind, randomised, cross‐over trial with interventions: MPH placebo Phases Washout if previously medicated 8‐week trial, 2 weeks on each arm. Performed in 2 cohorts (several years apart, same personnel)
Participants	Number of participants screened: not stated Number of participants included: 71 (39 + 32, cohorts 1 and 2, respectively) Number of participants followed up: 71 (57 boys, 14 girls) Number of withdrawals: not stated Diagnosis of ADHD: DSM‐III‐R or DSM‐IV (subtype not stated) Age: mean: 8.9 ± 1.9 years (range 6‐12) IQ: mean 103.8 MPH‐naive: not stated Ethnicity: white (87%), African American (6%), Asian (1%), Hispanic (6%) Country: USA Setting: outpatient clinic Comorbidity: Tourette’s syndrome (96%), chronic motor tic disorder (4%), ODD (56%), CD (7%), overanxious or generalised anxiety (30%), simple phobia (7%), OCD (11%) Comedication: not stated Other sociodemographics: none Inclusion criteria DSM‐III‐R or DSM‐IV diagnosis of ADHD Chronic motor tic disorder or Tourette’s syndrome ADHD clinical criteria at both school and home Exclusion criteria Too severely ill (dangerous to self or others) Psychotic IQ < 70 Seizure disorder Major organic brain dysfunction Major medical illness Medical or other contraindication to medication (other than tics) Pervasive developmental disorder Tics so severe at intake that the parent or the child requested immediate intervention Extremely mild tics at intake
Interventions	Participants were randomly assigned to 1 of 4 possible drug condition orders of placebo or IR‐MPH (0.1 mg/kg (mean 4.5 mg; SD 1.6), 0.3 mg/kg (mean 9.3 mg; SD 3.0) and 0.5 mg/kg (mean 14.3 mg; SD 3.3)), twice/d for 2 weeks, each under double‐blind conditions. Upper limit was 20 mg/d Administration schedule: twice daily, 3.5 h apart. Most days, a morning dose and a noon dose, 7 days/week Duration of each medication condition: 2 weeks Washout before trial initiation: minimum washout periods for children receiving medication at referral were as follows: 1 week for stimulants (n = 10), 3 weeks for neuroleptic or SSRI (n = 2) and 2 weeks for clonidine (n = 1) Medication‐free period between interventions: none Titration period: none Treatment compliance: not stated
Outcomes	ADHD symptoms Teachers Abbreviated Teacher Rating Scale (total score (Hyperkinesis Index) and ADHD (factor 1) and Emotional lability (factor 2) subscales) IOWA CTRS (Inattention‐Impulsivity‐Overactivity and Oppositional Defiant subscales): twice/week, weekdays Parents Abbreviated Parent Rating Scale (total score (Hyperkinesis Index) and ADHD (factor 1) and Emotional lability (factor 2) subscales): Saturdays and Sundays, every week General behaviour IOWA CTRS (Oppositional Defiant subscale) Non‐serious AEs Physician Assessment of clinical status and heart rate, BP and weight: biweekly (n = 57) Tics: YGTSS (includes 4 behaviourally anchored subscales: total Motor Tic score, Total Phonic Tic score, Overall Impairment Rating and Global Severity score), completed for all but the first 12 participants. Additional measures: Shapiro Tourette Syndrome Severity Scale (tic frequency, severity and impairment), Global Tic Rating Scale and Two‐Minute Tic and Habit Count, completed for first 12 participants only. Both rated at 2‐week intervals Parents and teachers Global Tic Rating Scale: twice a week for each week of the trial Stimulant Side Effects Checklist: rated twice a week
Notes	Sample calculation: no Ethics approval: yes Comment from trial authors Children were not excluded if previous treatment with stimulants had purportedly induced or exacerbated their tics Key conclusion of trial authors In this trial, IR‐MPH was found to be a safe and effective short‐term treatment for ADHD in children with chronic tic disorder, but complete normalisation of all problem behaviours often is not achieved at acceptable doses Comments from review authors Given our concern about the possibility of a type II error (i.e. erroneously concluding that MPH did not have an adverse effect on tics), we performed follow‐up repeat‐measure ANOVAs on each respondent category, even when the main effect of dose was not significant Use of a cross‐over design may result in carry‐over effects. However, differences in change scores for tic frequency (simulated classroom) and severity (YGTSS ‐ Global Severity score), respectively, between baseline and placebo in children who received placebo first and last were non‐significant and minuscule (i.e. effect size = 0.08 and 0.19, respectively) Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: no Any withdrawals due to AEs: no Funding source: this trial was supported in part by a research grant from the Tourette Syndrome Association Incorporated, and by Public Health Service (PHS) grant number MH45358 from NIMH Email correspondence with trial authors: April 2014. We obtained supplemental information from trial authors
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Dose schedules were counterbalanced and assigned on a random basis
Allocation concealment (selection bias)	Low risk	Medication was administered twice daily, approximately 3.5 h apart, 7 d/week, and was dispensed in dated, sealed envelopes at 2‐week intervals
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind conditions
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information
Incomplete outcome data (attrition bias) All outcomes	Low risk	None required withdrawal of medication 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