Gadow 1995.

Study characteristics
Methods	Randomised, placebo‐controlled, double‐blind, cross‐over trial with 2 interventions: MPH in 2 or 3 dosages Placebo Phases Washout if medications before trial 8‐week RCT with 2 weeks on each arm Open‐label follow‐up at 24 months
Participants	Number of participants screened: not stated Number of participants included: 34 (31 boys, 3 girls) Number of participants followed up: RCT 34, minimal effective dose, after RCT 27; 12‐month follow‐up 30; 18‐month follow up 26; 24‐month follow‐up 26 Number of withdrawals: RCT: 0 Diagnosis of ADHD: DSM‐III‐R (subtypes not stated) Age: mean 8 years and 10 months (range 6.1 years‐11.9 years) IQ: mean 105.9 (SD 13.7, range no information) MPH‐naive: 24 (71%) Ethnicity: white (85%), African American (3%), Asian (3%), Hispanic (9%), other (0%) Country: USA Setting: outpatient clinic Comorbidity: data from only 21 children from Gadow 1995: tics (100%); anxiety or depressive disorder, or both (8/21; 38%); OCD (3/2; 14%); most of the children also had ODD or CD and academic problems Comedication: not during RCT. 4 children were treated with an anti‐tic medication in combination with MPH at some time during the course of follow‐up (neuroleptic 3, clonidine 1) Other sociodemographics: none Inclusion criteria Meet DSM III‐R diagnostic criteria for ADHD and chronic motor tic disorder or Tourette's disorder ADHD had to be a primary reason for seeking clinical services In general, had to be above the cut‐off on 2 or 3 parent‐ and teacher‐rated hyperactivity and/or ADHD behaviour rating scales Written signed statement from parents consenting to their child’s participation Exclusion criteria Dangerous to self or others Tics: the major clinical management concern Psychosis IQ < 70 Seizure disorder Major organic brain dysfunction Major medical illness Contraindications to medication (other than tics) Pervasive developmental disorder
Interventions	Participants were randomly assigned to 1 of 4 possible drug condition orders of doses: 0.1 mg/kg (mean 4.4 mg), 0.3 mg/kg (mean 9.0 mg) and 0.5 mg/kg (mean 14.0 mg) of MPH and placebo Upper dosage limit was 20 mg. When the 0.5‐mg/kg dose was not preceded by a LD condition, the child was gradually built up to MD. Build‐up days occasionally fell on scheduled school observation days. Observers were unaware of these days and observations were conducted as usual, but these data were excluded from the analyses Administration schedule: twice/d (or 3 times/d) at morning and noon, approximately 3.5 h apart, 7 d/week Duration of each medication condition: 2 weeks Washout before trial initiation: MPH 1 week, antipsychotic 3 weeks, clonidine 2 weeks Medication‐free period between interventions: none Titration period: none Treatment compliance: parents and nurses were asked to return unused medication envelopes, which allowed researchers to assess compliance. No further information was provided in the paper Regarding 24‐month follow‐up: total daily dose of MPH, minimal effective dose ‐ after RCT mean 16.5 mg (range 5 mg‐40 mg); second visit mean 28.5 mg (range 15 mg‐60 mg); third visit mean 29.2 mg (range 10 mg‐90 mg); and 4th visit mean 34.5 mg (range 15 mg‐92 mg)
Outcomes	During 8‐week RCT ADHD symptoms Parents Abbreviated CPRS: rated Saturday and Sunday each week Mothers’ Objective Method for Subgrouping: rated by parents Saturday and Sunday each week Teachers Abbreviated CTRS, 10‐item: rated 2 d/week for each intervention period IOWA CTRS: rated 2 d/week for each intervention period General behaviour Peer Conflict Scale: parent‐ and teacher‐rated, 2 times/week Classroom Observation Code: observer‐rated, 4 days for each treatment condition ADHD School Observation Code: observer, 3‐4 days for each treatment condition Code for Observing Social Activity: observer, lunch and playground, 20‐30 min, 4 days for each treatment condition Non‐serious AEs Side Effects Checklist: 13 items, rated by parents on Saturday and Sunday and rated by teacher twice/week Global Tic Rating Scale: rated by parents on Saturday and Sunday and rated by teacher twice/week Motor and vocal tic category: observers coded presence or absence of tics in the classroom, lunchroom or playground, 4 times for each medication condition Physician evaluations YGTSS: rated every second week Tourette Syndrome Unidentified Rating Scale: rated every 2nd week Global Tic Rating Scale (assessed in only 22 participants): rated every 2nd week Shapiro Tourette Syndrome Severity Scale (assessed in only 22 participants): rated every 2nd week Motor tic frequency tics: rated in 180 5‐s intervals in a simulated classroom; tics were coded as present or not present in each interval, rated every 2nd week Weight: assessed every 2nd week Heart rate: assessed every 2nd week BP: assessed every 2nd week During 24‐month follow‐up Physician evaluations All rated at minimally effective dose (right after RCT) 6 months, 12 months, 18 months and 24 months YGTSS Shapiro Tourette Syndrome Severity Scale 3 subscales from Tourette Syndrome Unified Rating Scale Total number of tics Number of tics observed in 2 min of quiet conversation with physician LeWitt Disability Scale, which assesses tics and symptoms of comorbidity Global Tic Rating Scale BP Heart rate Pulse Weight Parent ratings Based on last 2 weeks and rated at minimal effective dose (right after RCT) 6 months, 12 months, 18 months and 24 months Stimulant Side Effects Checklist Global Tic Rating Scale
Notes	Sample calculation: yes Ethics approval: no information Comments from trial authors "Magnitude of clinical improvement associated with 0.3 mg/kg dosage vs 0.5 mg/kg dosage was generally trivial for many children" "0.5 mg/kg dosage was associated with more side effects, but fortunately they were generally of limited clinical significance" "Generalisability of findings from this trial is subject to several qualifications. First, our data pertain to observed treatment effects over an 8‐week period and therefore cannot address the issue of tic exacerbation as a function of long‐term drug exposure. Furthermore, the findings pertain only to children with ADHD with tics of mild to moderate severity that occur frequently enough to be observed during 15‐minute intervals" Key conclusions of trial authors "During the course of this short‐term drug evaluation, physician, teacher and parent ratings were in agreement that MPH did not lead to worsening of the severity of children's tic disorders" "MPH is an effective drug for the treatment of ADHD and oppositional and aggressive behaviour" "Follow‐up trial showed that long‐term treatment with MPH seems to be safe and effective for the management of ADHD behaviours in many (but not necessarily all) children with mild to moderate tic disorders. Nevertheless, careful clinical monitoring is mandatory, to rule out the possibility of drug‐induced tic exacerbation in individual patients" Comments from trial authors (limitations) 2‐year follow‐up component was not blinded. Although obstacles to creating and maintaining a long‐term double‐blind trial with a placebo group are daunting, failure to do so does introduce the possibility of bias Absence of a no‐treatment group does not allow inferences about natural changes in tic status over time Comments from review authors Well‐designed trial No exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH. 26 children received stimulant medication throughout the follow‐up interval; of these children, 1 was switched to dextroamphetamine. However, we have chosen to use in our analyses results for all 26 All included articles include a mix of different protocols, so total numbers of included participants differ from article to article Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: no; children were not excluded from participation in the trial if they had prior experience with stimulant drug therapy, or if such therapy purportedly had exacerbated their tics Any withdrawals due to AEs: no Funding source: research grants from the Tourette Syndrome Association and the NIMH Email correspondence with trial authors: April 2013. We emailed trial authors for supplemental information regarding cross‐over data. Data were not available. Also no further data for the interventions were available
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Dose schedules were counterbalanced and assigned on a random basis
Allocation concealment (selection bias)	Low risk	Medication and identically matching placebos were dispensed to parents and school nurses in dated, sealed envelopes at 2‐week intervals
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Parents, teachers, participants, observers and physicians were blinded to the identity of those conditions
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Medication was administered under double‐blind conditions (i.e. no one involved in clinical management of the participant, data collection or interaction with the school knew the identity of treatment conditions)
Incomplete outcome data (attrition bias) All outcomes	Low risk	Trial describes how many people were included in the different analyses 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 or received