Tourette's Syndrome Study Group 2002.

Study characteristics
Methods	16‐week, multi‐centre, randomised, double‐blind, placebo‐controlled, parallel trial with 4 arms: MPH clonidine MPH + clonidine placebo Phases: 3 Weeks 1‐4: clonidine/placebo dose titration Week 5‐8: addition of MPH/placebo dose titration Weeks 9‐16: maintenance therapy
Participants	Number of participants screened: not stated Number of participants included: 136 Number of participants followed up: 121 (MPH 33, placebo 25, clonidine 30, MPH + clonidine 33) Number of withdrawals: 19 (MPH 4, placebo 7, clonidine 4, clonidine + MPH 4) Diagnosis of ADHD: DSM‐IV: MPH: combined 32%, hyperactive‐impulsive 3%, inattentive 65%; placebo: combined 19%, hyperactive‐impulsive 0%, inattentive 81%; clonidine: combined 21%, hyperactive‐impulsive 3%, inattentive 76%; clonidine + MPH: combined 33%, hyperactive‐impulsive 3%, inattentive 64% Mean age: MPH 10.7 years (SD 2.0); placebo 9.7 years (SD 1.8); clonidine 9.7 years (SD 1.8); clonidine + MPH 10.6 years (SD 1.9). Total age range 7‐14 Sex: MPH 34 boys, 3 girls; placebo 29 boys, 3 girls; clonidine 29 boys, 5 girls; clonidine + MPH 24 boys, 9 girls Stimulant‐naive: 42% Ethnicity: MPH 81% white; placebo 94% white; clonidine 94% white; clonidine + MPH 85% white Country: USA Setting: outpatient clinic Comorbidity: tic disorder diagnosis 100%; primarily OCD and ODD. Furthermore, CD, generalised anxiety disorder and major depressive disorder. MPH: OCD (11%), ODD (33%). Placebo: OCD (22%), ODD (41%). Clonidine: OCD (15%), ODD (48%). Clonidine + MPH: OCD (16%), ODD (31%) Comedication: not stated IQ: > 70 Other sociodemographics: participant groups were similar, except that participants assigned to MPH (alone or in combination with clonidine) are approximately 1 year older, present a higher proportion of pubertal cases, show underrepresentation of the inattentive subtype of ADHD (and overrepresentation of the combined subtype) and have lower baseline Conners' Abbreviated Symptom Questionnaire (ASQ)‐Teacher scores. A higher proportion of girls was found in the combined treatment group Inclusion criteria DSM‐IV for ADHD Designated teacher in daily direct contact with the participant had to indicate the presence of a sufficient number of ADHD symptoms (rated as "pretty much" or "very much") in the classroom setting using the Disruptive Behavior Disorders Rating Scale (updated to DSM‐IV) to meet DSM‐IV criteria; and had to rate the severity of ADHD symptoms above specified cut‐off scores (boys: grade 2 to 3 = 10, grade ≥ 4 = 9; girls: grade 2 to 3 = 7, grade ≥ 4 = 6) on the IOWA CTRS Investigator’s rating of global functioning on the CGAS had to be 70 (indicating difficulty in ≥ 1 area, such as school) DSM‐IV for Tourette's disorder, chronic motor tic disorder or chronic vocal tic disorder Exclusion criteria Secondary tic disorder (tardive tics, neuroacanthocytosis, Huntington disease) Major depression, pervasive developmental disorder, autism, psychosis, anorexia nervosa, bulimia, serious cardiovascular or other medical disorder that would preclude the safe use of MPH or clonidine, impaired renal function, pregnancy Mental disability The following cardiac conditions: prolonged QTc interval (> 440 milliseconds), high‐grade ventricular ectopy, atrioventricular block > 1 degree, bundle branch block, intraventricular conduction block (100 milliseconds), pacemaker rhythm or heart rate < 60 on the ECG, cardiomyopathy, complex heart disease, aortic or pulmonary stenosis, family history of long QT syndrome, cardiomyopathy or premature sudden death (age 45 years), history of syncope and BP < 2 SD from age‐ and sex‐adjusted mean Other medications for treatment of ADHD, tics or other associated behavioural symptoms. Any such treatment had to be discontinued ≥ 6 weeks (2 weeks for MPH) before enrolment
Interventions	Participants were randomly assigned to MPH (Ritalin; Novartis) alone, clonidine alone, clonidine + MPH or placebo Number randomised to each group: MPH 37, placebo 32, clonidine 34, MPH + clonidine 33 MPH dosage: MPH alone 25.7 mg/d, MPH + clonidine 26.1 mg/d Administration schedule: 2‐3 times daily Duration of intervention: 12 weeks (4‐week titration of MPH, 8‐week maintenance phase) Titration period: 4‐week initial dose titration period for clonidine, after which came 4‐week dose titration for MPH. Both titration periods took place after randomisation Treatment compliance: pill count monitored compliance
Outcomes	ADHD symptoms ADHD Conners' Abbreviated Symptom Questionnaire for Teachers (ASQ‐Teacher): rated at baseline and at week 16 IOWA CTRS: rated at baseline and at week 16 Conners' Abbreviated Symptom Questionnaire for Parents (ASQ‐Parent): rated at baseline and at weeks 8, 12 and 16 General behaviour IOWA CTRS: rated at baseline and at week 16 Quality of life CGAS: rated by site investigator at baseline and at weeks 8, 12 and 16 Non‐serious AEs YGTSS: rated by site investigator at weeks 8, 12 and 16 TSSR: parent/participant‐ and teacher‐rated at weeks 8, 12 and 16 (teacher ratings only at week 16) Global Tic Rating Scale: parent/participant‐ and teacher‐rated at weeks 8, 12 and 16 (teacher ratings only at week 16) Vital signs, ECG: rated at weeks 8, 12 and 16 Side Effects Rating Scale: rated at weeks 8, 12 and 16 (teacher ratings only at week 16) Independent safety monitoring committee, consisting of child psychiatrist, paediatric cardiologist, paediatrician and statistician; reviewed data regarding AEs throughout the trial
Notes	Sample calculation: yes; 120 participants Ethics approval: yes; the protocol was approved by the institutional review board at each site Comment from trial authors "Our study did exclude participants with known cardiac problems, so the safety of combined clonidine and MPH in this group was not addressed." Key conclusions of trial authors "Our study indicates that prior concerns that MPH worsens tics and that the drug should be avoided in patients with tics may be unwarranted" "The most effective treatment for ADHD in our trial was the combination of clonidine and MPH, although the incremental benefit of adding clonidine to MPH came at the expense of additional side effects, particularly sedation" Comments from review authors Data extracted from week 4 to week 16 (from when MPH was introduced to participants) Not able to use trial data in our analyses Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: no Any withdrawals due to AEs: not stated Funding: the National Institute of Neurological Disorders and Stroke, the General Clinical Research Center, the National Center for Research Resources, the Tourette Syndrome Association Boeringer Ingelheim Inc. (particularly Dr. Virgil Dias), for supplying clonidine and matching placebo; Bausch and Lomb, Inc., for supplying small gifts for our study participants
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation. Stratification by centre (investigator) and sexual maturity status (prepubertal: Tanner stage I to II; pubertal: Tanner stage III to V). Blocking was used to ensure approximate balance among treatment groups within each stratum
Allocation concealment (selection bias)	Low risk	Sealed envelopes that contained participants' treatment assignments
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinded: participants, clinicians, data collectors, outcome assessors, data analysts, data safety and monitoring committee, manuscript writers
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Only the programmer in the Biostatistics Center who generated the plan and the pharmacist in the Pharmacy Center who packaged and labelled the drug were aware of treatment assignments
Incomplete outcome data (attrition bias) All outcomes	Low risk	Primary statistical analyses were performed according to the ITT principle and were based on all randomly assigned participants, as randomised. For analysis of outcome variables for efficacy, if a participant was missing a response at a particular visit, the last available observation for that participant was carried forward and imputed for that visit Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): no
Selective reporting (reporting bias)	Low risk	No indication of selective reporting