| Study characteristics |
| Methods |
Multi‐centre, randomised, double‐blind, 16‐week, parallel trial with 2 × 2 factorial design:
MPH alone MPH and clonidine clonidine alone placebo
2 successive 4‐week titration periods followed by an 8‐week maintenance period |
| Participants |
Number of participants screened: 205
Number of participants included: 122 (98 boys, 24 girls)
Number followed up: 93 (MPH 18, placebo 10, MPH + clonidine 24, clonidine 31)
Number of withdrawals: 44 (MPH 11, placebo 20, MPH + clonidine 8, clonidine 5)
DSM‐IV diagnosis of ADHD (combined (76%), hyperactive‐impulsive (4%), inattentive (20%))
Age: mean 9.5 (range not reported)
IQ: > 70
MPH‐naive: 57 (46.7%)
Ethnicity: white (77.9%), African American (10.7%), Hispanic (6.6%), other (4.9%)
Country: USA
Setting: outpatient clinic
Co‐morbidity: ODD (47%), CD (9%)
Co‐medication: not allowed, but all participants received protocol‐based behavioural interventions
Other sociodemographics: participant groups were similar except for a higher percentage of white children in the clonidine group and some minor differences with regard to family history of ADHD and tics
Inclusion criteria
Children 7‐12 years of age in school DSM‐IV ADHD, any subtype: indication of a sufficient number of ADHD symptoms on the Disruptive Behavior Disorders Rating Scale as rated by a teacher Rating of ADHD symptoms above specified cut‐off scores (boys: grades 2‐3 = 10; grades ≥ 4 = 9; girls: grades 2‐3 = 7, grades ≥ 4 = 6) on the IOWA‐CTRS Indication of the presence of sufficient ADHD symptoms at home on the IOWA‐CPRS Investigators rating of global functioning on the CGAS ≤ 70, with difficulty evident in ≥ 2 areas, such as school and home ADHD must be viewed as worthy of treatment with medications, as judged by the parent and the site investigator Informed consent/assent signed Designated school for each participant agrees to participate in the trial by completing all required questionnaires and following all specified procedures Child must be able to swallow the tablets and capsules used in this trial
Exclusion criteria
Evidence of a tic disorder Major depression Pervasive developmental disorder Autism Psychosis Mental disability Anorexia nervosa Bulimia Serious cardiovascular (e.g. significant hypotension, congenital heart disease) or other medical disorder that would preclude safe use of MPH or clonidine Impaired renal function or pregnancy Family history of long QT syndrome, cardiomyopathy or premature (age 45 years) sudden death Prolonged QTc interval (> 440 milliseconds), high‐grade ventricular ectopy, atrioventricular block beyond first degree, bundle branch block, intraventricular conduction block (> 100 milliseconds), pacemaker rhythm or HR < 60 bpm on the ECG, significant hypotension, cardiomyopathy, congenital heart disease, aortic or pulmonary stenosis, history of syncope BP ≥ 2 SD above or below the age‐ and sex‐adjusted mean Stimulants had to be discontinued ≥ 2 weeks before enrolment Any other psychotropic medications, anxiolytics or hypnotics had to be discontinued ≥ 6 weeks before enrolment
Previous use of MPH or clonidine was permitted |
| Interventions |
Participants were randomly assigned to IR‐MPH or placebo
Number randomised to each group: MPH 29, placebo 30, MPH + clonidine 32, clonidine 31
Mean MPH dosage: 0.76 ± 0.54 mg/kg/d (30.2 ± 18.9 mg/d (MPH‐only group) and 25.4 ± 18.2 mg/d (MPH + clonidine))
Administration schedule: 1‐3 times daily (morning, noon and afternoon)
Duration of intervention: 12‐16 weeks
Washout before trial initiation: 2 weeks
Titration period: 8‐week flexible‐dose titration period (4 weeks for clonidine, then 4 weeks for MPH) initiated after randomisation
Maintenance period of optimal dose: 8 weeks
Treatment compliance: monitored using pill counts (results of monitoring not stated) |
| Outcomes |
ADHD symptoms
ADHD‐RS (ADHD RS‐IV, 18‐item): child psychiatrist‐rated at baseline and at 16 weeks ASQ‐teacher: rated at baseline and at 4, 8, 12 and 16 weeks ASQ‐parent: rated at baseline and at 4, 8, 12 and 16 weeks IOWA Conners' Rating Scale: teacher‐rated at baseline and at 4, 8, 12 and 16 weeks
Quality of life
Non‐serious AEs
Pittsburgh Side Effects Rating Scale (20 items, modified from the original 13 items to include potential clonidine side effects): parent‐ and teacher‐rated at baseline and at 4, 8, 12 and 16 weeks. Spontaneous self‐reports of AEs: parent‐ and participant‐rated at baseline and at 4, 8, 12 and 16 weeks, or by telephone calls conducted between visits Weight, ECG, supine and standing BPs and pulse at visits 4, 8, 12 and 16
|
| Notes |
Sample calculation: yes; sample size of 140 participants (35 per treatment group) was determined to provide between 80% and 90% power to detect a group difference (effects of clonidine)
Ethics approval: yes; approved by the institutional review board at each site
Comments from trial authors
Overall, findings should be viewed cautiously in the light of the relatively small sample size and differential rates of attrition across groups Findings are limited by the exclusion of children with certain co‐morbid disorders such as mood and anxiety disorders, known cardiac problems or abnormal ECGs Also, given that all participants received psychoeducational and behavioural interventions as part of the protocol, these results may be limited to settings in which such behavioural interventions are applied Trial relied largely on parent and teacher questionnaires to identify possible side effects of medications. However, such rating scales may overestimate rates of medication side effects because sometimes such complaints reflect other factors, such as underlying conditions or co‐morbid psychopathology
Key conclusions of trial authors
Based on Conners' Teachers Abbreviated Symptom Questionnaire; MPH offers best combination of efficacy and tolerability for ADHD Clonidine, used alone or with MPH, appears safe and well tolerated in childhood ADHD Trial provides evidence that measures of quality of life for the family are sensitive to pharmacological treatment for ADHD
Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: no
Any withdrawals due to AEs: moderate to severe AEs were cited as a reason for withdrawal in 8 participants: MPH + clonidine 5, clonidine 2, MPH 1
MPH + clonidine: irritability (n = 1), tearfulness and irritability (n = 1), headaches (n = 1), itching (n = 1), asymptomatic ECG abnormalities (prolonged QTc) (n = 1) MPH: tachycardia and palpitations (n = 1)
Funding source: NIH and National Institute of Neurological Disorders and Stroke
Email correspondence with trial authors: March 2014 to June 2014. We attempted to obtain supplemental efficacy data from the trial authors |
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Low risk |
Computer‐generated randomisation plan included stratification by centre (investigator) and by sexual maturity status (Prepubertal: Tanner I‐II, Pubertal: Tanner III‐V) |
| Allocation concealment (selection bias) |
Low risk |
Only the programmer in the Biostatistics Centre and the pharmacist knew the allocation |
| Blinding of participants and personnel (performance bias)
All outcomes |
Low risk |
MPH (or matching placebo) powder packaged in gelatin capsules |
| Blinding of outcome assessment (detection bias)
All outcomes |
Low risk |
All investigators, trial co‐ordinators, teachers, parents and children were blinded to treatment assignments |
| Incomplete outcome data (attrition bias)
All outcomes |
Unclear risk |
Statistical analyses were performed according to the ITT principle, and last available observations were carried forward and imputed when needed for both efficacy and safety measures. However, only data from the ADHD‐RS for children who completed the titration period were analysed
Selection bias (e.g. titration after randomisation → exclusion): no |
| Selective reporting (reporting bias) |
Low risk |
No indication of selective reporting |
