Childress 2009.

Study characteristics
Methods	5‐week, multi‐centre, multiple‐setting, phase III, double‐blind, randomised, placebo‐controlled, parallel‐trial with 4 arms Placebo ER‐d‐MPH 10 mg ER‐d‐MPH 20 mg ER‐d‐MPH 30 mg 1‐3 weeks titration and 2‐4 weeks maintenance period dependent on the allocated active drug group
Participants	Number of participants screened: 332 Number of participants included: 253 (163 boys, 90 girls) Number of participants followed up: ER‐d‐MPH 161 (10 mg, n = 56; 20 mg, n = 54; 30 mg, n = 51), placebo 57 Number of withdrawals: ER‐d‐MPH 27 (10 mg, n = 10; 20 mg, n = 8; 30 mg, n = 9), placebo 8 Diagnosis of ADHD: DSM‐IV (combined (73.9%), hyperactive‐impulsive (2.8%), inattentive (21.7%), missing data (1.6 %)) Age: mean 8.7 years (6‐12 years) IQ: not stated MPH‐naive: 69.2% Ethnicity: white (57.7%), African American (28.9%), Asian (0.8%), other (12.6%) Country: 34 centres in the USA Setting: outpatient clinic Comorbidity: respiratory, thoracic and mediastinal disorders (MPH 26.9%, placebo 38.1%), immune system disorders (MPH 22.5%, placebo 14.3%), nervous system disorders (MPH 18.7%, placebo 19.0%), surgical and medical procedures (MPH 15.4%, placebo 11.0%), infections and infestations (MPH 14.3%, placebo 17.5%) and skin and subcutaneous tissue disorders (MPH 11.0%, placebo 9.5%) Comedication: ≥ 1 concomitant medication or non‐drug therapy after start of trial (MPH 39.0%, placebo 44.4%). The most common concomitant medications were analgesics, antihistamines and allergy medications Other sociodemographics: none reported. Treatment groups were well balanced in relation to participant background characteristics, and baseline demographics were comparable among treatment groups Inclusion criteria 6‐12 years of age DSM‐IV‐TR diagnosis of ADHD Patients attending school had to have the same teacher (English or Math) for the entire duration of the trial, who was willing and able to spend sufficient time with the patient to make valid weekly assessments Drug‐naive or not treated with any MPH‐related medication during the month before the trial Patients receiving psychological or behavioural therapies before the screening visit were considered eligible to participate, provided that therapy had been ongoing for ≥ 3 months with the same therapist Patients had to have academic competence appropriate to their age and the following subscale total scores on Conners’ ADHD/DSM‐IV Scales ‐ Teacher Version: for boys, baseline scores on Conners’ ADHD/DSM‐IV Scales ‐ Teacher Version, Total subscale were required to be 27 for those 6‐8 years old, 24 for those 9‐11 years old and 19 for those 12 years old. For girls, respective baseline cut‐off scores on Conners' ADHD/DSM‐IV Scales ‐ Teacher Version, for the same age groups were 16, 13 and 12 Exclusion criteria Home‐schooled children Any medical condition that interfered with trial assessments or that was not stable for ≥ 3 months before screening Clinically significant abnormalities detected during screening Family history of long‐QT syndrome, current diagnosis or history of cardiac abnormalities, seizures, psychiatric disorders such as schizophrenia, schizoaffective disorder, severe OCD, CD, autism, chronic tic disorder, Tourette's disorder or any mood or anxiety disorder Antidepressants, antipsychotics, herbal preparations with psychotropic effects, amphetamine‐based medications, benzodiazepines, barbiturates, sedatives or hypnotics, MAOI and atomoxetine had to be stopped 1‐4 weeks before randomisation according to their half‐lives. All concomitant medications that could interfere with absorption, metabolism and distribution of trial drug were excluded from the start of screening until the end of all evaluations. Over‐the‐counter analgesics, short‐term antibiotic treatment for minor infections and any medication needed to treat AEs were allowed Additionally, patients who were judged by the investigator as likely to be non‐compliant with trial procedures, including those with a suspected history of substance abuse and those living with a person diagnosed with a substance abuse disorder, or whose parent or guardian was unable or unwilling to complete Conners’ ADHD/DSM‐IV Scales ‐ Parent Version Pregnancy or lactation Positive drug screen
Interventions	Participants were randomly assigned to ER‐d‐MPH or placebo Fixed MPH dosage: 10 mg, 20 mg or 30 mg Number of participants randomly assigned: ER‐d‐MPH 188 (10 mg, n = 66; 20 mg, n = 62; 30 mg, n = 60), placebo 65 Administration schedule: once daily, morning Duration of intervention: 5 weeks Washout before trial initiation: up to 28 days (duration dependent on the half‐life of any previous psychotropic medication) Titration period: 1‐3 weeks, initiated after randomisation Treatment compliance: 86% completed
Outcomes	ADHD symptoms Conners' ADHD/DSM‐IV ‐ Teacher Version: rated by teacher at baseline and each week Conners' ADHD/DSM‐IV ‐ Parent Version (including 12‐item ADHD Index and 18‐item DSM‐IV Subscale total): rated by parent or guardian at baseline and each week Non‐serious AEs Regular monitoring and recording of AEs, serious AEs, vital signs, body weight, ECG, physical examination, haematology parameters, blood chemistry and urinalysis. While vital signs were recorded at every visit, physical, laboratory and ECG evaluations were completed during the screening visit and the final trial visit. Weight was recorded at baseline and at the final visit. Notable value for weight loss was defined as a decrease from baseline weight at trial end of 7%
Notes	Sample calculation: yes; 252 participants (63 per treatment group) Ethics approval: institutional review boards or ethical review committees at each centre approved the trial Comment from trial authors Limitations: short duration of trial, forced‐dose titration, not powered to assess differences in treatment effects within ER‐d‐MPH groups Key conclusions of trial authors All 3 doses of ER‐d‐MPH (10 mg, 20 mg or 30 mg/d) were significantly more effective than placebo in improving ADHD symptoms, as confirmed by teacher, parent and clinician Additionally, ER‐d‐MPH was well tolerated and demonstrated a consistent safety profile. Mean changes from baseline in vital signs in ER‐d‐MPH groups were small, clinically irrelevant, unrelated to dose and similar to placebo Despite the forced‐titration design of the trial, the cardiovascular safety profile of ER‐d‐MPH (10 mg/d, 20 mg/d and 30 mg/d) is similar to placebo in children with ADHD Comment from review authors Additionally, participants judged by the investigator as likely to be non‐compliant with trial procedures were excluded Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: no Any withdrawals due to AEs: yes, 6 all in the MPH groups Funding source: Novartis Pharmaceuticals Corporation. Novartis Pharma has been helping with development of the manuscript Email correspondence with trial authors in December 2013. We have contacted trial authors twice in an attempt to obtain supplemental information regarding blinding, allocation concealment and weight loss. We have not received a response
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was performed by using a validated system that automated the assignment of treatment arms to randomisation numbers in the specified ratio
Allocation concealment (selection bias)	Low risk	Allocation concealed
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Double‐blind, but no detailed description
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Double‐blind, but no detailed description
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT population. LOCF 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