Lin 2014.

Study characteristics
Methods	8‐week, multi‐centre (31 sites in 5 countries), double‐blind, placebo‐controlled, comparator (OROS‐MPH), parallel trial with 3 interventions: edivoxetine OROS‐MPH placebo Phases Screening Clinical treatment Discontinuation
Participants	Number of participants screened: 448 Number of participants included: 340 (70.6% boys, 29.4% girls) Number of participants followed up: 210 Number of withdrawals: 60 Diagnosis of ADHD: DSM‐IV‐TR (combined (70.9%), hyperactive‐impulsive (4.1%), inattentive (25%)) Age: mean 11.6 years (range 6‐17) IQ: not stated MPH‐naive: all participants treated with MPH were medication‐naive. 44% of placebo‐treated participants, 47% of edivoxetine‐treated participants in the 0.1 mg/kg/d arm and 49% of edivoxetine‐treated participants in each of the 0.2 mg/kg/d and 0.3 mg/kg/d arms had used stimulants previously Ethnicity: white (72.6%), African American (not stated), Asian (not stated), Hispanic (not stated), other (not stated) Country: USA, Canada, Taiwan, Mexico and Puerto Rico Setting: outpatient clinic Comorbidity: ODD ("less than 20%") Comedication: not stated Other sociodemographics: none Inclusion criteria ADHD DSM‐IV‐TR diagnosis > 6 years and < 17 years and 9 months of age at the time of informed consent Diagnosis confirmed with the K‐SADS‐PL, and ADHD‐RS‐IV, score > 1.5 SD above age/sex norms and CGI‐S ADHD score > 4 Exclusion criteria Body weight < 18 kg or > 75 kg History of bipolar I or II disorder, or psychosis, seizure disorder or pervasive developmental disorder; motor tics or a diagnosis of Tourette's syndrome; marked anxiety, tension or agitation sufficient to contraindicate treatment with OROS‐MPH History of EEG abnormalities Clinically significant abnormal ECG Serious or unstable medical illness Any medical condition that would markedly increase sympathetic nervous system activity (e.g. catecholamine‐secreting neural tumour) Requiring daily use of medications with sympathomimetic activity (e.g. albuterol, pseudoephedrine) Any medical condition that would be exacerbated by an increase in norepinephrine tone Current or past history of clinically significant hypertension
Interventions	Participants were randomly assigned to 1 of 4 possible drug condition orders of 18 mg, 36 mg or 54 mg OROS‐MPH and placebo Mean MPH dosage: not stated Administration schedule: 1/d Duration of each medication condition: 8 weeks Washout before trial initiation: all MPH‐naive Medication‐free period between interventions: no Titration period: none, initiated after randomisation Treatment compliance: not stated
Outcomes	ADHD symptoms ADHD‐RS‐IV, parent‐rated, investigator‐administered and ‐scored: weekly, parent‐rated (administered and scored by qualified personnel at the investigative site based on an interview with the parent and the participant) CGI ‐ ADHD ‐ Improvement Scale CGI‐S ADHD SNAP, 4th Edition Conners' Comprehensive Behavior Rating Scales Non‐serious AEs AEs, vital signs, clinical laboratory tests (e.g. chemistry, haematology, urinalysis), physical examination and ECGs C‐SSRS: occurrence, severity and frequency of suicide‐related thoughts and behaviours
Notes	Sample calculation: not stated Ethics approval: yes Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: no Any withdrawals due to AEs: yes (3 participants) Funding source: Ely Lilly Email correspondence with trial authors: April 2015. We emailed trial authors to ask for supplemental information/data but have received no response
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Interactive voice response system was used for randomisation and to determine which trial drug should be dispensed
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not stated
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias) All outcomes	High risk	Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): yes, exclusion of MPH non‐responders (after randomisation)
Selective reporting (reporting bias)	High risk	Clear indication of selective reporting