Wigal 2013.

Study characteristics
Methods	4‐ to 6‐week, open‐label treatment (dose optimisation), cross‐over, 2‐week double‐blind trial with 2 interventions: MPH (NWP06 ‐ liquid formulation of ER‐MPH) placebo Phases: 2
Participants	Number of participants screened: 45 (32 boys, 12 girls) entered the open‐label phase and were randomised at baseline visit Number of participants included: 39 entered the double‐blind cross‐over trial Number of participants followed up: 39 Number of withdrawals: 0 Diagnosis of ADHD: DSM‐IV (combined (70.5%), hyperactive‐impulsive (2.3%), inattentive (27.3%)) Age: mean 8.8 years (range 6‐12) IQ: not stated MPH‐naive: 0 (0%) Ethnicity: white 35 (79.5%), black/African American 4 (9.1%), Asian 3 (6.8%), other 2 (4.5%) Country: USA Setting: outpatient clinic Comorbidity: elimination disorder (4; 9.1%), ODD (8; 18.2%), specific phobias (2; 4.5%) Comedication: no Other sociodemographics: none Inclusion criteria ADHD diagnosis by psychiatrist, psychologist, developmental paediatrician or paediatrician Pharmacological treatment for ADHD and has experienced suboptimal efficacy or a safety or tolerability issue with current regimen, or has been in need of a long‐acting liquid formulation CGI Scale score > 3 ADHD‐RS score (Hyperactive‐Impulsive or Inattentive subscale) > 90th percentile for age and sex Exclusion criteria Comorbidity (DSM‐IV Axis I), with the exceptions of specific phobia, motor skills disorders, ODD, sleep disorders, elimination disorders, adjustment disorders, learning disorders or communication disorders IQ < 80 Chronic disease: seizure disorder, thyroid disease, Tourette’s disorder or family history of Tourette’s disorder or tics, serious cardiac conditions, cardiomyopathy, serious arrhythmias, structural cardiac disorders, glaucoma or severe hypertension Any investigational medication 15 days before screening Atomeoxetine inhibitor 30 days before screening
Interventions	Participants were randomly assigned to different sequences of MPH and placebo Mean MPH dosage: 32.8 mg/d Administration schedule: 4 times/d Duration of each medication condition: 1 week Washout before trial initiation: yes (1 day for stimulants) Medication‐free period between interventions: no Titration period: 3 weeks before randomisation Treatment compliance: 2 withdrawals of assent/consent, 2 AEs, 1 lack of efficacy, 1 LTFU, all during the open‐label phase
Outcomes	ADHD symptoms SKAKMP, ADHD‐RS (open‐label phase) Non‐serious AEs 42 participants (93.3%) experienced a TEAE. 3 (6.7%) participants experienced severe adverse effects (affect lability, aggression and initial insomnia), and 2 (4.4%) participants had to discontinue medication (affect lability and aggression) Open‐label phase: participants experienced decreased appetite (55.6%), abdominal pain upper (42.2%), affect lability (26.7%), initial insomnia (22.2%), insomnia (17.8%) and headache (17.8%). Other AEs reported in > 5% of participants included vomiting, diarrhoea, logorrhoea, aggression, dizziness, irritability, fatigue, upper respiratory tract infection, cough and flushing Double‐blind phase: 11 (24.4%) participants had an AE while receiving NWP06, and 5 (11.1%) participants had an AE while receiving placebo
Notes	Sample calculation: no Ethics approval: yes Comments from trial authors "This study of NWP06 allowed inclusion of patients who were either treatment naive or had previously been treated with stimulants (...)"; "Subjects were required to have been in need of pharmacological treatment for ADHD (...)" "Our population more closely reflects a real‐world population and provides a more rigorous test of the study drug" Key conclusion of trial authors "NWP06 resulted in significant improvement in the Swanson, Kotkin, Agler, M‐Flynn and Pelham‐combined score at 4 h post dose as compared with placebo among completers. This study shows that NWP06 significantly improved ADHD symptoms in school‐aged children and was well tolerated" Comments from review authors Laboratory school environment and lack of the ADHD‐RS Race/ethnicity does not reflect a real‐world population Inclusion of MPH responders only/exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: yes, there was an open‐label titration phase before randomisation, during which 2 participants discontinued due to AEs and 1 due to lack of efficacy. Also participants had to be in treatment with suboptimal efficacy (no inclusion of placebo responders). Any withdrawals due to AEs: no Funding source: trial received funds from NextWave Pharmaceutics (Belden and Berry are with NextWave) Email correspondence with trial authors: emailed trial authors to request additional information but have not received a response.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	High risk	Results from open‐label phase
Blinding of outcome assessment (detection bias) All outcomes	High risk	Results from open‐label phase
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants in the double blind phase followed up Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): no
Selective reporting (reporting bias)	Low risk	ADHD‐RS not reported (used only in the open phase)