Wigal 2017.

Study characteristics
Methods	A 1‐week parallel‐trial with 2 arms: ER‐MPH chewable tablets placebo Phases: 3 (open‐label phase (6 weeks), double blind‐phase (1 week), follow‐up 1‐2 weeks after)
Participants	Number of participants screened: 90 entered the open‐label phase Number of participants included: 86 randomised in the double‐blind trial Number of participants followed up: 85 (ITT population, 53 (62.4%) boys, 32 (37.6%) girls) Number of withdrawals: 1 during double‐blind (lost to follow‐up) Diagnosis of ADHD: confirmed at screening (23 (27.1%) inattentive, 0 hyperactive/impulsive, 62 (72.9%) combined) Age: 9.6 years (SD 1.69, range 6‐12) IQ: not measured MPH‐naive: not stated Ethnicity: Hispanic/Latino (n = 13, 15.3%), non‐Hispanic/‐Latino (n = 72, 84.7%) Country: USA Setting: multi‐site, outpatient Comorbidity: not allowed Comedication: not allowed Additional sociodemographics: white (n = 49, 57.6%), black/African American (n = 30, 35.3%), Asian (n = 1, 1.2%), other (n = 5, 5.9%) Inclusion criteria Children aged 6‐12 years with ADHD who require pharmacologic treatment for this condition Investigator administered CGI‐S score of at least 3 (mildly ill) Investigator administered ADHD‐RS (ADHD‐RS‐IV) Home Version score in the 90th percentile or greater for gender and age on the hyperactive–impulsive subscale, inattentive subscale, and/or total score at screening or baseline Exclusion criteria Current primary psychiatric diagnosis of severe anxiety disorder, CD, pervasive developmental disorder, eating disorder, OCD, major depressive disorder, bipolar disorder, or other psychiatric disorder, substance abuse disorder, or a personal or family history of Tourette’s syndrome Clinically significant or severe medical illness or condition, including seizure disorder, cardiac disorders or conditions (including severe hypertension), untreated thyroid disease, or a history of HIV or hepatitis B or C infections Clinically significant abnormal laboratory results or a positive test for illicit drug use at screening History of hypersensitivity or lack of efficacy to MPH Other serious illnesses or conditions that would put the patient at particular risk for safety events or would interfere with treatment/assessment of ADHD Psychotropic agents were prohibited. Sedative hypnotics were prohibited within 24 h before screening, except sedative hypnotics that had been prescribed as sleep aids (at bedtime only) for at least 30 days before the baseline visit. (Promethazine (1 ER‐MPH chewable tablet‐treated patient, for viral infection) was the only sedative hypnotic reported in this trial.) Pharmacologic treatments for ADHD, including non‐investigational stimulant medications for the control of ADHD, were allowed until 24 h before the baseline visit for the open‐label, dose‐optimisation period
Interventions	Participants were randomly assigned to 2 different groups, either placebo or ER‐MPH chewable tablet at optimised dose (between 20‐60 mg/d) Number randomised to each group: 44 placebo, 42 ER‐MPH chewable tablet Mean medication dosage: not stated Administration schedule: daily Duration (of (each) medication): 7 weeks of MPH for MPH group, 6 weeks MPH + 1 week placebo for placebo group Washout before trial initiation: a minimum of 24‐h before open‐label phase. No information on wash‐out period before double‐blind trial initiation Titration period: 6 weeks before double‐blind week. Starting at a dose of 20 mg, participants could either be increased or decreased by 10‐20 mg/d once a week to a maximum of 60 mg/d and a minimum of 20 mg/d, depending on a clinical judgement by the investigators Treatment compliance: not stated
Outcomes	ADHD symptoms SKAMP Rating Scale Serious AEs C‐SSRS Spontaneous reporting Non‐serious AEs Vital sign measurements AE queries
Notes	Sample calculation: no Ethics approval: yes; “The protocol, consent and assent forms, and the investigator’s brochure received institutional review board approval before initiation of the study” Comments from trial authors "The exclusion of participants with significant co‐occurring psychiatric or medical illness may limit the generalisability of these findings to a wider patient population." "Although comparable bioavailability has been demonstrated for 40 mg MPH ERCT [ER‐MPH chewable tablet] and 40 mg IR MPH in a chewable tablet formulation given as 2 20 mg doses 6 h apart, no comparative data on the pharmacokinetics of the 20 and 60 mg MPH ERCT [ER‐MPH chewable tablet] doses are available." "[…] no data were collected for analysis of patient socioeconomic status or intelligence, so effects of those factors could not be assessed in the current study" "[…] the study did not include an active comparator. Efficacy for MPH ERCT [ER‐MPH chewable tablet] was demonstrated versus placebo, but direct comparison with other effective ADHD medications would require additional study" Key conclusion of trial authors "Safety and tolerability findings from this study are consistent with those of other MPH ER formulations, including oral tablets and capsules, transdermal patch, and oral suspension." “The potential availability of a safe and effective chewable MPH ER tablet would provide a new valuable formulation option, addressing an unmet need for patients with ADHD who dislike the other available formulations, cannot swallow tablets or capsules, or would prefer the convenience of a chewable tablet.” Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH: yes Any withdrawals due to AEs: not stated for double‐blind period (1 during open‐label phase) Funding: this research was sponsored by NextWave Pharmaceuticals, a wholly owned subsidiary of Pfizer, Inc Email correspondence with trial authors: September and November 2021. We contacted the trial authors for information regarding risk of bias through personal email in September and November 2021, but no answer was received.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was conducted according to a fixed schedule using a permuted block design stratified by clinical site.
Allocation concealment (selection bias)	Low risk	The randomisation code was maintained centrally by the clinical supply group, and the trial team and investigator site personnel were blinded throughout the trial.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Mention of double‐blind, method not stated
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The investigators who recorded the AEs did not conduct the efficacy evaluations, and the classroom raters collecting efficacy data had no duties outside the classroom and were not aware of AEs collected by the investigators.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Efficacy analyses were based on the ITT population, which included all participants who received at least 1 dose of the trial drug and had at least 1 post‐baseline assessment of the primary efficacy variable. Safety assessments were based on the enrolled safety population Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): no
Selective reporting (reporting bias)	Low risk	All protocol outcomes are reported