Childress 2017.

Study characteristics
Methods	A 1‐week parallel trial with 2 arms: ER‐MPH orally disintegrating tablet (ODT) placebo Phases: 5 (screening, washout, open‐label stepwise dose optimisation, dose stabilisation, and double‐blind parallel group treatment)
Participants	Number of participants screened: 87 entered open‐label phase Number of participants included: 83 Number of participants followed‐up: 80 (82 included in full analysis) (54 boys (65.9%), 28 girls (34.1%) Number of withdrawals: 3 Diagnosis of ADHD: DSM‐IV‐TR (65 (74.7%) combined type, 1 (1.1%) hyperactive‐impulsive type, 21 (24.1%) inattentive type) Age: mean 9.2 years (SD 1.75, range 6‐12) IQ: not stated MPH‐naive: 0% Ethnicity: Hispanic/Latino (n = 28, 34.1%), not Hispanic/Latino (n = 54 (65.9%). Race was reported: white (n = 65, 79.3%), black or African American (n = 10, 12.2%), Asian (n = 2, 2.4%), Native Hawaiian or other Pacific Islander (n = 1, 1.2%), and other (n = 4, 4.9%) Country: USA Setting: outpatient clinic, laboratory classroom setting Comorbidity: most were specified as exclusion criteria Comedication: exclusion criterion Additional sociodemographics: none Inclusion criteria Age 6‐12 DSM‐IV‐TR diagnosis of ADHD, any type Positive response to a stable dose of MPH (20–60 mg of Metadate CD (UCB, Inc, Smyrna, GA) or comparable dose of another ER‐MPH or IR formulation) for at least 1 month before screening A score of > 3 (mildly ill) on the clinician‐administered CGI‐S scale > 90th percentile normative value for gender and age on the ADHD‐RS‐IV total score, inattentive or hyperactive/impulsive subscales on day 1 after MPH washout Exclusion criteria History of poor response, known allergy, serious adverse reactions to any MPH formulation or allergy to any of the components of the ER‐MPH ODT Comorbidity that made ADHD diagnosis difficult Need for additional medication to control ADHD symptoms Known medical conditions that would preclude the use of ER‐MPH ODT (or history (within the past year) Presence of clinically significant disease or dysfunction that—in the opinion of the investigator—could put the participant at substantial risk or confound trial results Current or recent history (within the past year) of drug abuse in the immediate family or by someone living at the participant’s home, Positive urine drug screen for other stimulant medications or drugs of abuse at the screening visit Significant cognitive impairment Chronic medical illnesses Structural cardiac defects Significant abnormal lab tests
Interventions	After the screening period, all participants went through a washout period of 3‐7 days, then an open‐label dose optimisation period of 4 weeks, then a 1‐week dose stabilisation week at their optimised dose (20‐60 mg). Participants were randomly assigned to: ER‐MPH ODT (at optimised dose between 20‐60 mg) or ODT placebo Number randomised to each group: intervention = 44, placebo = 41 Mean medication dosage: 34.3mg (SD 9.06) Administration schedule: once daily in the morning Duration of each medication: ER‐MPH ODT group: 42.6 days; placebo group: 35.5 days; ER‐MPH ODT plus 7 days placebo Washout before trial initiation: 3‐7 days before open‐label period depending on prior medications Titration period: 4 weeks before randomisation Treatment compliance: drug adherence was assessed at each visit from visits 3‐8 by recording pill counts of returned medication. Non‐adherence was defined as taking < 75% of the trial medication between 2 consecutive visits. No participants were excluded on lack of compliance
Outcomes	ADHD symptoms SKAMP Score, assessed at baseline and at 1, 3, 5, 7, 10, 12, and 13 h post‐dose Serious AEs Spontaneous reporting C‐SSRS; Children’s Baseline version "The C‐SSRS (Children’s Baseline version) assessment was performed at visit 1, and the C‐SSRS (Children’s Since‐Last‐Visit version) assessment was performed at each visit, starting at visit 2" (Childress 2017 p 69) Non‐serious AEs Assessed on classroom day
Notes	Sample calculation: yes, 84 Ethics approval: yes, “The study was approved by a central Institutional Review Board (IRB; Copernicus Group, Research Triangle Park, NC), and each site, if required, submitted the protocol and consent/assent forms to its local IRB” Comments from trial authors "The duration was relatively short and the trial enrolled only children aged 6–12 years without comorbidities that could potentially confound trial results, consistent with other phase 3 trial designs. Therefore, results may not be relevant for some patients who have ADHD" "Only participants with a previous history of response to MPH were included after being washed out of their current treatment before receiving ER‐MPH ODT" Key conclusion of trial authors "The results of this trial demonstrate the efficacy, safety, and tolerability of ER‐MPH ODT in the laboratory classroom trial" "Although it is difficult to draw conclusions between formulations without head‐to‐head comparisons, this ER‐MPH ODT appears to have a duration of efficacy similar to that of other ER‐MPH products compared with placebo in laboratory classroom studies" Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH: yes Any withdrawals due to AEs: no Funding source: supported by funds from Neos Therapeutics, Inc Email correspondence with trial authors: trial authors were contacted for information regarding risk of bias through personal email in August and October 2021, but no answer was received.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The trial is referred to as randomised, however the method used to generate the allocation sequence is not described in sufficient detail to allow an assessment of whether it produced comparable groups.
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Several mentions of “double blind” and the “double blind phase” or “double blind classroom”, but no information on method or if the blinding was successful.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Protocol mentions blinding of outcome assessors, but the method is not stated
Incomplete outcome data (attrition bias) All outcomes	Low risk	The 1 participant who was excluded from the full analysis set did not have a baseline SKAMP rating and also had a positive drug screen for amphetamine. 2 other participants were excluded from the per‐protocol set because they used prohibited medications. One had been assigned to placebo and the other to ER‐MPH ODT Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): no
Selective reporting (reporting bias)	Low risk	Outcomes according to protocol/trial registration