NCT02536105.

Study characteristics
Methods	A 4‐week cross‐over trial with 4 arms: ER‐MPH tablets 1 Placebo ER‐MPH tablets 2 ER‐MPH for suspension Phases: 3 (screening and wash‐out, open‐label titration phase, and double‐blind trial)
Participants	Number of participants screened: 88, of which 80 were included in the open‐label phase Number of participants included: 76 randomised in double‐blind trial (59 boys, 21 girls) Number of participants followed‐up: 67 in MPH tablet 1 group, 72 in placebo group, 66 in MPH tablet 2 group, 68 in oral suspension group Number of withdrawals: unclear Diagnosis of ADHD: DSM‐5 (subtype not stated) Age: mean 9.45 (SD 1.86, range 6‐12) IQ: not stated MPH‐naive: not stated Ethnicity: Asian (n = 2), black or African American (n = 14), white (n = 45), mixed race (n = 16), race unknown or not reported (n = 3) Country: USA Setting: outpatient Comorbidity: specific phobia, motor skills disorders, ODD, sleep disorders, elimination disorders, adjustment disorders, learning disorders, or communication disorders are allowed Comedication: no Additional sociodemographics: none Inclusion criteria Male and female outpatients Aged 6‐12 years at time of screening Judged by the investigator to be physically healthy and suitable for participation in the trial Diagnosis of DSM‐5: ADHD combined, predominantly inattentive or hyperactive/impulsive presentation, per clinical evaluation and confirmed by the MINI‐KID CGI‐S ≥ 3 ≥ 90th percentile normative value for gender and age on the ADHD RS‐IV total score at screening or baseline Trial participant has a parent/legal guardian who is willing and able to give written informed consent for him/her to participate in the trial Trial participant must be able to give assent to participate in the trial Trial participant and legal guardian must be able to speak and understand English Able to tolerate multiple finger pricks Willing to comply with all trial procedures Exclusion criteria Current (last month) psychiatric diagnosis other than specific phobia, motor skills disorders, ODD, sleep disorders, elimination disorders, adjustment disorders, learning disorders, or communication disorders. Participants with school phobia or separation anxiety will not be eligible Cognitively impaired, in the investigator's opinion Any clinically significant chronic medical condition that, in the judgment of the investigator, may interfere with the participant's ability to participate in the trial Seizure disorder excluding a history of febrile seizures Thyroid disease Tourette's disorder or chronic tic disorder (mild medication‐induced tics are allowed) Serious cardiac condition including cardiomyopathy, serious arrhythmias, structural cardiac disorders, or severe hypertension Glaucoma Current or recent (within the past 6 months) DSM‐5 drug dependence or substance abuse (excluding nicotine and caffeine) Pregnant or nursing female participants. Female participants must have a negative urine pregnancy test at screening as well as 4 additional visits and must be abstinent or use adequate and reliable contraception throughout the trial Currently treated and satisfied with ADHD medication Current psychotropic medications other than sedative hypnotics for sleep Use of atomoxetine, clonidine, guanfacine or a MAOI within 28 days of the baseline visit Participation in another investigational medication trial within 30 days prior to screening Clinically significant abnormal laboratory result, ECG result, physical examination, or vital signs at screening that the investigator considers to be inappropriate to allow participation in the trial Planned use of prohibited drugs from the baseline visit through the end of the trial History of allergic reaction or a known or suspected sensitivity to any substance that is contained in the trial drugs Food allergies that are determined by the PI as too severe to be easily accommodated for during the trial Inability to swallow trial medication
Interventions	Participants were randomly assigned to 1 of 24 different medication orders of 1 week of 3 different types of MPH at optimised dosage (between 18‐72 mg) or placebo Number randomised to each group: not stated Mean medication dosage: not stated Administration schedule: not stated Duration of each medication: 1 week Washout before trial initiation: 3‐7 days (with the exception of atomoxetine, clonidine, guanfacine or a MAOI, which require a 28‐day washout) Medication‐free period between interventions: none Titration period: appears to be 8 weeks (until visit 8 in trial protocol) Treatment compliance: not stated
Outcomes	ADHD symptoms SKAMP (SKAMP‐Attention, SKAMP‐Deportment, SKAMP‐Quality of Work, and SKAMP‐Compliance) assessed at 0.5, 1.5, 2.5, 4, 5, 6, 8, 10 and 12 h post‐dose on each classroom day Serious AEs C‐SSRS: no information on timing of outcome assessment available Non‐serious AEs Spontaneously reported
Notes	Sample calculation: yes, 150 Ethics approval: yes Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH: yes, during the dose‐optimisation phase Any withdrawals due to AEs: not stated Funding source: Massachusetts General Hospital Email correspondence with trial authors: August 2021. We contacted the trial authors for information regarding risk of bias and first‐period data through personal email in August 2021; however, as the contact investigator has retired, we were unable to receive any answers.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The order of assignment will be generated by a statistician who is not involved in any of the trial procedures"
Allocation concealment (selection bias)	Low risk	Blinding ensured at external facility
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"The external facility will ensure the packaging for the placebo and active are identical"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Only one staff member unblinded at all times for emergencies
Incomplete outcome data (attrition bias) All outcomes	Low risk	"The missing data will not be imputed and the incomplete individual observations will be included in the analyses as the non‐linear mixed effect modeling approach used to conduct the PK and the PK/PD [Pharmacokinetic‐Pharmacodynamic] analyses does not require complete data sets" Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): no
Selective reporting (reporting bias)	High risk	ADHD‐RS‐IV and CGI‐S not reported