Froehlich 2018.

Study characteristics
Methods	A 4‐week cross‐over trial with 4 arms 1 week of LD‐LA‐OROS‐MPH (Concerta) 1 week of MD‐LA‐OROS‐MPH (Concerta) 1 week of HD‐LA‐OROS‐MPH (Concerta) 1 week of placebo Phases: 1
Participants	Number of participants screened: 194 met inclusion criteria Number of participants included: 171 (122 boys, 49 girls) Number of participants followed‐up: 168 (154 for sleep outcomes) Number of withdrawals: 3 (found from table on ClinicalTrials.gov) (14 further for sleep outcomes) Diagnosis of ADHD: DSM‐IV (45 combined, 0 hyperactive‐impulsive and 126 inattentive) Age: 8.4 (SD 1.3, range 7‐11) IQ: inattentive‐type: 107.8 (SD 13.3), combined‐type: 105.6 (SD 12) MPH‐naive: 100% Ethnicity: white (n = 139), black (n = 21), Hispanic/Latino (n = 4), other (n = 3) Country: USA Setting: outpatient Comorbidity: comorbid ODD, CD, depression, and anxiety disorders were allowed unless determined to be the primary cause of ADHD symptomatology or necessitating different treatment. Anxiety disorder = 2, mood disorder = 2, disruptive behavior disorder = 45 Comedication: no medication for psychological or psychiatric problems Additional sociodemographics: none Inclusion criteria Consent: the family must provide signature of informed consent by a parent or legal guardian. Children must also assent to trial participation Age at screening: 7.0 years‐11.9 years, inclusive Sex: includes male and female children ADHD diagnostic status: meets DSM‐IV criteria for ADHD, predominantly inattentive or combined subtype with CGI‐S rating corresponding to at least "moderately ill" Cognitive functioning: IQ > 80 as estimated by Vocabulary and Block Design subtests of the WISC‐IV, or an IQ of ≥ 80 when administered the Full Scale Version of the WISC‐IV Absence of learning disability: on the abbreviated Wechsler Individual Achievement Test‐2nd edition Reading and Math subtests, participants must score > 80. However, children may also be included if they receive a score of ≥ 75 on the Word Reading and/or Math subtests, as long as this score is not a significant discrepancy from their full‐scale IQ score (e.g. a difference of > 1 SD or 15 points). School: enrolled in a school setting rather than a home‐school programme Exclusion criteria Understanding level: participant and/or parent cannot understand or follow trial instructions Psychiatric medications: current or prior history of taking any medication for psychological or psychiatric problems Behavioral interventions: current active participation in ADHD‐related behavioral interventions or counselling Exclusionary psychiatric conditions: children with mania/hypomania and/or schizophrenia will be excluded. The following comorbid diagnoses will not be excluded unless they are determined to be the primary cause of ADHD symptomatology (see below for description of this decision process): PTSD, phobias and anxiety disorders, OCD, major depression/dysthymia, eating disorders, elimination disorders, trichotillomania, tic disorder, ODD, CD Organic brain injury: history of head trauma, neurological disorder, or other organic disorder affecting brain function Cardiovascular risk factors: children with a personal history or family history of cardiovascular risk factors will be excluded, or given the option of participating in the trial after obtaining an ECG and a signed letter from a paediatric cardiologist verifying the safety of their participation in a trial of MPH. In this case, families will be responsible for the costs of ECG and cardiologist evaluation. If for any reason a family is unable to assume the cost of the ECG and cardiologist evaluations but still wishes for their child to participate, trial staff will determine on a case‐by‐case basis whether the trial budget allows the trial to offer financial assistance to the families for these evaluations.
Interventions	Participants were randomly assigned to 1 of 6 different medication orders, of 3 different medication weeks of OROS‐MPH (Concerta) at a high, medium and low dose, and 1 week of placebo. Number randomised to each group: not stated Mean medication dosage: 18 mg, 27 mg, 36 mg for children ≤ 25kg; 18 mg, 36 mg or 54 mg for children > 25kg; sample mean maximum dose = 1.57 mg/kg/d) Administration schedule: not stated Duration (of (each) medication): 3 weeks of OROS‐MPH (Concerta), 1 week at each dose, 1 week of placebo Washout before trial initiation: not applicable, all were MPH‐naive Medication‐free period between interventions: not stated Treatment compliance: not stated
Outcomes	ADHD symptoms VADPRS VADTRS Data on ADHD symptoms were not reported in a way that could be used for this review. Trial authors were contacted, but no data were received. Serious AEs Spontaneous reporting Non‐serious AEs Parent‐completed Pittsburgh Side Effect Rating Scale (including sleep outcomes)
Notes	Sample calculation: no Ethics approval: institutional Review Board‐approved protocol Comments from trial authors "Our trial limitations include its short‐term nature, so we are unable to comment on the longer‐term persistence of the documented MPH response patterns." "In addition, in accordance with usual clinical practice, we depended on parent and teacher ADHD symptom ratings to determine MPH response, rather than using direct behavioral observations or neuropsychological measures." Key conclusion of trial authors No factors have been identified that consistently predict MPH response in children with ADHD. There is growing interest in a new ADHD‐related phenotype called sluggish cognitive temp (SCT), and the relationship between SCT symptomatology and medication response. Higher levels of specific SCT symptoms related to being sleepy and slow moving were linked to a diminished MPH response in this trial. Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH: no Any withdrawals due to AEs: not stated Funding source: data collection for the project was supported by the NIMH (Bethesda, MD) by R01MH074770 [Epstein] and K23MH083881 [Froehlich], while investigators’ time on the project was funded by NIMH K24MH064478 [Epstein], K23MH083027 [Brinkman], and R01MH070564 [Stein]). Email correspondence with trial authors: August and November 2021 We received supplemental information regarding risk of bias through personal email correspondence with the trial authors in August 2021 (Storm 2021b [pers comm]). Inquiries for outcome data was also made but no answer was received in either September and November 2021.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated list was used to randomise participants equally to one of 6 dosing schedules
Allocation concealment (selection bias)	Low risk	Trial medication consisted of identical capsules filled with either an inert white powder (placebo) or the prescribed dose of OROS‐MPH (Concerta_ over‐encapsulated to preserve double‐blind
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Trial pills were identical capsules filled with either an inert white powder (placebo) or the prescribed dose of MPH over‐encapsulated to preserve the blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Yes, outcome assessors were blind to allocation
Incomplete outcome data (attrition bias) All outcomes	Low risk	Only 3 participants did not complete the medical trial. 17 missing data for sleep outcomes, LOCF (high risk of bias for this particular outcome) Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): no
Selective reporting (reporting bias)	High risk	Family satisfaction with medication trial not reported