Wigal 2015.

Study characteristics
Methods	A 1‐week parallel trial with 5 arms: MPH‐MLR 10 mg MPH‐MLR 15 mg MPH‐MLR 20 mg MPH‐MLR 40 mg Placebo Phases: 4 (screening, double‐blind, open‐label, and safety follow‐up)
Participants	Number of participants screened: 280 Number of participants included: 230 (154 (67%) boys, 76 (33%) girls) Number of participants followed up: 221 Number of withdrawals: 9 Diagnosis of ADHD: DSM‐IV‐TR (140 combined, 6 hyperactive‐impulsive, 75 inattentive, 9 not reported) Age: mean 10.8 years (SD 3.0, range 6‐18) IQ: IQ < 80 was an exclusion criterion MPH‐naive: 146 of 221 (66%); "Two‐thirds of the sample were stimulant naïve, and one‐third of the sample (75/221) had a medication washout" Ethnicity: race was measured: white (n = 158, 68.7%), black (n = 53, 23%), Asian (n = 3, 1.3%), other (n = 16, 7%) Country: USA Setting: outpatient Comorbidity: many comorbidities were exclusion criteria (see exclusion criteria). Most common comorbidities were ODD (n = 22) and enuresis (n = 14) Comedication: CNS medication was an exclusion criterion, many illnesses were exclusion criteria, no further information Sociodemographics: none Inclusion criteria Age 6‐18 years ADHD diagnosis with ADHD‐RS‐IV scores ≥ 90th percentile relative to the general population of children by age and sex at screening or baseline (diagnosis of all subtypes (except “not otherwise specified” ) as defined in the DSM‐IV‐TR In need of treatment for ADHD and able to have 2‐day washout from previous medication Patients had to require pharmacological treatment for ADHD Female participants of child‐bearing potential not pregnant and practice birth control Participant and parent/guardian willing to comply with protocol Signed consent and assent Exclusion criteria IQ < 80 WASI Current primary psychiatric diagnosis of other listed disorders ‐ severe anxiety disorder, CD, psychotic disorder, pervasive developmental disorder, eating disorder, OCD, major depressive disorder, bipolar disorder, substance use disorder, chronic tic disorder, or a personal or family history of Tourette’s syndrome as defined by the DSM‐IV‐TR criteria and supported by the K‐SADS‐PL Chronic medical illnesses: seizure, hypertension, thyroid disease, cardiac, family history of sudden death, glaucoma Use of MAOIs or psychotropic CNS medications having effect exceeding 14 days from screening Planned use of prohibited drugs Is pregnant or breast‐feeding Significant ECG or laboratory abnormalities Experimental drug or medical device within 30 days prior to screening Hypersensitivity to MPH Inability or unwillingness to comply with protocol Well controlled on current ADHD treatment Inability to take oral capsules
Interventions	4 phases Screening (≤ 28 days) and washout (≥ 48 h) Double‐blind fixed‐dose phase (1 week) Open‐label dose‐optimisation phase (11 weeks) Follow‐up call after 30 days/21 month open‐label compassionate use extension Participants were randomly assigned to: 5 different groups, 4 receiving MPH‐MLR (biphentin MPH extended release capsules) of either 10 mg, 15 mg, 20 mg or 40 mg, or placebo capsules Number randomised to each group: MPH‐MLR 10 mg: 49, MPH‐MLR 15 mg: 44, MPH‐MLR 20 mg: 45, MPH‐MLR 40 mg: 45, placebo: 47 Patients weighing < 25 kg were not assigned to receive the 40 mg dose Mean medication dosage: forced‐dose: 10 mg, 15 mg, 20 mg or 40 mg Administration schedule: once daily at 10.00 am Duration (of (each) medication): 1 week Washout before trial initiation: minimum 48 h Treatment compliance: no information
Outcomes	ADHD symptoms ADHD‐RS‐IV. We do not have enough data to include this outcome in our analysis. Serious AEs Spontaneous reporting Non‐serious AEs Spontaneous reporting at each visit Vital signs Physical examination ECG Clinical laboratory evaluations CSHQ. There is not enough data on the CSHQ available for us to include it in the analysis.
Notes	Sample calculation: yes; “It was estimated that a total sample size of 225 would have 80 % power to detect a mean difference […]” Ethics approval: yes; “The study protocol, amendments, and informed consent form were reviewed and approved by an Institutional Review Board for each study site.” Comments from trial authors “fixed dosing used during the double‐blind phase might have resulted in study patients who were over or under‐treated with MPH‐MLR” “The double‐blind period was short and, overall, the study duration was only 12 weeks, thus limiting a clear understanding of long‐term efficacy” “The brief washout period (2 days), while equaling or exceeding at least 5 half‐lives for ADHD medications patients may have been using prior to study entry, may have resulted in inflated baseline scores for some patients[…]” Key conclusion of trial authors “Methylphenidate (MPH) multilayer bead extended release (ER) capsules (MPH‐MLR; Aptensio XRTM) administered once daily demonstrated significant dose‐related improvements in Attention‐Deficit/ Hyperactivity Disorder Rating Scale, 4th Edition(ADHD‐RS‐IV) scores compared with placebo in children and adolescents with ADHD” “The safety profile of MPH‐MLR is consistent with other ER MPH formulations” “The results of this phase III study indicate that MPH‐MLR, with a novel release profile, offers a valuable option for the treatment of ADHD in children and adolescents” Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH: yes, known hypersensitivity to MPH was an exclusion criteria Any withdrawals due to AEs: yes, 3 Funding source: Rhodes Pharmaceuticals […]. Medical writing assistance was provided by Linda Wagner, PharmD, from Excel Scientific Solutions and funded by Rhodes Pharmaceuticals LP Email correspondence with trial authors: September and November 2021. We contacted the trial authors for information regarding risk of bias and CSHQ data 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	"Patients were randomised (1:1:1:1:1) to receive MPH‐MLR 10 mg, 15, 20, or 40 mg or placebo following a computer‐generated randomisation schedule with patients assigned the next random number arranged in an ABCDE block design with each letter representing one of the 5 treatment groups. There was no site stratification in randomization. Patients weighing <25 kg were not assigned to receive the 40 mg dose”
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"All trial treatments (MPH‐MLR 10, 15, 20, 30, 40, 50, 60 mg, placebo) were given orally once daily in the morning, no later than 10 a.m. and were packaged in bottles of ten capsules for a 1‐week dispensing interval and bottles of 30 for 4‐ and 8‐week dispensing intervals. Lot numbers used during the double‐blind phase were A07983‐2. 002L01 (10 mg), A07983‐002L02 (15 mg), A07983‐3. 002L03 (20 mg), A07983‐002L04 (40 mg), and A07983‐001L02 (placebo)"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias) All outcomes	Low risk	"The model had class terms for treatment (5 levels), site (sites with less than ten patients were combined into a pseudo site), and a covariate term for baseline ADHD‐RS‐IV total score. The same model was applied to the ITT population as a sensitivity analysis. Subjects not completing the double‐blind phase had the decrease in total score set to zero for the sensitivity analysis." Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): no
Selective reporting (reporting bias)	High risk	“Incidence of adverse findings using various measures of safety, tolerability, and quality of life assessments following administration of once daily Biphentin” (NCT01239030) Quality of life is mentioned as an outcome in the protocol but not in the full report. It is described that the C‐SSRS is assessed at screening and at the end of the double‐blind phase, but the results are not included.