Huang 2021.

Study characteristics
Methods	A 2‐week 2‐way cross‐over trial with 2 arms: LA‐MPH formulation (ORADUR‐MPH) placebo Phases: 3 (open‐label titration period (2–4 weeks), double‐blinded and placebo‐controlled 2‐way cross‐over treatment phase (4 weeks), and follow‐up phase (2 weeks))
Participants	Number of participants screened: 110 participants entered the open‐label period Number of participants included: 103 randomised. Participants were randomly assigned to 1 of 2 possible drug condition orders. Number of participants followed up: 100 (ITT population: 99; 72.2% boys, 28.8% girls) Number of withdrawals: 5; 3 withdrew after randomisation, 2 withdrew after the 1st treatment periods (1 in each group) Diagnosis of ADHD: DSM‐5 (of the ITT population 75% were combined type and 25% were inattentive type) Age: mean: LA‐MPH, placebo: 9.16 years (SD 2.42); placebo, LA‐MPH: 8.96 years (SD 2.39) (range 6‐18) IQ: < 80 was an exclusion criterion, no further information MPH‐naive: not stated Ethnicity: not stated Country: Taiwan Setting: outpatient Comorbidity: no Comedication: concomitant medication was an exclusion criterion Additional sociodemographics: parental education level Father’s education level: senior high or below: LA‐MPH, placebo 19 (38%), placebo, LA‐MPH 21 (42%). College or above: LA‐MPH, placebo 30 (60%), placebo, LA‐MPH 28 (56%) Mother’s education level: senior high or below: LA‐MPH, placebo 20 (40%), placebo, LA‐MPH 16 (32%). College or above: LA‐MPH, placebo 29 (58%), placebo, LA‐MPH 31 (62%) Inclusion criteria 6‐18 years Clinical diagnosis of ADHD according to the DSM‐5 criteria within the last year Able to swallow the trial‐specific capsule (18 mm) without difficulty Ability to provide written informed consent by participants and their parents/guardians Exclusion criteria ADHD treatment for > 1 year or ADHD treatment within 30 days before the trial treatment initiation Participants that by investigator's evaluation are very anxious, tense or agitated Known allergies to any of the LA‐MPH ingredients Estimated IQ < 80 Taking a concomitant medication (e.g. MAOI) that is likely to interfere with safe administration of MPH within 14 days prior to the trial treatment initiation Joining other clinical studies and receiving any other investigational medical products within 30 days prior to the trial treatment initiation Glaucoma (narrow angle glaucoma), ongoing seizure disorder or any systemic disease Any disorder involving tics, Tourette's syndrome, or a family history of Tourette's syndrome Any psychotic disorders Clinically significant gastrointestinal problems, including narrowing of the gastrointestinal tract If participants or their caregiver(s) (in the case of participants whose parents/caregivers were to fill out the trial questionnaires) had exhibited drug or alcohol abuse/dependence within the last 6 months Psychological, familial, sociological, or geographical condition potentially hampering compliance with the trial protocol and follow‐up schedule By the investigators' discretion, participants with serious or unstable medical illness that will interfere with the evaluations of trial efficacy and safety In the investigators' opinion, participants cannot understand or follow the instructions given in the trial
Interventions	Participants were randomly assigned to 1 of 2 possible orders of 2 weeks of LA‐MPH (22 mg/d, 33 mg/d or 44 mg/d depending on optimal dose) and 2 weeks of placebo Number randomised to each group: LA‐MPH, placebo 50, placebo, LA‐MPH 50 Mean medication dosage: of the 99 who received 2 weeks of LA‐MPH: 30.56 mg/d (SD 8.40 mg/d, range 22–44 mg/d) and 0.92 mg/kg/d (SD 0.28 mg/kg/d, range 0.42–1.90 mg/kg/d) Administration schedule: once daily in the morning, 20 min after breakfast Duration (of (each) medication): LA‐MPH 2 weeks, placebo 2 weeks Washout before trial initiation: medication within the past 30 days was an exclusion criterion. There was minimum 1 week treatment at optimal dosage before randomisation. No washout period between open‐label and blinded trial period Medication‐free period between interventions: no washout period between interventions Titration period: 2‐4 weeks, where each participant was titrated to their optimal dosage of either 22 mg/d, 33 mg/d or 44 mg/d Participants who were unable to tolerate 22 mg of MPH were withdrawn. After optimisation, each participant had 1 additional week at their optimal dosage Treatment compliance: pill count and parental reporting. No information on adherence
Outcomes	ADHD symptoms Chinese SNAP‐IV‐Parent Chinese SNAP‐IV‐Teacher K‐SADS‐E ‐ Chinese CTRS Revised: Short) ‐ Chinese version Serious AEs Spontaneous reporting Non‐serious AEs Open‐ended questions during an initial clinical interview at each visit by the investigators A structured interview by the investigators based on a standard questionnaire that includes all potential adverse effects BP measure Heart rate measurement Body weight assessment Physical examination findings
Notes	Sample calculation: yes; “By assuming that the mean difference between MPH and the placebo in terms of the SNAP‐IV total score at 2 weeks was to be −6.0, the individual standard deviations (SDs) would have been 10.0. Based on such information, the total sample size was estimated using a one‐sided significance level of 2.5% and a power of 80%. If an 18% dropout rate is included, then we need to recruit at least 110 subjects to this trial to obtain a target sample size of 90 for evaluation.” Ethics approval: yes Comments from trial authors “The small sample size may partially explain the low power to detect group differences” “[…] [limitations] include the short treatment period, the lack of control regarding the time of day that reports are completed, the exclusion of ADHD patients with comorbidities such as other psychiatric disorders, the fact that the recruited population consisted largely of male subjects, and the lack of either a parallel placebo‐controlled trial or a head‐to‐head comparison with standard psychopharmacotherapic treatment for ADHD.” “[…] MPH gives rise to several easily recognizable AEs, one such being decreased appetite; such well‐known adverse effects may lead to a loss of blinding and thus influence rating of symptom, particularly when this is carried out by parents and assessors who have knowledge of reported adverse effects.” Key conclusion of trial authors "Our findings indicate that ORADUR‐MPH [LA‐MPH] is an efficacious, safe, and well‐tolerated medication for treating children and adolescents with ADHD and that it does this by reducing their ADHD core symptoms without serious AEs. It provides another treatment option for patients with ADHD." Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH: yes, during an open‐label titration phase before randomisation Any withdrawals due to AEs: yes, 1 Funding source: this work is supported by Orient Pharma Co, Ltd. Email correspondence with trial authors: August and October 2021. We contacted the trial authors for information regarding risk of bias and first period data 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)	Low risk	Based on a computer‐generated random sequence, the trial participants were randomly assigned into either the LA‐MPH or the placebo parts of the trial at a 1:1 ratio
Allocation concealment (selection bias)	Unclear risk	Nothing stated
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Double‐blinded, no mention of method “[…] methylphenidate gives rise to several easily recognizable AEs, one such being decreased appetite; such well‐known adverse effects may lead to a loss of blinding and thus influence rating of symptom, particularly when this is carried out by parents and assessors who have knowledge of reported adverse effects.”
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias) All outcomes	Low risk	Only 5 participants withdrew during the double‐blind phase (2 of them were included in the ITT sample). Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): no
Selective reporting (reporting bias)	High risk	Conners' Continuous Performance Test (CPT‐II) performance in LA‐MPH vs. placebo is mentioned in protocol, but no outcomes are reported