Kollins 2021.

Study characteristics
Methods	A 1‐week parallel‐trial with 2 arms: SerdexMPH/dexMPH (SDX/d‐MPH) placebo
Participants	Number of participants screened: 178 (155 participants included in open‐label phase) Number of participants included: 150 randomised (92 male, 58 female) Number of participants followed up: 149 Number of withdrawals: 1 lost to follow‐up Diagnosis of ADHD: DSM‐5 (percentage of combined (88%), hyperactive‐impulsive (0%) and inattentive (12%)) Age: mean 9.6 (range 6‐12) IQ: not stated MPH‐naive: 89 (59.3%) Ethnicity: 76 white, 56 black/African American, 7 Asian, 10 multiracial, 1 other Country: USA Setting: outpatient clinic, laboratory classroom Comorbidity: some were specified as exclusion criteria Comedication: not stated Additional sociodemographics: none Inclusion criteria Age 6‐12 DSM‐5 diagnosis of ADHD Score of at least 3 (mildly ill) on the clinician administered CGI‐S scale and an ADHD‐RS‐5 total score of at least 28 Exclusion criteria Known non‐response to MPH treatment History of allergic reaction or sensitivity to MPH History of substance use disorder Clinically significant medical abnormalities such as cardiovascular abnormalities, and any chronic condition of the CNS Any of the following: bipolar I or II disorder, major depressive disorder, CD, OCD, any history of psychosis, autism spectrum disorder, disruptive mood dysregulation disorder, intellectual disability, Tourette's syndrome, or confirmed genetic disorder with cognitive and/or behavioral disturbances Significant suicidal ideation or a history of suicide attempt, as assessed by the C‐SSRS
Interventions	Participants were randomly assigned to receive either their optimised dose of SDX/d‐MPH (ER) or placebo for 7 days Number randomised to each group: MPH 74, placebo 76 Mean medication dosage: not stated Administration schedule: the appropriate blinded treatment was taken at home, once daily in the morning, on days 22–27 Duration (of (each) medication): 7 days Washout before trial initiation: 2 days Titration period: 3 weeks before randomisation Treatment compliance: not stated
Outcomes	ADHD symptoms SKAMP assessed by independent investigation at baseline and day 7 Serious AEs Assessed at each trial visit General behavioral Weekly Rating of Evening and Morning Behavior—Revised (WREMB‐R) scores (total score, and morning and evening subscores), parent‐rated at baseline and day 7 Non‐serious AEs The occurrence of TEAEs was assessed at each visit, beginning with the 1st dose of the Dose Optimisation Phase and ending with the follow‐up or early termination visit
Notes	Sample calculation: yes (126) Ethics approval: the trial was approved by an Institutional Review Board. Comments from trial authors “The duration of the double‐blind Treatment Phase, while consistent with similar studies, was relatively short.” (Kollins 2021, p. 606) “the eligibility criteria resulted in a fairly homogeneous sample of children without comorbidities, potentially limiting the generalizability of the findings” (Kollins 2021, p. 606) “On the morning of the laboratory classroom day, baseline SKAMP‐C scores were significantly higher (i.e. more severe symptoms) in subjects treated with SDX/d‐MPH compared with placebo” (Kollins 2021, p. 606) “These collective findings suggest that after a period of chronic administration, opponent processes that outlast the acute effects of the stimulant may last for several days or more” (Kollins 2021, p. 606) “This apparent ‘‘rebound’’ phenomenon has implications for understanding the onset and duration, and likely the overall magnitude of observed efficacy in laboratory classroom studies” (Kollins 2021, p. 606) Key conclusion of trial authors “In this dose‐optimized, randomized, controlled laboratory classroom study, SDX/d‐MPH showed significant improvements in ADHD symptoms compared with placebo in children 6–12 years of age, with a rapid onset and extended duration of effect. SDX/d‐ MPH was safe and generally well tolerated, with adverse effects comparable with those observed with other stimulant medications.” (Kollins 2021, p. 606) “SDX/d‐MPH is a recently approved ADHD product (Azstarys) containing a molar ratio of 70% SDX, a novel prodrug of d‐MPH, and 30% d‐MPH. In this study of children (6–12 years of age) with ADHD, SDX/d‐MPH was efficacious and generally well tolerated, with a rapid onset and extended duration of effect.” (Kollins 2021, 606) Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH: yes Any withdrawals due to AEs: no Funding source: clinical research was funded by KemPharm, Inc. Funding for editorial and writing assistance in the form of proofreading, copyediting, and fact‐checking was provided by Corium, Inc Supplemental information regarding the risk of bias assessment was requested through personal email correspondence with the authors in July 2022 but no answer was received.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information about sequence generation available
Allocation concealment (selection bias)	Unclear risk	No information about method of allocation concealment available
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Randomisation was stratified by trial site. Neither the participant, the investigator, nor the sponsor knew a given participant’s treatment assignment. The appropriate blinded treatment was taken at home, once daily in the morning, on days 22–27
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Randomisation was stratified by trial site. Neither the participant, the investigator, nor the sponsor knew a given participant’s treatment assignment. The appropriate blinded treatment was taken at home, once daily in the morning, on days 22–27
Incomplete outcome data (attrition bias) All outcomes	Low risk	Efficacy analyses were conducted in the ITT population Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): no
Selective reporting (reporting bias)	Low risk	No indication of selective reporting, all outcomes are reported