Schrantee 2016.

Study characteristics
Methods	A 16‐week parallel‐trial with 2 arms: MPH placebo Phases: 2:4 (1‐week actigraphy baseline, 16‐week parallel trial followed by 1‐week washout, 1‐week actigraphy follow‐up)
Participants	Number of participants screened: 75 boys Number of participants included: 50 (100% boys) Number of participants followed‐up: 48 (46 for sleep measurements) Number of withdrawals: 2 from the placebo group. Sleep outcomes were excluded for another 2 participants due to analytic errors Diagnosis of ADHD: DSM‐IV (21 combined, 1 hyperactive‐impulsive and 28 inattentive type) Age: placebo 11.3 MPH 11.4 (range 10‐12) IQ: MPH 103.22 (SD 21.01), placebo 103.35 (15.05) MPH‐naive: 100 % Ethnicity: not stated Country: the Netherlands Setting: outpatient Comorbidity: many were an exclusion criterion Comedication: many were an exclusion criterion Additional sociodemographics: none Inclusion criteria Male outpatients newly diagnosed with ADHD all subtypes as defined in the DSM‐IV Exclusion criteria Co‐morbid Axis I psychiatric disorders requiring treatment with medication at trial entry, and a history of major neurological or medical illness (including epilepsy, traumatic brain injury and chronic severe tics or Tourette syndrome) IQ < 80 ("(as measured by a subtest of the Wechsler Intelligence Scale for children‐Revised (WISC‐R), National Adult Reading Test (NART), authorized Dutch translation [23])" Bottelier 2014 p. 4, secondary reference under Schrantee 2016) Current or previous treatment with medications that influence the dopamine system (for adults before 23 years of age) such as: neuroleptics, antipsychotics, D2/D3 agonists (pramipexole and ropinirole) Current or previous dependency of drugs that influence the DA system (for adults before 23 years of age), such as: MDMA, amphetamine, methamphetamine, cocaine, heroin and LSD Version 6, November 2013 17 of 44Protocol ID/34509.000.10 ePOD‐MPH Contraindications to MPH treatment: cardiovascular diseases such as hypertension, arrhythmia, hyperthyroidism, glaucoma, suicidality, psychosis, Tourette disorder Prenatal use of MPH by mother of the patients Contraindications to MRI (metal implants, pacemakers, claustrophobia, etc.)
Interventions	Participants were randomly assigned to 2 different interventions, either flexible dose MPH (starting with 0.3 mg/kg day in 1‐2 doses) or placebo Number randomised to each group: 25 Mean medication dosage: MPH‐group 31.3043 mg/d (information from 23 participants) Administration schedule: individually fixed times during the day. 1‐2 times Duration (of (each) medication): 16 weeks Washout before trial initiation: NA Titration period: trial dosage can be increased weekly with 5‐10 mg/d to a maximum of 60 mg daily Treatment compliance: adherence to the trial medication was monitored at each of the 5 control visits
Outcomes	Serious AEs Spontaneous reporting Non serious AEs Quality of sleep measured by: SE prior to, during, and one week after treatment discontinuation, assessed using actigraphy, sleep onset latency, total sleep time, TIB, WASO, number of wake bouts (WBnumber), mean wake bout time (WBmean), interdaily stability (IS), intradaily variability (IV), the amount of activity during the 5 h with the lowest activity (L5) and during the 10 h with the highest activity, the amplitude of the sleep‐wake rhythm (AMP)
Notes	Sample calculation: no Ethics approval: yes. The institutional review board of the Academic Medical Center approved the trial. Comments from trial authors "Owing to its complexity, the power of the trial was limited, especially because we examined 3 different brain regions, which could have increased the risk of a type I error." Key conclusion of trial authors Because significant relationships between changes in cortical ROIs and changes in symptom severity were not observed, the functional significance remains uncertain. The results of this RCT yield partial support for the hypothesis that MPH treatment in development is associated with reduced cortical thinning in childhood, but not adulthood. "We found a strong, positive effect of 16 weeks MPH treatment on the timing, duration and quality of sleep in boys with ADHD." Comments from review authors As data for the population aged 10‐12 are available separately, we have included these data as a part of a larger study, in which 49 men between 23‐40 also participated. Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH: no Any withdrawals due to AEs: yes, 1 in the placebo group Funding source: this trial was funded by faculty resources of the Academic Medical Center, University of Amsterdam, and by grant 11.32050.26 from the European Research Area Network Priority Medicines for Children (Sixth Framework Programme). Dr Rombouts was supported by Vici (Netherlands Organisation for Scientific Research), and Dr Andersen was supported by grant DA‐015403 from the National Institute on Drug Abuse. Email correspondence with trial authors: September 2021. We received supplemental information regarding mean medication dosage and vested interest through personal email correspondence with the trial authors in September 2021. (Storm 2021g [pers comm]).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomly assigned (1:1) using a permuted block randomisation scheme generated by the local Clinical Research Unit to either IR‐MPH or matching placebo treatment for 16 weeks
Allocation concealment (selection bias)	Low risk	The hospital pharmacy (Alkmaar) assigned participants to a specific allocation, using sequentially numbered containers.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The placebo tablet was identical to the MPH tablet with respect to appearance and was manufactured and labelled according to guidelines (2003/94/EG). The treating physician prescribed the medication under double‐blind conditions on clinical guidance (reduction in ADHD symptoms), in accordance with Dutch treatment guidelines. After trial end, blinding was checked with the participant and his psychiatrist as well as the trial investigators.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Participants as well as care providers and research personnel were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	“Missing values for the CBF (3.6% [14 of 392] due to dropout and 10.7% [42 of 392] in total) and clinical assessments (3.6% [14 of 392] due to dropout and 18.9% [74 of 392] in total) were replaced using nearest neighbor interpolation within age and medication group.” Comment: High‐risk method of analysis. Only 2 withdrawals from outcomes other than sleep, therefore low risk for general behaviour. Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): no
Selective reporting (reporting bias)	Low risk	All outcomes from trial protocol reported