Matthijssen 2019.

Study characteristics
Methods	A 7‐week parallel discontinuation trial with 2 arms: continuation of ER‐MPH treatment gradual withdrawal over 3 weeks to 4 weeks of placebo Phases: 1
Participants	Number of participants screened: 530 Number of participants included: 104 Number of participants followed‐up: 94 (73 (77.7%) boys, 21 (22.3%) girls) Number of withdrawals: 25, 10 of whom did not receive allocated intervention Diagnosis of ADHD: no diagnosis by specified diagnostic tool required Age: MPH (continuation): mean 13.8 years (SD 2.2), placebo (discontinuation): mean 13.6 years (SD 2.2, range 8 years‐17 years) IQ: IQ < 70 was an exclusion criterion MPH‐naive: 0% (discontinuation trial) Ethnicity: European white ethnicity (MPH: n = 47 (100%), placebo: n = 46 (97.9%)) Country: the Netherlands Setting: outpatient Comorbidity: not stated Comedication: both medication and interventions used before trial initiation was allowed during the trial, as long as it did not fall within the exclusion criteria. 35 received comedication; of these: 32 received melatonin, 4 received hay fever medication, 2 received asthma medication, 1 received antipsychotic medication Additional sociodemographics: none Inclusion criteria Children between the age of 8‐18, any ethnicity or cultural background Using MPH as prescribed in clinical practice in any dosage or form for ≥ 2 years. If a child had stopped the medication during, for instance, a weekend or a school holiday, they could still participate if the period of not using MPH had not exceeded 2 continuous months during the past 2 years During the past 4 weeks, participants should have used ER‐MPH at either 36 mg or 54 mg/d. Children who were originally not using 36 or 54 mg/d of ER‐MPH could switch to one of these dosages, whichever was the closest to the dosage they were already using, for at least 4 weeks to allow them to participate in the trial. Children with an IQ > 70 (based on a previous IQ test or attending regular education) Parents (or the legal guardian) and children (≥ 12 years) have provided informed consent to participate in the trial Exclusion criteria The intent to start new psychosocial or pharmacological therapies during the trial period Inability on the part of the child or the parents to understand or comply with the trial protocol Presence of a severe medical or psychiatric condition the treatment of which would have interfered with the trial Participants could not start during or 7 weeks before the summer vacation period, to allow for investigating discontinuation effects during regular school attendance.
Interventions	Participants were randomly assigned to 2 different groups, 1 continued either 36 or 54 mg of ER‐MPH for 7 weeks, the other discontinued medication by withdrawing gradually over 3 weeks period (week 1: 36 mg/d, week 2: 27 mg/d, week 3: 18 mg/d) followed by 4 weeks of complete placebo Number randomised to each group: discontinuation group (placebo) = 53, continuation group (ER‐MPH group) = 51 Mean medication dosage: continuation group at baseline: 0.93 mg/kg/d (SD 0.29) Administration schedule: participants used the same schedule for taking their medication as they did before the trial (e.g. daily or with weekend stops). Duration (of (each) medication): placebo group: 36 mg/d during week 1, 27 mg/d during week 2, 18 mg/d during week 3, and placebo for weeks 4 through 7. MPH group: 7 weeks of MPH Treatment compliance: not stated
Outcomes	ADHD symptoms ADHD‐RS CTRS‐R:S Serious AEs Spontaneous reporting to investigator by child or parents General behaviour Strength and Difficulties Questionnaire Retrospective Modified Overt Aggression Scale (R‐MOAS) Quality of life The parent‐ and child‐rated Revised questionnaire for Children and adolescents to record health‐related quality of life (KINDL‐R) Non‐serious AEs Spontaneous reporting to investigator by child or parents
Notes	Sample calculation: yes, 120 (60 in each arm); “With this sample size, it is possible to detect an effect size (Cohen’sd) of 0.251 with a power of 0.80 and alpha of 0.05, as calculated with the program G*Power, version 3.1.” Sample size calculation was not met Ethics approval: the trial was approved by national and local institutional review board committees. Comments from trial authors “We cannot exclude the possibility that the differential impact of discontinuation on inattention and hyperactivity impulsivity symptoms according to investigator and teacher ratings were due to limited statistical power" “Those who declined to participate may have felt more confident that the medication was helpful and may therefore have been unwilling to risk being assigned to the placebo condition” “we lack evaluations of participants prior to the discontinuation trial” “The apparent absence of ongoing effectiveness in older youths may partially be explained by the lessened sensitivity of investigator or teacher ratings of ADHD symptoms, as older youths are less likely than younger children to display overt hyperactivity” Key conclusion of trial authors “[…]Our study suggests that methylphenidate is still an effective treatment after 2 years of use, even if the treatment effect size appeared rather small.” “[…]the fact that most participants in our study did not experience significant worsening after discontinuation of methylphenidate supports guideline recommendations to periodically assess whether there is a continued need for methylphenidate treatment[…]” Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH: only children and adolescents who had used MPH for ≥ 2 years were included Any withdrawals due to AEs: yes, 1 Funding source: The Netherlands Organization for Health Research and development (ZonMw, grant 836011014) Email correspondence with trial authors: August and October 2021. We received information regarding risk of bias through personal email correspondence with the trial authors in August and October 2021 (Storm 2021d [pers comm])
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The trial pharmacy dispensed trial medication for either continued active medication or discontinuation according to 2 separate computer‐generated randomisation lists, for each dosage. A block‐randomisation of 6 was used to ensure even groups.
Allocation concealment (selection bias)	Low risk	Placebo capsules matched to medication. Dispensed by trial pharmacy
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The trial medication consisted of an over‐encapsulation of MPH in an osmotic‐controlled release oral delivery system (18 mg, 27 mg, 36 mg, and 54 mg). The over‐encapsulation was backfilled with lactose monohydrate for blinding purposes. Matching placebo capsules contained only the filler.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessors were not told the randomly determined treatment allocation of the trial participants. To ensure blinding the outcome assessors did not rate AEs and families were instructed not to discuss AEs with the outcome assessors.
Incomplete outcome data (attrition bias) All outcomes	High risk	"Analyses were conducted on the full data set, which included all participants who received at least 1 dose of the trial drug. In those who had withdrawn from the trial, we used ratings that were obtained at the time of trial termination." "A chi‐square test was used to analyse whether there was a difference between the two groups in the number of participants prematurely withdrawing from the trial." 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. The following outcomes will be part of separate reports: Barkley Side Effect Rating scale (BSERS), Family atmosphere questions, Parental Frustrations Questionnaire (PFQ), Child Depression Inventory (CDI)