Gonzalez‐Heydrich 2010.

Study characteristics
Methods	Cross‐over trial with 2 interventions: OROS‐MPH placebo Phases: number of phases varied by dose group. For all dose groups, after completing first phase, participants were on a 1‐week washout period before cross‐over. Participants assigned to 1 of 3 maximum OROS‐MPH dose groups in randomly assigned order Group 1: 1 week LD‐MPH, 1 week placebo Group 2: 1 week LD‐MPH, 1 week MD‐MPH, 1 week placebo Group 3: 1 week LD‐MPH, 1 week MD‐MPH, 1 week HD‐MPH, placebo Participants assigned to next group after 3 participants have successfully completed preceding group with no side effects
Participants	Number of participants screened: 40 Number of participants included: 33 (19 boys, 14 girls) Number of participants followed up: 33 Number of withdrawals: 0 Diagnosis of ADHD: DSM‐IV‐R (combined (51.1%), inattentive (48.5%)) Age: mean 10.5 years (SD 3.0, range 6.4‐17.5) IQ: mean 89.7 (SD 16.9, range 59‐123) MPH‐naive: not stated Ethnicity: not stated Country: USA Setting: hospital ward Comorbidity: epilepsy (100%), others (not stated) Comedication: yes, continuation of previous medication allowed. All participants were currently on a stable dose of antiepileptic medication. Other sociodemographics: none Inclusion criteria Speaks English IQ > 35 and score > 35 on Scales of Independent Behavior Revised (SIB‐R) Broad Independence Scale (both IQ and adaptive functioning at the moderate mental disability level or higher) Diagnosis of epilepsy by International League Against Epilepsy criteria 26 (repeated, afebrile, unprovoked seizures with a seizure within the past 5 years) DSM‐IV‐R diagnosis of ADHD Score ≥ 4 on CGI severity scale for ADHD Score > 90% on ADHD‐RS, Parent Version; investigator scored for age and sex on inattentive, hyperactive‐impulsive or total score at first visit Has not taken stimulants or alpha‐adrenergic medications for > 2 weeks before trial entry If taking antidepressants, neuroleptics or lithium, doses have been stable for > 4 weeks Currently on an antiepileptic drug regimen with stable doses for > 4 weeks before trial entry Seizure‐free for > 1 month before trial entry Prescribing clinician for epilepsy anticipates the need for a stable antiepileptic drug regimen for the duration of the trial Guardian gives permission for trial personnel to communicate with prescribing epilepsy clinician Teacher agrees to fill out ADHD‐RS at baseline and at the end of each arm of the trial Exclusion criteria Has had a seizure within the month preceding trial entry Change in antiepileptic drug regimen or dose within 4 weeks of trial entry History of moderate or severe AE related to MPH History of any psychotic disorder Current acute major depression or bipolar mania Current psychiatric disorder requiring pharmacotherapy (other than ADHD) Unstable significant medical condition other than epilepsy Any known conditions that may make treatment with MPH medically inadvisable Not currently working with a physician for epilepsy treatment Previously participated in a trial that provided adequate treatment with ER‐MPH Weighs < 9 kg Pregnant Unwilling to use an effective form of contraception Child has taken a stimulant (MPH, an amphetamine preparation or pemoline), an alpha‐adrenergic (clonidine or guanfacine) or other ADHD medication within 2 weeks of the screening telephone interview (children will not be withdrawn from psychotropic medications to be enrolled in the trial)
Interventions	Participants were randomly assigned to different possible drug condition orders of MPH and placebo. Each child was given 5 mg of IR‐MPH in the morning and at noon for 1 day. If this dose was tolerated, 18 mg of OROS‐MPH was administered in the morning for the remaining 6 days of the 1st week. For group 1, maximum dose remained 18 mg, and MPH and placebo arms lasted 1 week. For group 2, a further 1 week of OROS‐MPH at a dose of 36 mg was given in the morning for 1 week; this group was also administered placebo for 2 weeks. For group 3, maximum dose was 54 mg in the morning, and each arm of the cross‐over lasted 3 weeks Mean MPH dosage: 11 participants < 1 mg/kg/d, 13 participants 1‐1.5 mg/kg/d, 9 participants 1.5‐2 mg/kg/d Administration schedule: 1 dose in the morning Duration of each medication condition: 1 week Washout before trial initiation: participants were not allowed to have taken ADHD medication within 2 weeks before the telephone interview screening Medication‐free period between interventions: yes; 1 week Titration period: no Treatment compliance: not stated
Outcomes	ADHD symptoms ADHD‐RS‐IV, Observer, Parent, Teacher Version; CGI‐ADHD‐Severity: clinician‐rated at baseline and at end of each cross‐over week Serious AEs Seizure Classification Interview: observer, baseline and during trial Non‐serious AEs Barkley Side Effects Checklist ‐ Modified: observer, each trial visit
Notes	Sample calculation: no Ethics approval: not stated Comment from trial authors "Considering exposure time, we observed increased daily risk of seizures with increasing dose of OROS methylphenidate, suggesting that potential safety concerns require further trial" Key conclusions of trial authors No serious AEs and no carry‐over effects were noted in the cross‐over trial A larger trial is needed to assess the effect of OROS‐MPH on seizure risk Cross‐over design, including participants with frequent seizures, could maximise power and address high participant heterogeneity and recruitment difficulties Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: yes Any withdrawals due to AEs: no Funding source: supported by NIMH grant, Number K23 MH066835 Email correspondence with trial authors: April 2014. We obtained supplemental efficacy data from trial authors.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation lists for each maximum‐dose group were prepared by a statistician and maintained by the research pharmacist
Allocation concealment (selection bias)	Low risk	Randomisation lists for each maximum‐dose group were prepared by a statistician and maintained by the research pharmacist
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants were randomly assigned to take OROS‐MPH or placebo. Principal investigator was blind to medication status. In cases of seizure worsening... Data and Safety Monitoring Board (DSMB) and Institutional Review Board (IRB) were informed of these seizures. trial personnel, the DSMB and the IRB were not unblinded through this process, as the participant would not be exposed again to the same condition
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Principal investigator was blinded to medication status
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	5 participants discontinued treatment while taking placebo and 14 while taking OROS‐MPH; however, all were included in all analyses Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): no
Selective reporting (reporting bias)	High risk	All outcomes reported referred to parent‐ and teacher‐rated versions of ADHD‐RS‐IV, and to clinician‐rated ADHD Severity measured weeks 1 to 4 in the protocol. Barkley Total scores (although significantly different) were not reported, although individual effects were reported