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. 2023 Mar 27;2023(3):CD009885. doi: 10.1002/14651858.CD009885.pub3

Brams 2012.

Study characteristics
Methods Randomised, double‐blind, 3‐period × 3‐treatment cross‐over trial in a 12‐h laboratory classroom setting with 3 interventions
  • 20 mg ER‐d‐MPH

  • 30 mg ER‐d‐MPH

  • Placebo


Each period lasted 7 days
Participants Number of participants screened: not stated
Number of participants included: 165 (57% boys, 43% girls)
Number of participants followed up: 157
Number of withdrawals: 8
Diagnosis of ADHD: DSM‐IV (combined or predominantly hyperactive‐impulsive subtype)
Age: mean 9.6 years (range 9.3 to 10.0)
IQ: above normal
MPH‐naive: 0%
Ethnicity: white (38.2%), African American (31.5%), Hispanic (22.4%), other (7.9%)
Country: USA
Setting: outpatient clinic (laboratory classroom)
Comorbidity: no significant medical illness
Comedication: not stated
Other sociodemographics: none
Inclusion criteria
  • Boys and girls aged 6‐12 years

  • Meeting DSM‐IV criteria for primary diagnosis of ADHD combined subtype or predominantly hyperactive‐impulsive subtype

  • Girls of childbearing potential required to have a negative urine pregnancy test before enrolment and, if sexually active, to use adequate and reliable contraception

  • Stabilised on a total daily dose or nearest equivalent dose of 40 mg‐60 mg of MPH or 20 mg‐30 mg d‐MPH (36 mg and 54 mg of ER‐MPH and 10 mg‐20 mg of transdermal MPH were allowed) for ≥ 2 weeks before screening


Exclusion criteria
  • Children or their parents/guardians were unable to understand or follow instructions necessary to responsibly participate in the trial

  • Children were deemed by the investigator to have below average cognitive ability

  • Home‐schooled

  • Previously diagnosed with Gilles de la Tourette's disorder or similar tic disorder (medication‐induced tics were not excluded)

  • History of a seizure disorder

  • History of or concurrent long QT syndrome or QTc > 450 milliseconds at screening, or any clinically significant ECG abnormality

  • Significant medical or psychiatric illness or substance abuse disorder

  • Children were taking an antidepressant or other antipsychotic medications

  • Children initiated psychotherapy within the 3 months before screening

  • Positive urine drug screen

  • Children with a poor prior response, or known sensitivity, to all MPH or d‐MPH products, based on medical history

  • Children currently taking non‐MPH‐based medications for ADHD

  • Those taking or planning to take any other investigational drug within 30 days of trial start

  • Children who had previously participated in an analogue classroom trial within 6 months before screening

  • ALT/AST, gamma glutamyl transferase or serum creatinine > 2 x the upper limit of normal at screening

Interventions Participants were randomly assigned to 1 of 6 possible drug condition orders of 20 mg ER‐d‐MPH, 30 mg ER‐d‐MPH and placebo
Administration schedule: once daily, morning
Duration of each medication condition: 7 days
Washout before trial initiation: 1 week
Medication‐free period between interventions: no
Titration period: none (fixed doses)
Treatment compliance: no information
Outcomes ADHD symptoms
  • SKAMP (‐combined, ‐attention and ‐deportment), performed by independent blinded raters throughout the 12‐h testing period


Serious AEs
  • Spontaneously reported serious AEs were recorded weekly


1 participant experienced 2 serious AEs (peritonsillar abscess and oral bullae) while receiving 20 mg ER‐d‐MPH and was hospitalised for 6 days for the peritonsillar abscess. Serious AEs were considered not related to trial drug. Participant discontinued the trial for missed trial drug during hospitalisation
Non‐serious AEs
  • Vital signs were assessed, and spontaneously reported AEs were recorded weekly

  • Heart rate and BP were measured after weeks 1 and 2

  • Weight was measured and ECG tests were conducted at screening and at the final visit

Notes Sample calculation: no
Ethics approval: yes
Comments from trial authors
  • Limited exposure to both doses of ER‐d‐MPH for each participant to 1 week

  • Potential for carry‐over effects between trial periods due to cross‐over design

  • Children with the inattentive subtype of ADHD were excluded from this analysis

  • Efficacy data presented as change from pre‐dose scores, rather than as effect sizes or response rates

  • Pharmacokinetic and pharmacodynamic data were not collected and analysed

  • Results reported for school‐aged children may not be relevant to other ADHD patient populations

  • Higher percentage of girls recruited


Key conclusions of trial authors
  • Significantly greater improvement in ADHD symptoms was noted with 30 mg ER‐d‐MPH compared with 20 mg ER‐d‐MPH at hours 10 through 12

  • Tolerability was comparable between doses. 30‐mg dose of ER‐d‐MPH may provide further benefit to patients who do not maintain optimal symptom control later in the day with 20‐mg ER‐d‐MPH

  • ADHD symptoms significantly improved with 30 mg ER‐d‐MPH compared with 20 mg ER‐d‐MPH at hours 10 to 12 in all ethnic parameters, with a statistically significant difference in the white subgroup

  • 30 mg ER‐d‐MPH may provide further benefit to patients of all ethnic backgrounds who do not obtain optimal late‐day symptom control with 20 mg ER‐d‐MPH


Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: yes; children with a poor prior response, or known sensitivity, to all MPH or d‐MPH products based on medical history were excluded
Withdrawals due to AEs: no
Funding source: Novartis Pharmaceuticals Corporation
Email correspondence with trial authors: September 2013. Not possible to contact trial authors
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Participants were randomly assigned to 1 of 6 treatment sequences. All participants were given the lowest available number from the randomisation numbers provided at each site. A randomisation list was produced by using a validated system that automated the random assignment of treatment sequences to randomisation numbers in the specified ratio
Allocation concealment (selection bias) Low risk Randomisation data were kept strictly confidential until the time of unblinding
Blinding of participants and personnel (performance bias)
All outcomes Low risk All trial medications and packaging were identical in appearance for blinding purposes. Participants, parents, trial centre personnel and those who assessed outcomes were blinded to trial treatment
Blinding of outcome assessment (detection bias)
All outcomes Low risk All trial medications and packaging were identical in appearance for blinding purposes. Participants, parents, trial centre personnel and those who assessed outcomes were blinded to trial treatment
Incomplete outcome data (attrition bias)
All outcomes Low risk 8 dropouts from the MPH group. The ITT population included all randomly assigned participants who took ≥ 1 dose of trial medication and had ≥ 1 post‐dose efficacy measurement. The safety population consisted of all participants who took ≥ 1 dose of trial medication
Selection bias (e.g. titration after randomisation → exclusion): no
Selective reporting (reporting bias) Unclear risk No published protocol