Brams 2008.

Study characteristics
Methods	Randomised, double‐blind, cross‐over, multi‐centre trial evaluating the efficacy of the following over an 8‐h laboratory classroom day in children with ADHD ER‐d‐MPH (20 mg/d) placebo Phases: baseline: day 0 period 1: days 1‐7 (Sunday‐Saturday), when Saturday is assessment day (8‐h laboratory classroom day) period 2: days 7‐15 final visit: day 15
Participants	Number of participants screened: 92 Number of participants included: 86 (53 boys, 33 girls). Participants were randomly assigned to 1 of 2 possible drug condition orders Number of participants followed up: 86 Number of withdrawals: 0 Diagnosis of ADHD: DSM‐IV (combined (87.2%), hyperactive‐impulsive (0%), inattentive (12.8%)) Age: mean 9.5 years (range 6‐12) IQ: > 70 MPH‐naive: 0% Ethnicity: white (48.8%), African American (24.4%), Asian (2.3%), Hispanic (23.3%) Country: USA Setting: multi‐centre, outpatient clinic (laboratory classroom) Comorbidity: not stated Comedication: no antidepressant or other antipsychotic medication Other sociodemographics: none   Inclusion criteria DSM‐IV criteria for a diagnosis of ADHD of any type, as established by the K‐SADS‐PL 6‐12 years of age Only children whose parents or legal guardians, or both, provided written informed consent before any trial‐related procedures were performed were enrolled Girls of child‐bearing potential were required to have a negative urine pregnancy test before enrolment and, if sexually active, to be using adequate and reliable contraception (e.g. double‐barrier method), which was documented in the medical record Exclusion criteria Children or their parents/guardians were unable to understand or follow instructions as needed to participate in the trial Children deemed by investigators to have below‐average cognitive capacity, or to be home‐schooled Previously diagnosed with Gilles de la Tourette's syndrome or a tic disorder (medication‐induced tics were not excluded) History of seizure disorder, or history of, or concurrent, significant medical or psychiatric illness or substance abuse disorder Taking an antidepressant or other antipsychotic medication; those who initiated psychotherapy within the 3 months preceding screening and those with a positive urine drug screen were deemed ineligible Poor response or known sensitivity to all MPH or d‐MPH formulations based on past medical history Taking other medications for ADHD Prospective participants taking or planning to take any other investigational drug within 30 days of the start of the trial Previously participated in an analogue classroom trial within 6 months before screening
Interventions	Participants were randomly assigned to 1 of 2 possible drug condition orders of once‐daily, ER‐d‐MPH 20 mg (Focalin XR (Novartis Pharmaceuticals Corporation) and placebo Mean MPH dosage: fixed dose of 20 mg Administration schedule: once daily in the morning Duration of each medication condition: 7 days Washout before trial initiation: 1 week before the trial Titration period: before trial participation, all participants were stabilised on a total daily dose or nearest equivalent dose of MPH 40 mg to 60 mg or d‐MPH 20 mg to 30 mg for ≥ 2 weeks before screening Treatment compliance: not stated
Outcomes	ADHD symptoms Primary efficacy outcome Change on the SKAMP: combined score from pre‐dose to the 0.5‐h post‐dose time point during the 8‐h classroom day. Rated by observer Change in SKAMP: combined scores from pre‐dose to 1, 2, 4, 6 and 8 h post‐dose. Rated on classroom day by observers Change from pre‐dose on SKAMP: Attention and Deportment scores at all time points (0.5, 1, 2, 4, 6 and 8 h post‐dose) Conners’ ADHD/DSM‐IV Scales, Parent: completed by parent/legal guardian on classroom day Non‐serious AEs Vital signs: recorded at each visit (days 0, 7, 14) Spontaneously reported AEs, including serious AEs, at the end of each treatment period Heart rate and BP measured at pre‐dose, 4 and 8 h post‐dose at days 7 and 14 Weight at screening and at day 15 ECG at screening and at day 15
Notes	Sample calculation: yes Ethics approval: not stated Comments from trial authors Several limitations with regard to the design of this trial should be considered in interpretation of these data Participant population was required to have had previous exposure to MPH or d‐MPH. It is likely that this patient population already demonstrated a therapeutic response to MPH or d‐MPH, as well as tolerance to these drugs Only a fixed dosage of 20 mg/d was evaluated, making it difficult to compare results observed in the current trial with those of other doses currently available, or when treatment is optimised Key conclusions of trial authors Compared with placebo, once‐daily, ER‐d‐MPH 20 mg provided rapid and significant improvement at 0.5 h post dose in attention, deportment and academic performance, which was sustained for 8 h post‐dose Overall, once‐daily ER‐d‐MPH 20 mg was well tolerated In an analysis of parental assessment of diary responses, children appeared better organised, and morning preparation for school was smoother and less frustrating, with once‐daily ER‐d‐MPH compared with placebo Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: yes; children with poor response or known sensitivity to MPH or d‐MPH were excluded Withdrawals due to AEs: no Funding source: Novartis Pharmaceuticals Corporation Email correspondence with trial authors: September 2013. We received an email from Dr. Brams, in which we were told that Novartis had control and ownership of trial data. Consequently, we had to contact the Public Affairs Department at Novartis to request the information (e.g. protocols) (Krogh 2013a [pers comm])
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The randomisation list was generated by the trial sponsor, who used an automated random assignment of treatment sequences to randomisation numbers in the specified ratio
Allocation concealment (selection bias)	Low risk	All trial medications and packaging were identical in appearance for blinding purposes
Blinding of participants and personnel (performance bias) All outcomes	Low risk	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	Participants, parents, trial centre personnel and those who assessed outcomes were blinded to trial treatment
Incomplete outcome data (attrition bias) All outcomes	Low risk	The safety population consisted of all participants who took ≥ 1 dose of trial medication. The efficacy population included all randomly assigned participants who provided valid efficacy measurements for both treatment periods Selection bias (e.g. titration after randomisation → exclusion): no
Selective reporting (reporting bias)	Unclear risk	No published protocol