Wigal 2003.

Study characteristics
Methods	Double‐blind, 2‐stage, cross‐over, pharmacokinetic and pharmacodynamic trial with 4 interventions IR‐MPH (Ritalin) 10 mg IR‐or ER‐MPH 40:60 (treatment C) IR‐or ER‐MPH 30:70 (treatment D) Placebo Phases: initial screening week, stage 1 cross‐over of IR‐MPH (Ritalin) vs placebo, stage 2 cross‐over of treatment C and treatment D. 4 weeks, with each trial period lasting 1 week
Participants	Number of participants screened: not stated Number of participants included: 27 Number of participants followed up: 25 (21 boys, 4 girls) Number of withdrawals: 4 Diagnosis of ADHD: DSM‐IV (subtype not stated) Age: mean 10 ± 1.4 years (range 7‐12) IQ: not stated MPH‐naive: not stated Ethnicity: white (88%), African American (8%), Asian (4%), Hispanic (0%), other (0%) Country: USA Setting: outpatient clinic (laboratory classroom and community) Comorbidity: not stated Comedication: not stated Other sociodemographics: none Inclusion criteria 1 of 3 DSM‐IV ADHD diagnostic criteria as specified in the DISC or the SNAP, or both 7‐12 years of age In need of MPH treatment Positive MPH response Prior successful treatment of ADHD symptoms with a MPH product without AEs MPH products restricted to IR‐MPH twice daily, with the first daily dose required to be between 7.5 mg and 15 mg, and the second daily dose required to be between 5 mg and 15 mg, yielding a total daily dose of between 12.5 mg and 30 mg; or a ER‐MPH product taken once daily, with the single daily dose required to be 20 mg Oral or written consent by both children and parents Normal BP, pulse rate and temperature Girls had to be premenarchal Exclusion criteria Participation in another drug trial during the preceding 30 days Concurrent illness or condition with symptoms that could affect performance of any of the tests performed Family history of drug abuse Unable to follow instructions given in the trial Individuals who were severely depressed, psychotic, anxious, tense or agitated; or who had seizures or a family history of Tourette’s syndrome, with primary diagnosis of ODD or CD Participants taking a medication in addition to MPH for ADHD Documented allergy or intolerance to MPH Individuals who were diagnosed with hyperthyroidism, were lactose‐intolerant or had glaucoma Participants unable to comply with blood drawing procedures during initial screening Use of any of the following medications: amphetamines, pemoline, tricyclic antidepressants, MAOIs, SSRIs, neuroleptics, benzodiazepines or benzodiazepine derivatives, clonidine, anticonvulsant medications, cough/cold preparations containing stimulants or sedatives
Interventions	Participants were randomly assigned to 1 of 2 possible drug condition orders of MPH and placebo in each of the 2 stages, 1 and 2, with each treatment period lasting 1 week. Stage 1 Treatment A Participants were given 1 encapsulated tablet of IR‐MPH (Ritalin) (10 mg) and 1 capsule of placebo after breakfast, and 1 encapsulated tablet of IR‐MPH (Ritalin) (10 mg) after lunch for 7 days Treatment B Participants were given 2 placebo capsules after breakfast and 1 placebo capsule after lunch for 7 days Stage 2 Half of the participants in each treatment group were randomly assigned to 20 mg/d dosage of MPH, the other half to 40 mg/d dosage Treatment C Participants were given a daily morning dose (after breakfast) of 2 20 mg capsules of the 40:60 prototype formulation or one 20 mg capsule of the 40:60 prototype formulation and 1 capsule of placebo; and a midday dose (after lunch) of 1 capsule of placebo for 7 days Treatment D Participants were given a daily morning dose (after breakfast) of 2 20 mg capsules of the 30:70 prototype formulation or one 20 mg capsule of the 30:70 prototype formulation and 1 capsule of placebo; and a midday dose (after lunch) of 1 capsule of placebo for 7 days Blood samples (3 mL) were collected pre‐dose and at 0.5, 1.5, 2, 3, 4.5, 6, 7.5 and 9 h after the morning dose on the last day (Saturday) of each treatment week Mean MPH dosage: 20 mg/d or 40 mg/d Administration schedule: once daily or twice daily Time points: mornings and after lunch Duration of each medication condition: 1 week Washout before trial initiation: not stated Medication‐free period between interventions: 1 day (Sundays) Titration period: none Treatment compliance: not stated
Outcomes	ADHD symptoms SKAMP (10‐item) Scale: deportment and attention ratings performed every 1.5 h (0 to 9 h) at the end of each treatment week, by laboratory classroom teachers SKAMP (10‐item) Scale: rated on weekdays by community classroom teachers CLAM (16‐item): rated Monday, Wednesday and Friday by community classroom teachers and parents General behaviour CLAM (16‐item) Scale: ratings performed once every Monday, Wednesday and Friday of each treatment week by the regular community classroom teacher and the parents Non‐serious AEs Side Effects Rating form completed during all treatments by the children’s regular community classroom teacher on Monday, Wednesday and Friday of each treatment week, daily by parents and each Saturday by the University of California at Irvine Child Developmental School (UCI‐CDC) classroom teacher All AEs occurring during the trial were reviewed by the investigator to assess their relationship to drug treatment (unrelated, unlikely, possibly, probably, almost certainly) In addition, each sign or symptom reported was graded on a 3‐point scale (mild, moderate or severe), and date and time of onset, time relationship to drug dosing, duration and outcome were noted Clinical laboratory tests were performed at the local laboratory at baseline and at the end of the trial, and included blood count with differential, biochemistry (Na (sodium), K (potassium), Ca (calcium), PO4 (phosphate), total protein, glucose, alkaline phosphatase, AST, ALT, total bilirubin, creatinine, albumin) and urinalysis (osmolality, pH (power of hydrogen) level, glucose, protein, white blood cells and casts) Vital signs, including BP and heart rate, were measured at each visit to the laboratory classroom Body weight: 36.9 ± 7.6 kg Height: 142 ± 8.4 cm
Notes	Sample calculation: not stated Ethics approval: yes; trial protocol and participant's informed consent form were approved by the Institutional Review Board (Office of the Vice Chancellor for Research, University of California at Irvine) Key conclusion of trial authors "Both MPH formulations, given once in the morning, were superior to placebo and comparable with Ritalin b.i.d. [twice/d] treatment on all primary efficacy measures." Comments from review authors Prototype formulation used ‐ this may not be bioequivalent to the marketed formulation Selective reporting of safety findings ‐ omission of data obtained by AEs rating form. Pre‐specified primary outcome measure for efficacy (of prototype formulations versus placebo) ‐ regular community classroom teacher. CGI scores from Collegiate Learning Assessment (CLA) results presented only in Figure 4; no mean (SD) values provided in publication Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: yes; positive MPH response was an inclusion criterion. Serious AEs were an exclusion criterion. Any withdrawals due to AEs: no Funding source: Celltech Americas Incorporated Email correspondence with trial authors: July 2014. Emailed trial authors twice for supplemental information but have received no response.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Qualified participants were randomly assigned to a 2‐stage, double‐blind trial sequence consisting of 4 trial treatments, each lasting for a period of 1 week
Allocation concealment (selection bias)	Low risk	MPH (Ritalin) (10 mg) tablets were placed into capsule shells by Eurand Americas Incorporated. Resulting capsules were tested according to US Pharmacopeial Convention (USP) dissolution conditions for MPH tablets and showed a dissolution profile comparable with intact Ritalin tablets. All medications were supplied in white, opaque, size 3, hard gelatin capsule shells, and were packaged in blister cards to enhance compliance
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Ritalin (10 mg) tablets were placed into capsule shells by Eurand Americas Incorporated. Resulting capsules were tested according to US Pharmacopeial Convention (USP) dissolution conditions for MPH tablets and showed a dissolution profile comparable with intact Ritalin tablets. All medications were supplied in white, opaque, size 3, hard gelatin capsule shells, and were packaged in blister cards to enhance compliance
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information
Incomplete outcome data (attrition bias) All outcomes	High risk	Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): yes
Selective reporting (reporting bias)	Unclear risk	"Because the administration of the Side Effects Rating Form involved queries about specific adverse events, the frequency of adverse events reported in the parents’ and teachers’ Side Effect Rating Form was higher than that obtained from the reports elicited by general inquire (data not shown)"