Weiss 2007.

Methods	A  5‐11 week randomised, double‐blind, cross‐over comparison of Long duration multi‐layer release (MLR) methylphenidate Immediate release (IR) methylphenidate 6‐month open‐label extension period on MLR‐methylphenidate
Participants	Cross‐over phase Number of participants screened: 110 Number of participants included: 90 Number of participants followed up: 79 Number of withdrawals: 11 Diagnosis of ADHD: DSM‐IV (subtype: not stated) Age: mean 11.0, range 6.4‐17.5 years old IQ: above 80 Sex: 74 males, 16 females Methylphenidate‐naïve: 59% Ethnicity: white: 83%, African American: 6%, Asian: 4%, others: 7%) Country: Canada Comorbidity: oppositional defiant disorder (37.5%) Comedication: none Sociodemographics: not stated Open‐label phase Number of participants included: 76 Number of participants followed up: 61 Number of withdrawals: 15 Diagnosis of ADHD: DSM‐IV (subtype: not stated) Age: mean 11.0, range 6.4‐16.8 years old IQ: above 80 Sex: 62 males, 14 females Methylphenidate‐naïve: not stated Ethnicity: not stated Country: Canada Comedication: none Sociodemographics: not stated Inclusion criteria Children 6‐17 years of age with a DSM‐IV diagnosis of ADHD, all subtypes Patients who are currently taking MPH for ADHD and who have responded positively to the treatment, or methylphenidate naïve patients Intelligence quotient of 80 or greater on the Wechsler Intelligence Scales for Children (WISC‐III) within the previous 12 months Participants parents must have been mentally and physically competent to provide written informed consent for their child with an ability to read, speak, and understand English and otherwise able to comply with the study protocol Patients who are otherwise able to comply with the study protocol The patient must have had a score of 1.5 or greater SD from the norm on the Conners' ADHD Index as assessed during a no‐treatment baseline week using the Conners' Teacher Rating Scale‐Revised (CTRS‐R) Criteria for entering the open‐label phase: the patients must choose to continue receiving MLR‐MPH after completion of the first part of the study Exclusion criteria Patients with a true allergy to methylphenidate or amphetamines, history of serious adverse reactions to methylphenidate or are known to be methylphenidate non‐responders. Non‐response defined as methylphenidate use at various doses for a period of ≥ 4 weeks at each dose with little or no clinical benefit Patients with a history of tension, agitation, glaucoma, thyrotoxicosis, tachyarrhythmias or severe angina pectoris or patients with serious or unstable medical illness Patients with anxiety of sufficient severity to warrant treatment Patients with Tourette's syndrome of sufficient severity to warrant treatment Patients currently receiving guanethidine, pressor agents, MAOIs, coumarin anticoagulants, anticonvulsants, phenylbutazone, tricyclic antidepressants, selective serotonin reuptake inhibitors and herbal remedies Patients known or suspected to have a history of drug or alcohol abuse Patients with a history of disorders of the sensory organs, particularly deafness, severe or profound mental retardation, pervasive developmental disorders, such as autism or childhood schizophrenia, or seizure disorders Patients with any other unstable psychiatric conditions
Interventions	Cross‐over Methylphenidate type: long duration multi‐layer release methylphenidate or immediate release methylphenidate Mean methylphenidate dosage: MLR‐MPH: 32.0 (SD 8.4) mg; IR‐MPH: 32.5 (SD 8.6) mg Administration schedule: MLR‐MPH: once daily in the morning. IR‐MPH: twice daily, morning and noon Duration of each medication condition: 2 weeks on a stable dose Washout: 1 week baseline medication washout period Titration period: initial daily dose was based on body weight. Daily dose was titrated in 10‐mg increments over a period of 2‐3 weeks at weekly clinical visits. Titration was halted if the dose was not tolerated, or if the investigator‐rated CGI‐I scale was rated 1‐2. There were 2 weeks of observation on this stable dose Treatment compliance: not stated
Outcomes	Non‐serious adverse events Cross‐over Clinical assessment of Side Effects (CASE). The scale consist of 26 possible adverse events. Teacher and parent rated by telephone interview before next clinical visit. Side effects, including sleep quality, were assessed on daily basis Open‐label 3 follow‐up visits at 2, 4 and 6 months. CASE; teacher and parent rated by telephone interview just before next clinical visit The 4 cases that dropped out due to side effects dropped out because of the following events: Long‐duration multi‐layer release methylphenidate Apathy, nervousness, somnolence Insomnia, nervousness, somnolence, vocal tics Immediate release methylphenidate Anorexia, dizziness, headache, nausea, pain Apathy, asthenia, depression
Notes	Sample calculation: yes Ethics approval: the study protocol and consent form were approved by the Research Ethics Committees at each site Funding: Purdue Pharma Vested interests/authors' affiliations: the study was sponsored by Purdue Pharma (Canada). Dr Weiss is a consultant for Eli Lilly, Janssen‐Ortho, Novartis, Purdue Pharma and Shire. Dr Hechtman is a consultant for Eli Lilly, Janssen‐Ortho, Novartis, Purdue Pharma and Shire. Drs. Hechtman, Jain, Quinn, and Weiss are on the advisory board for Purdue Pharma. Dr Turgay is a consultant for the same company. Mr. Donnelly, Mr. Reiz, Mr. Harsanyi, and Dr Darke are employees of Purdue Pharma. The other authors have no financial relationships to disclose Key conclusions of the study authors: clinical implications of the study results include that once daily, MLR‐MPH is an effective treatment for ADHD that produces equivalent improvements to twice‐daily dosing of IR‐MPH in home and school situational behaviour, while maintaining a favourable side‐effect profile and a prolonged duration of effect Comments from the study authors: a large portion of participants were previous methylphenidate responders, which may have reduced any chance of finding differences. As participants received active medication in both phases if the study, higher effect sizes could be expected because of investigators' and participants' expectation, although this would more closely approximate the clinical situation than a comparison placebo Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes Supplemental information regarding protocol, data for CASE, adverse events on the 4 dropouts, and data on all periods received through personal email correspondence with study funder, Purdue Pharma in August 2013 (Harsanyi 2013 [pers comm])