B. Full Novartis CTRD Template

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1 Sponsor Novartis Pharmaceuticals Corporation Generic Drug Name Methylphenidate hydrochloride Therapeutic Area of Trial Neuroscience/Psychiatry Approved Indication B. Full Novartis CTRD Template Methylphenidate hydrochloride is currently indicated in the treatment of ADHD in children aged 6 years or older, and in adults. Methylphenidate hydrochloride is also indicated in the treatment of narcolepsy. Protocol Number CRIT124D2302 Title A 40-week, randomized, double-blind, placebo-controlled, multicenter efficacy and safety study of methylphenidate hydrochloride extended release in the treatment of adult patients with childhood-onset of attention deficit hyperactivity disorder (ADHD) Study Phase Phase IIIb Study Start/End Dates Study Start: 24 Nov 2010 (first patient first visit) Study Completion: 07 Aug 2012 (last patient last visit) Study Design/Methodology This was a randomized, double-blind, placebo-controlled, multicenter efficacy and safety study in adult patients with ADHD with the following treatment periods: pre-randomization period, treatment Period 1 (3 weeks titration followed by 6 weeks fixed-dose), treatment Period 2 (5 weeks titration to individual optimal dose) and treatment Period 3 (6 months withdrawal). Centers 67 centers in 9 countries: Belgium (5), Colombia (3), Denmark (1), Germany (28), Norway (2), Singapore (1), South Africa (3), Sweden (3), United States (21) 1 P a g e

2 Publication 1. V. Kumar, Y. Ginsberg, T. Tvedten, T. Arngrim, A. Philipsen, P. Gandhi, CW. Chen, M. Huss. RIT-AB RIT-AB Methylphenidate hydrochloride modified release (MPH-LA) in adults with attention deficit hyperactivity disorder (ADHD): Safety. ADHD Atten Def Hyp Disord. 2013; (5): Y. Ginsberg, M. Huss, A. Philipsen, T. Tvedten, T. Arngrim, D. Gruener, K. Carter, CW. Chen, P. Gandhi, V. Kumar. Methylphenidate hydrochloride modified release (MPH-LA) in adults with attention deficit hyperactivity disorder (ADHD): self-rated, observer-rated and physician-rated assessments show consistently significant improvement compared to placebo. ADHD Atten Def Hyp Disord. 2013; (5): V. Kumar, Y. Ginsberg, T. Tvedten, T. Arngrim, D. Gruener, A. Philipsen, K. Carter, CW. Chen, M. Huss. RIT-AB week, double-blind, placebo-controlled, efficacy and safety study of methylphenidate hydrochloride modified release (MPH-LA) in adult ADHD: study design. ADHD Atten Def Hyp Disord. 2013; (5): M. Huss, Y. Ginsberg, A. Philipsen, T. Tvedten, T. Arngrim, D. Gruener, K. Carter, CW. Chen, V. Kumar. RIT-AB week, double-blind, placebo-controlled, efficacy and safety study of methylphenidate hydrochloride modified release (MPH-LA) in adult ADHD. ADHD Atten Def Hyp Disord. 2013; (5): Test Product (s), Dose(s), and Mode(s) of Administration Investigational therapy was methylphenidate hydrochloride, modified release hard capsules taken once daily in doses of 40, 60, or 80 mg Statistical Methods Statistical methods: Evaluation of the change from baseline to the end of Period 1 (Week 9) treatment in the total score of the DSM-IV ADHD RS was performed using an analysis of covariance (ANCOVA) model with treatment group and center as factors, and baseline DSM-IV ADHD RS total score as covariate. For the SDS, the same ANCOVA model was utilized with treatment group and center as factors, and baseline SDS total score as covariate. For treatment failure during Period 3, a logistic-regression analysis using treatment as factor and DSM-IV ADHD RS total score at baseline 1 and baseline 2 as covariates was performed. Any missing DSM-IV ADHD RS scores were imputed based on the Multiple Imputation (MI) approach and the dichotomized responses (failure/non-failure) were created according to the treatment failure definition. A logistic regression model with treatment as factor and baseline (visit 3 value) as covariate was performed to analyze the proportion of patients with clinical improvement on the CGI-I scale. The same logistic model was performed for CGI-S scale. The same ANCOVA models were utilized for CAARS and ASRS rating scales. 2 P a g e

3 Study Population: Inclusion/Exclusion Criteria and Demographics Inclusion Criteria Diagnosis of attention deficit/hyperactivity disorder (ADHD) with a confirmed onset in childhood according to DSM-IV criteria Female patients of childbearing potential must be practicing an acceptable method of contraception Exclusion Criteria Patients with body mass index (BMI) less than 18.5 kg/m 2 or more than 35 kg/m 2 History of alcohol or substance abuse within the last six months History of seizures or use of anticonvulsant medication Any psychiatric condition that requires medication or may interfere with study participation Pre-existing cardiovascular disorders including severe hypertension, heart failure, myocardial infarction, etc. Significant respiratory, hepatic, gastrointestinal, renal, hematological or oncologic disorder Diagnosis of glaucoma, hyperthyroidism, pheochromocytoma Diagnosis of family history of Tourette s syndrome Pre-existing cerebrovascular disorders such as cerebral aneurysm, vascular abnormalities including vasculitis or stroke 3 P a g e

4 Participant Flow 4 P a g e

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6 Baseline Characteristics 6 P a g e

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9 Outcome Measures Primary Outcome Result(s) 9 P a g e

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44 Other Relevant Findings 44 P a g e

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53 Date of Clinical Trial Report 7 November 2012 Date Inclusion on Novartis Clinical Trial Results Database 06 August P a g e