Clinical Trial Results Database Page 1

Sponsor Novartis

Generic Drug Name Vildagliptin (LAF237)

Therapeutic Area of Trial

Approved Indication Investigational

Study Number CLAF237A2327E1

Title An 80-week extension to a multicenter, randomized, double-blind, active controlled study to compare the effect of 24 weeks treatment with LAF237 50 mg bid to 8 mg qd in drug-naïve patients with type 2 diabetes

Phase of Development Phase III

Study Start/End Dates 26 Nov 2004 to 10 Apr 2007

Study Design/Methodology

This was an 80-week, multicenter, randomized, double-blind, extension study with two treatment arms. Patients maintained the treatment regimen assigned during the core trial throughout the extension. In the core study, drug naïve patients with type 2 diabetes (HbA1c 7.5-11%) were ran- domized to vildagliptin 50 mg bid or rosiglitazone 8 mg (2 x 4 mg) qd in a ratio of 2:1 to maxi- mize exposure with vildagliptin relative to rosiglitazone.

The last visit of the core study was the first visit of the extension study. Eligible patients then completed 7 additional visits over a period of 80 weeks of treatment with vildagliptin or rosigli- tazone. Rescue medication () for inadequate glycemic control (fasting plasma glucose [FPG] > 180 mg/dL) was allowed during this extension phase (but was prohibited during core

Clinical Trial Results Database Page 2 study). Centers 155 centers in 10 countries: Argentina (4), Austria (5), Brazil (5), Canada (9), France (5), Finland (6), Germany (13), Hungary (10), Spain (9), and United States (89)

Publication Rosenstock J, Niggli M, and Maldonado-Lutomirsky M. Long-term 2-year safety and efficacy of vildagliptin compared with rosiglitazone in drug-naïve patients with type 2 diabetes mellitus.

Diabetes, Obesity and Metabolism, 11, 2009, 571-578 PMID: 19383032 Objectives Primary objective(s) Long-term safety of vildagliptin compared to rosiglitazone during 104 weeks of treatment Long-term efficacy of vildagliptin compared to rosiglitazone by comparing change in HbA1c from core baseline to extension study endpoint at 104 weeks

Secondary objective(s) Change in HbA1c between extension baseline (24 weeks) and extension study endpoint (104 weeks) Change in fasting plasma glucose between core study baseline and extension study endpoint (104 weeks) Change in fasting plasma glucose between extension study baseline (24 weeks) and extension study endpoint (104 weeks) Change in Homeostasis Model Assessment Beta Cell Function (HOMA B) between core study baseline and extension study endpoint (104 weeks) Change in Homeostasis Model Assessment Resistance (HOMA IR) between core study baseline and extension study endpoint (104 weeks)

Test Product (s), Dose(s), and Mode(s) of Administration Vildagliptin 50 mg oral tablets for twice daily administration (before breakfast, before evening meal) Rosiglitazone 4 mg oral tablets for twice daily administration (before breakfast, no evening ad- ministration)

Clinical Trial Results Database Page 3 Reference Product(s), Dose(s), and Mode(s) of Administration None

Criteria for Evaluation Primary variables The primary efficacy variable was HbA1c

Secondary variables Fasting plasma glucose Beta cell function: HOMA B Insulin resistance: HOMA IR Body weight Fasting lipids

Safety and tolerability Safety assessments included adverse events, hypoglycemic events and serious adverse events, physical examination, vital signs, laboratory evaluations, and electrocardiograms (ECGs)

Pharmacology Not applicable

Other Not applicable

Statistical Methods

The primary endpoint for analysis was the change from core baseline to extension endpoint, with day 1 of the core study as day 1 of the core + extension period. The change from the end of the core study (week 24) was also determined for specific variables (HbA1c and FPG). Data were censored at the last measurement prior to start of rescue medication. The primary efficacy variable, mean change from core baseline in HbA1c at the end of the study, was analyzed using an ANCOVA model with treatment and pooled center as classification vari- ables and baseline HbA1c as the covariate, using the extension intent-to-treat (ITT) population as the primary population. This analysis was also performed based on the extension per-protocol population to assess the long-term glycemic control in patients who completed the study treat- ment. The critical secondary efficacy variable FPG and other secondary endpoints were analyzed in the same way as HbA1c, in the extension ITT population only. Safety parameters, including observations regardless of rescue medication (and for some analyses prior to start of rescue medication) were evaluated and summarized by treatment group.

Clinical Trial Results Database Page 4 Study Population: Inclusion/Exclusion Criteria and Demographics

Patients must have completed the core study (CLAF237A2327) in order to be eligible for enroll- ment in this extension study. Key inclusion criteria from the core study are: drug-naive patients with type 2 diabetes, 18-80 years of age, with HbA1c 7.5-11%, body mass index (BMI) 22-45 kg/m2, and fasting plasma glucose (FPG) < 270 mg/dL (15 mmol/L). Inclusion criteria for the extension study were: written informed consent to participate in the ex- tension study, and ability to comply with all study requirements. Patients were excluded from the extension study due to premature discontinuation from the core study, use of concomitant medications that interfered with interpretation of study results, and failure to comply with the core study protocol. Exclusion criteria included pregnant or lactating female; a history of type 1 diabetes, any secon- dary forms of diabetes, acute metabolic diabetic complications within the past 6 months; acute infections which may affect blood glucose control within the past 4 weeks; a series of cardiac- related conditions (Torsades de Pointes, ventricular tachycardia or fibrillation; percutaneous coronary intervention in the past 3 months; myocardial infarction, coronary artery bypass sur- gery, or unstable angina within the past 6 months; congestive heart failure; second or third degree AV block, and prolonged QTc); treatment with class Ia, Ib, Ic, or III anti-arrhythmics; any of the following significant laboratory abnormalities: ALT, AST greater than 2.5 times the upper limit of the normal range, direct bilirubin greater than 1.3 times the upper limit of the normal range, serum creatinine levels > 2.5 mg/dL (220 μmol/L), clinically significant abnormal TSH, and fasting triglycerides > 700 mg/dL (> 7.9 mmol/L).

Clinical Trial Results Database Page 5 Number of Subjects

Demographic and Background Characteristics

Patient baseline demographic characteristics (Extension population) Demographic Vilda 50 mg bid Rosi 8mg qd Total variable N=396 N=202 N=598 Mean Age, years (SD) 54.41 (11.56) 54.18 (10.87) 54.33 (11.32) Females : Males 42.4% : 57.6% 45.5% : 54.5% 43.5 % : 56.5% Race Caucasian 311 (78.5%) 159 (78.7%) 470 (78.6) Other 85 (21.5%) 43 (21.3%) 128 (21.4) Mean Body Weight, kg (SD) 92.02 (19.51) 93.33 (19.24) 92.46 (19.41) HbA1c % Mean (SD) 8.58 (1.10) 8.63 (1.17) 8.59 (1.13) Duration of Type 2 Diabetes 1.98 (2.88) 2.60 (4.19) 2.19 (3.39) (years): Mean (SD) Primary Objective Result(s)

ANCOVA results for change in HbA1c (%) from core study baseline to exten- sion study endpoint (Extension ITT population)

Clinical Trial Results Database Page 6 Secondary Objective Result(s)

Change in HbA1c (%) from extension study baseline (Week 24) to extension study endpoint (Extension ITT population)

ANCOVA results for change in fasting plasma glucose (mmol/L) from core study baseline to extension study endpoint (Extension ITT population)

ANCOVA results for change in fasting plasma glucose (mmol/L) from exten- sion study baseline (Week 24) to extension study endpoint (Extension ITT population)

Mean change Week 24 mean from Week 24 95% CI for change from Treatment N (SE) (SE) Week 24 p-value Extension ITT population Vilda 50mg bid 295 8.23 (0.13) 1.42 (0.15) (1.13, 1.71) <0.001 Rosi 8mg bid 162 7.43 (0.15) 0.72 (0.15) (0.43, 1.02) <0.001

ANCOVA results for change in HOMA-B and HOMA-IR from core study baseline to extension study endpoint (Extension ITT population)

Clinical Trial Results Database Page 7

Safety Results

Adverse Events by System Organ Class Number (%) of patients with AEs by primary system organ class, including all events regardless of rescue medication use (Extension Safety population)

Clinical Trial Results Database Page 8

10 Most Frequently Reported AEs Overall by Preferred Term n (%) Number (%) of patients reporting common AEs (greater or equal to 5% in any group) by preferred term, including all adverse events regardless of res- cue medication use (Extension Safety population)

Serious Adverse Events and Deaths Vilda 50mg bid Rosi 8mg qd No. (%) of subjects studied 393 198 No. (%) of subjects with AE(s) 318 (80.9%) 165 (83.3%)

Number (%) of subjects with n (%) n (%) serious or other significant events Death 2 (0.5%) 1 (0.5%) SAE(s) 40 (10.2%) 14 (7.1%) Discontinued due to SAE(s) 19(4.8%) 6 (3.0%)

Number (%) of patients with SAEs by primary system organ class, preferred term, and treatment including all events regardless of rescue medication use (Extension Safety population)

Primary system organ class Vilda 50mg bid Rosi 8mg qd Preferred Term N=393 N=198 n (%) n (%) Any primary system organ class 49(12.5) 18( 9.1) -Total Blood and lymphatic system disorders -Total 0( 0.0) 1( 0.5) Anaemia 0( 0.0) 1( 0.5) Cardiac disorders -Total 7( 1.8) 5( 2.5) Angina pectoris 1( 0.3) 0( 0.0)

Clinical Trial Results Database Page 9 Atrial fibrillation 1( 0.3) 0( 0.0) Cardiac failure congestive 1( 0.3) 1( 0.5) Cardio-respiratory arrest 1( 0.3) 0( 0.0) Coronary artery disease 2( 0.5) 3( 1.5) Mitral valve incompetence 1( 0.3) 0( 0.0) Myocardial infarction 2( 0.5) 2( 1.0) Myocardial ischaemia 0( 0.0) 1( 0.5) Ear and labyrinth disorders -Total 1( 0.3) 0( 0.0) Vertigo 1( 0.3) 0( 0.0) Eye disorders -Total 2( 0.5) 0( 0.0) Cataract 1( 0.3) 0( 0.0) Retinal detachment 1( 0.3) 0( 0.0) Gastrointestinal disorders -Total 6( 1.5) 2( 1.0) Abdominal pain 1( 0.3) 2( 1.0) Abdominal pain upper 1( 0.3) 0( 0.0) Eructation 1( 0.3) 0( 0.0) Gastric ulcer 1( 0.3) 0( 0.0) Gastrointestinal haemorrhage 1( 0.3) 0( 0.0) Ileus 1( 0.3) 0( 0.0) Lumbar hernia 1( 0.3) 0( 0.0) Nausea 1( 0.3) 0( 0.0) Tooth disorder 1( 0.3) 0( 0.0) General disorders and administration site conditions -Total 3( 0.8) 1( 0.5) Asthenia 1( 0.3) 0( 0.0) Chest pain 1( 0.3) 1( 0.5) Fatigue 1( 0.3) 0( 0.0) Malaise 1( 0.3) 0( 0.0) Hepatobiliary disorders -Total 2( 0.5) 1( 0.5) Cholangitis 1( 0.3) 0( 0.0) Cholecystitis chronic 0( 0.0) 1( 0.5) Cholelithiasis 1( 0.3) 1( 0.5) Infections and infestations -Total 9( 2.3) 5( 2.5) Appendicitis 1( 0.3) 0( 0.0) Arthritis infective 1( 0.3) 0( 0.0) Cellulitis 1( 0.3) 1( 0.5) Dengue fever 1( 0.3) 0( 0.0) Diverticulitis 0( 0.0) 2( 1.0) Otitis media chronic 1( 0.3) 0( 0.0) Pneumonia 3( 0.8) 0( 0.0) Salpingitis 0( 0.0) 1( 0.5) Staphylococcal abscess 0( 0.0) 1( 0.5) Tooth abscess 1( 0.3) 0( 0.0) Injury, poisoning and procedural complications -Total 2( 0.5) 2( 1.0) Hip fracture 1( 0.3) 0( 0.0) Meniscus lesion 1( 0.3) 0( 0.0) Skeletal injury 0( 0.0) 1( 0.5) Upper limb fracture 0( 0.0) 1( 0.5) Investigations

Clinical Trial Results Database Page 10 -Total 1( 0.3) 1( 0.5) HIV test positive 0( 0.0) 1( 0.5) Weight decreased 1( 0.3) 0( 0.0) Metabolism and nutrition disorders -Total 2( 0.5) 0( 0.0) Diabetes mellitus 1( 0.3) 0( 0.0) Diabetic ketoacidosis 1( 0.3) 0( 0.0) Musculoskeletal and connective tissue disorders -Total 5( 1.3) 0( 0.0) Arthritis 1( 0.3) 0( 0.0) Back pain 1( 0.3) 0( 0.0) Pain in extremity 1( 0.3) 0( 0.0) Rhabdomyolysis 1( 0.3) 0( 0.0) Trigger finger 1( 0.3) 0( 0.0) Neoplasms benign, malignant and unspecified (incl cysts and polyps) -Total 5( 1.3) 2( 1.0) Adenocarcinoma pancreas 0( 0.0) 1( 0.5) Bladder neoplasm 1( 0.3) 0( 0.0) Breast cancer 1( 0.3) 0( 0.0) Chondromatosis 0( 0.0) 1( 0.5) Colon cancer 1( 0.3) 0( 0.0) Prostate cancer 1( 0.3) 0( 0.0) Skin cancer 1( 0.3) 0( 0.0) Nervous system disorders -Total 10( 2.5) 1( 0.5) Cerebrovascular accident 2( 0.5) 0( 0.0) Diabetic neuropathy 1( 0.3) 0( 0.0) Dizziness 1( 0.3) 0( 0.0) Hypoaesthesia 1( 0.3) 0( 0.0) Ischaemic stroke 1( 0.3) 0( 0.0) Loss of consciousness 2( 0.5) 0( 0.0) Neuropathy 0( 0.0) 1( 0.5) Neuropathy peripheral 1( 0.3) 0( 0.0) Sciatica 1( 0.3) 0( 0.0) Syncope 1( 0.3) 0( 0.0) Psychiatric disorders -Total 1( 0.3) 0( 0.0) Depression 1( 0.3) 0( 0.0) Renal and urinary disorders -Total 6( 1.5) 0( 0.0) Calculus ureteric 1( 0.3) 0( 0.0) Calculus urinary 1( 0.3) 0( 0.0) Nephrolithiasis 1( 0.3) 0( 0.0) Renal colic 1( 0.3) 0( 0.0) Urinary incontinence 1( 0.3) 0( 0.0) Urinary retention 1( 0.3) 0( 0.0) Urinary tract obstruction 1( 0.3) 0( 0.0) Reproductive system and breast disorders -Total 2( 0.5) 0( 0.0) Menorrhagia 1( 0.3) 0( 0.0) Prostatitis 1( 0.3) 0( 0.0) Respiratory, thoracic and mediastinal disorders -Total 2( 0.5) 0( 0.0) Bronchospasm 1( 0.3) 0( 0.0) Nasal septum deviation 1( 0.3) 0( 0.0)

Clinical Trial Results Database Page 11 Tonsillar hypertrophy 1( 0.3) 0( 0.0) Vascular disorders -Total 1( 0.3) 1( 0.5) Aneurysm ruptured 1( 0.3) 0( 0.0) Aortic dissection 0( 0.0) 1( 0.5)

There were 3 deaths in the extension study. Two patients in the vildagliptin treatment group died (1 patient, atrial fibrillation and subsequent stroke; 1 patient, cardio-respiratory arrest due to choking). One patient in the rosiglitazone group died of a vascular disorder (aortic dissection).

Other Efficacy Results

ANCOVA results for percent change in fasting lipid parameters from core study baseline to extension study endpoint (Extension ITT population)

ANCOVA results for change in body weight (kg) from core study baseline to extension study endpoint (Extension ITT population)

Clinical Trial Results Database Page 12

Other Relevant Findings Four patients (1.0%) in the vildagliptin group (and no patients in the rosiglitazone group) re- ported a mild hypoglycemic events (grade 1). None of the patients discontinued due to hypogly- cemia; all hypoglycemic events were suspected by the investigator to be related to study medica- tion.

Date of Clinical Trial Report 30 August 2007

Date Inclusion on Novartis Clinical Trial Results Database

05 March 2008

Date of Latest Update

21 October 2009