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An Open Label, Multi-Center, Efficacy and Safety Study of Deferasirox in Iron Overloaded Patients with Non- Transfusion Dependent Thalassemia (THETIS)

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An Open Label, Multi-Center, Efficacy and Safety Study of Deferasirox in Iron Overloaded Patients with Non- Transfusion Dependent Thalassemia (THETIS) Clinical Development CICL670, Deferasirox, Exjade® Protocol CICL670E2419 / NCT01709838 An open label, multi-center, efficacy and safety study of deferasirox in iron overloaded patients with non- transfusion dependent thalassemia (THETIS) Authors Document type Amended Protocol Version EUDRACT number 2012-000650-64 Version number 02 (Clean) Development phase IV Document status Final Release date 04-Sep-2014 Property of Novartis Confidential May not be used, divulged, published, or otherwise disclosed without the consent of Novartis Novartis Confidential Page 20 Amended Protocol Version 02 (Clean) Protocol No. CICL670E2419 Protocol Summary Study title: An open label, multi-center, efficacy and safety study of deferasirox in iron overloaded patients with non-transfusion dependent thalassemia Study phase: Phase IV Study objectives: Primary objective To assess the efficacy of deferasirox in patients with non-transfusion dependent thalassemia based on change in liver iron concentration (LIC) from baseline after 52 weeks of treatment. Secondary objectives • Assess response rates in patients with baseline LIC values >15 mg Fe/g dw defined as the proportion of patients achieving an LIC<5 mg Fe/g dw and time to achieving LIC <5mg Fe/g dw • Assess long-term efficacy and safety of treatment to target LIC of 3 mg Fe/g dw followed by one or more treatment holidays until the LIC is ≥5 mg Fe/g dw • To evaluate the impact of deferasirox on adult Quality of Life (QoL) using the Medical Outcomes Study Short Form–36 (SF-36) (in patients >18 years of age) • To evaluate the impact of deferasirox on pediatric QoL using the Pediatric Quality of Life questionnaire (in patients 13 thru 18 years of age) • To evaluate the efficacy of deferasirox based on changes in LIC from baseline over time (approximately six month intervals) • To assess the correlation of change in SF and LIC at baseline and end of study (EOS) • To assess the efficacy of deferasirox based on change in LIC from baseline after 52 weeks of treatment by non-transfusion dependent thalassemia (NTDT) syndrome • To assess the efficacy of deferasirox based on change in SF from baseline over time • To evaluate the safety of deferasirox doses up to 30 mg/kg/day • To assess the efficacy of deferasirox on endocrine function based on change from baseline over time for total and free testosterone (males), luteinizing hormone (LH) and follicle stimulating hormone (FSH) (females), thyroid stimulating hormone (TSH), total and free T4, total and free T3, insulin, insulin resistance, fasting plasma glucose (FPG) and cortisol • To conduct pharmacokinetic (PK) analysis in a subset of patients Study population: Patients with non-transfusion-dependent congenital or chronic anemias inclusive of beta-thalassemia intermedia, HbE beta-thalassemia or alpha-thalassemia intermedia (HbH disease). Patients must be ≥ 10 years of age with a LIC ≥ 5 mg Fe/g dw and a serum ferritin ≥ 300 ng/mL. Number of patients: 117 Overview of study design: This will be an open label, single arm, multi-center study. A four week screening phase will determine patient eligibility. Deferasirox will be initiated at a dose of 10 mg/kg/day for 4 weeks. At week 4, dose escalation will then be dependent upon baseline LIC severity. At week 24, and approximately every 6 months thereafter (for up to five years), further dose adjustments may occur based on Week 24 LIC severity. The maximum dose of deferasirox throughout the study will be 30 mg/kg/day. Novartis Confidential Page 30 Amended Protocol Version 02 (Clean) Protocol No. CICL670E2419 Statistical considerations: The sample size was determined on the results observed in the ICL670E2209 trial, assuming a larger variance to reflect the broader patients population. 117 patients will have to be enrolled to obtain 90% power to detect a LIC absolute change of at least 2 mg Fe at Week 52 from the baseline value with a standard deviation of 6 mg Fe using a paired t-test at 5% two-sided significance level. Data from all centers participating in this study will be aggregated to have an adequate number of patients for the analyses. Standard descriptive analyses will include frequencies and percentages for categorical data, n, mean, standard deviation, minimum, median, 25th and 75th percentiles and maximum for continuous data. Novartis Confidential Page 40 Amended Protocol Version 02 (Clean) Protocol No. CICL670E2419 Table of contents Protocol Summary ............................................................................................................... 2 Table of contents ................................................................................................................. 4 List of figures ...................................................................................................................... 8 List of tables ........................................................................................................................ 8 List of abbreviations ............................................................................................................ 9 Glossary of terms ............................................................................................................... 11 Amendment 2 .................................................................................................................... 12 Amendment 1 .................................................................................................................... 16 1 Background........................................................................................................................ 20 1.1 Overview of disease pathogenesis, epidemiology and current treatments ............ 20 1.2 Introduction to investigational treatment(s) and other study treatment(s) ............. 21 1.2.1 Overview of deferasirox ........................................................................ 22 2 Rationale ............................................................................................................................ 25 2.1 Study rationale and purpose ................................................................................... 25 2.2 Rationale for the study design ............................................................................... 26 2.3 Rationale for dose and regimen selection .............................................................. 26 2.4 Rationale for choice of combination drugs............................................................ 26 2.5 Rationale for choice of comparators drugs ............................................................ 27 27 3 Objectives and endpoints ................................................................................................... 27 4 Study design ...................................................................................................................... 30 4.1 Description of study design ................................................................................... 30 4.2 Timing of interim analyses and design adaptations ............................................... 31 4.3 Definition of end of the study ................................................................................ 31 4.4 Early study termination .......................................................................................... 31 5 Population .......................................................................................................................... 32 5.1 Patient population .................................................................................................. 32 5.2 Inclusion criteria .................................................................................................... 32 5.3 Exclusion criteria ................................................................................................... 32 5.4 Exclusion criteria for pediatric patients ................................................................. 34 6 Treatment ........................................................................................................................... 34 6.1 Investigational treatment, other study treatment, supportive treatment ................. 34 6.1.1 Dosing regimen ..................................................................................... 34 6.2 Ancillary treatments ............................................................................................... 39 6.3 Concomitant medications ...................................................................................... 39 Novartis Confidential Page 50 Amended Protocol Version 02 (Clean) Protocol No. CICL670E2419 6.4 Guidelines for continuation of treatment ............................................................... 40 6.4.1 Change in patient weight ....................................................................... 40 6.4.2 Change in serum ferritin ........................................................................ 40 6.4.3 Change in liver iron content (LIC) as determined by liver MRI ........... 40 6.4.4 Serum creatinine and Creatinine clearance ........................................... 40 6.4.5 Increased urinary proteinuria/creatinine ratio ....................................... 41 6.4.6 Stevens-Johnson syndrome ................................................................... 41 6.4.7 Skin rash (other than SJS) ..................................................................... 41 6.4.8 Gastrointestinal disturbances ................................................................
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