Long-term, prospective, non-interventional, …

1 Clinical Development FTY720D (Fingolimod) Study protocol CFTY720D2406 Long-term, prospective, non- interventional , multinational, parallel-cohort study monitoring safety in patients with MS recently initiated with fingolimod once daily or treated with another approved disease-modifying therapy Authors: Linda Cappiello, Malika Cremer, Yvonne Geissbuehler, Estel Plana-Hortoneda, Ying Zhang Document type: Non- interventional Study Protocol Version number: Original protocol Development phase: IV Release date: 16-Dec-2011 Property of Novartis Confidential May not be used, divulged, published, or otherwise disclosed Template version 24 May 2011 This document (090095a883aa3700 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust manifested as of 12/20/2011 4:29:38 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Cremer Malika in Basel at Tue, Dec 20, 2011 17:29.

2 13 CETN ovartis Confidential Page 2 Non- interventional Study Protocol Protocol No. CFTY720D2406 Table of contents Table of contents .. 2 List of tables .. 3 List of abbreviations .. 5 Glossary of terms .. 7 Protocol synopsis .. 8 1 Introduction .. 10 Background .. 10 Purpose & rationale .. 12 2 Study objectives .. 12 Main objectives .. 12 Other objectives.

3 13 3 Study design .. 13 Study design .. 13 Interim analyses .. 14 4 Population and setting .. 14 Inclusion criteria .. 14 Exclusion criteria .. 15 Study completion .. 15 Change in medications of interest and premature study discontinuation .. 15 5 Data collection .. 15 Patient numbering .. 17 Patient demographics/other baseline characteristics .. 17 Treatments of interest .. 17 Variables of interest .. 18 Safety related measurements .. 18 Physical examination .. 18 Vital signs .. 19 Height and weight .. 19 Laboratory evaluations .. 19 Pulmonary function tests .. 19 Ophthalmic evaluation.

4 19 Dermatological evaluation .. 19 Pregnancy .. 19 Other measurements .. 20 6 Safety monitoring .. 20 This document (090095a883aa3700 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust manifested as of 12/20/2011 4:29:38 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Cremer Malika in Basel at Tue, Dec 20, 2011 17:29:13 CETN ovartis Confidential Page 3 Non- interventional Study Protocol Protocol No.

5 CFTY720D2406 Adverse 20 Serious adverse event 21 Pregnancy reporting .. 21 7 Data analysis .. 22 Patient demographic and other baseline 22 Treatment 23 Analysis of the main variables .. 23 Variables .. 23 Statistical model, hypothesis and method of analysis .. 23 Handling of missing values/censoring/discontinuations .. 24 Analysis of other variables .. 24 Safety-related outcomes of 24 Effectiveness variables .. 24 Sample size calculation .. 25 Interim analysis .. 26 8 Data review and database management .. 26 Site monitoring .. 26 Data capture and document retention.

6 26 Data quality assurance .. 26 Data coding .. 27 9 Limitations .. 27 10 Ethical considerations .. 27 Regulatory and ethical compliance .. 27 Informed consent procedures .. 27 Responsibilities of the investigator and IRB/IEC .. 28 Early termination of the study .. 28 Publication of study protocol and results .. 28 Protocol adherence and amendment .. 28 11 References .. 28 12 Appendix 1: Power calculations based on sample size of 3000 patients .. 30 13 Appendix 2: Power calculations based on sample size of 6000 patients .. 31 List of tables Table 5-1 Recommended data collection schedule.

7 16 This document (090095a883aa3700 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust manifested as of 12/20/2011 4:29:38 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Cremer Malika in Basel at Tue, Dec 20, 2011 17:29:13 CETN ovartis Confidential Page 4 Non- interventional Study Protocol Protocol No.

8 CFTY720D2406 Table 12-1 Power calculation for selected safety-specific outcomes under different assumptions for comparing fingolimod cohort (N=2000) vs. external databases assuming mean of 4 years follow-up .. 30 Table 12-2 Power calculation for selected safety outcomes under different assumptions for comparing fingolimod cohort (N=2000) vs. parallel cohort (N=1000) assuming mean of 4 years follow-up .. 31 Table 13-1 Power calculation for selected safety-specific outcomes under different assumptions for comparing fingolimod cohort (N=4000) vs. external databases assuming mean of 4 years follow-up.

9 32 Table 13-2 Power calculation for selected safety outcomes under different assumptions for comparing fingolimod cohort (N=4000) vs. parallel cohort (N=2000) assuming mean of 4 years follow-up .. 32 This document (090095a883aa3700 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust manifested as of 12/20/2011 4:29:38 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Cremer Malika in Basel at Tue, Dec 20, 2011 17:29:13 CETN ovartis Confidential Page 5 Non- interventional Study Protocol Protocol No.

10 CFTY720D2406 List of abbreviations ADEM Acute disseminated encephalomyelitis AE Adverse event ALT Alanine aminotransferase ARR Annualized relapse rate AST Aspartate aminotransferase AV Atrio-ventricular CI Confidence interval CNS Central nervous system CRF Case Report/Record Form CPO Country pharma organization CRO Contract research organization DLCO Carbon monoxide diffusing capacity DMT Disease-modifying therapy DS&E Drug safety & epidemiology EDC Electronic data capture EDSS Expanded disability status scale EU Europe / European FDA Food and Drug Administration FEV1 Forced expiratory volume within 1 second FVC Forced vital capacity GPP Good pharmacoepidemiology practices HR Hazard ratio ICF Informed consent form ICH International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use IEC Independent ethics committee IFN Interferon intra-muscular IN Investigator