Clinical Development LCI699 (osilodrostat) Protocol CLCI699C2301 / NCT02180217 A Phase III, multi-center, double-blind, randomized withdrawal study of LCI699 following a 24 week, single- arm, open-label dose titration and treatment period to evaluate the safety and efficacy of LCI699 for the treatment of patients with Cushing’s disease Authors Document type Amended Protocol Version EUDRACT number 2013-004766-34 Version number v05 (Clean) Development phase III Document status Final Release date 29-Jun-2018 Property of Novartis Confidential May not be used, divulged, published, or otherwise disclosed without the consent of Novartis Template version 19-Nov-2015 Novartis Confidential Page 2 Amended Protocol Version 05 (Clean) Protocol No. CLCI699C2301 Table of contents Table of contents ................................................................................................................. 2 List of figures ...................................................................................................................... 6 List of tables ........................................................................................................................ 7 List of appendices ................................................................................................................ 8 List of abbreviations ............................................................................................................ 9 Glossary of terms ............................................................................................................... 11 Amendment 5 (29-Jun-2018) ............................................................................................ 13 Amendment 4 (06-Jul-2017) ............................................................................................. 15 Amendment 3 (29-Mar-2016) ........................................................................................... 16 Amendment 2 (11-Mar-2015) ........................................................................................... 19 Amendment 1 (15-Jul-2014) ............................................................................................. 23 Protocol summary: ............................................................................................................. 25 1 Background ........................................................................................................................ 30 1.1 Overview of disease pathogenesis, epidemiology and current treatment .............. 30 1.1.1 Epidemiology and pathogenesis of Cushing’s syndrome and Cushing’s disease .................................................................................. 30 1.1.2 Current treatment modalities ................................................................. 31 1.1.3 Unmet medical need .............................................................................. 32 1.2 Introduction to investigational treatment(s) and other study treatment(s) ............. 33 1.2.1 Overview of LCI699 ............................................................................. 33 2 Rationale ............................................................................................................................ 42 2.1 Study rationale and purpose ................................................................................... 42 2.2 Rationale for the study design ............................................................................... 42 2.3 Rationale for dose and regimen selection .............................................................. 45 2.4 Rationale for choice of combination drugs ............................................................ 46 2.5 Rationale for choice of comparators drugs ............................................................ 46 2.6 Rationale for inclusion of patients post pituitary irradiation ................................. 46 2.7 Benefit-risk assessment of LCI699 in study population ........................................ 46 48 48 3 Objectives and endpoints ................................................................................................... 49 4 Study design ...................................................................................................................... 53 4.1 Description of study design ................................................................................... 53 4.1.1 Study Period 1 ....................................................................................... 53 4.1.2 Study Period 2 ....................................................................................... 54 4.1.3 Study Period 3 ....................................................................................... 55 Novartis Confidential Page 3 Amended Protocol Version 05 (Clean) Protocol No. CLCI699C2301 4.1.4 Study Period 4 ....................................................................................... 57 4.1.5 Optional Extension Period .................................................................... 58 4.1.6 Escape ................................................................................................... 58 4.1.7 Schematic diagram of core study design ............................................... 59 4.2 Timing of interim analyses and design adaptations ............................................... 59 4.3 Definition of end of the study ................................................................................ 59 4.4 Early study termination .......................................................................................... 59 5 Population .......................................................................................................................... 60 5.1 Patient population .................................................................................................. 60 5.2 Inclusion criteria .................................................................................................... 60 5.3 Exclusion criteria ................................................................................................... 61 6 Treatment ........................................................................................................................... 63 6.1 Study treatment ...................................................................................................... 63 6.1.1 Dosing regimen ..................................................................................... 64 6.1.2 Ancillary treatments .............................................................................. 66 6.1.3 Rescue medication ................................................................................ 66 6.1.4 Guidelines for continuation of treatment .............................................. 66 6.1.5 Treatment duration ................................................................................ 66 6.2 Dose escalation guidelines ..................................................................................... 67 6.3 Dose modifications ................................................................................................ 67 6.3.1 Dose modification and dose delay ........................................................ 67 6.3.2 Follow-up for toxicities ......................................................................... 70 6.3.3 Follow up on potential drug-induced liver injury (DILI) cases ............ 70 6.3.4 Anticipated risks and safety concerns of the study drug ....................... 71 6.4 Concomitant medications ...................................................................................... 72 6.4.1 Permitted concomitant therapy ............................................................. 72 6.4.2 Prohibited concomitant therapy ............................................................ 73 6.5 Patient numbering, treatment assignment or randomization ................................. 74 6.5.1 Patient numbering ................................................................................. 74 6.5.2 Treatment assignment or randomization ............................................... 74 6.5.3 Treatment blinding ................................................................................ 75 6.6 Study drug preparation and dispensation ............................................................... 75 6.6.1 Study drug packaging and labeling ....................................................... 75 6.6.2 Drug supply and storage ........................................................................ 76 6.6.3 Study drug compliance and accountability ........................................... 76 6.6.4 Disposal and destruction ....................................................................... 77 Novartis Confidential Page 4 Amended Protocol Version 05 (Clean) Protocol No. CLCI699C2301 7 Visit schedule and assessments ......................................................................................... 77 7.1 Study flow and visit schedule ................................................................................ 77 7.1.1 Screening ............................................................................................... 92 7.1.2 Run-in period ........................................................................................ 94 7.1.3 Treatment period ................................................................................... 94 7.1.4 End of treatment visit including study completion and premature withdrawal ............................................................................................