Global Clinical Development - General Medicine LJN452 Clinical Trial Protocol CLJN452A2202 / NCT02855164 A randomized, double-blind, placebo controlled, 3- part, adaptive design, multicenter study to assess safety, tolerability and efficacy of tropifexor (LJN452) in patients with non-alcoholic steatohepatitis (NASH) FLIGHT-FXR Document type: Clinical Trial Protocol EUDRACT number: 2015-005215-33 Version number: 03 (Clean) Clinical trial phase: II Release date: 05-Oct-2017 Property of Novartis Confidential May not be used, divulged, published, or otherwise disclosed without the consent of Novartis Clinical Trial Protocol Template Version 3.2 (July 2016) Novartis Confidential Page 2 Clinical Trial Protocol v03 (Clean) Protocol No. CLJN452A2202 Table of contents Table of contents .................................................................................................................2 List of tables ........................................................................................................................6 List of figures ......................................................................................................................7 List of abbreviations ............................................................................................................8 Glossary of terms...............................................................................................................12 Amendment 3 (05-Oct-2017) ............................................................................................13 Summary of previous amendments ...................................................................................16 Protocol summary..............................................................................................................20 1 Introduction .......................................................................................................................24 1.1 Background............................................................................................................24 1.2 Purpose ..................................................................................................................27 2 Study objectives and endpoints .........................................................................................27 2.1 Objectives and related endpoints...........................................................................30 3 Investigational plan ...........................................................................................................33 3.1 Study design...........................................................................................................33 3.2 Rationale for study design .....................................................................................38 3.3 Rationale for dose/regimen, route of administration and duration of treatment....39 3.3.1 Pre-Clinical Animal Studies..................................................................39 3.3.2 CLJN452X2101 – Healthy Volunteers .................................................41 3.3.3 Dose Selection.......................................................................................42 3.4 Rationale for choice of comparator .......................................................................43 3.5 Purpose and timing of interim analyses/design adaptations..................................43 3.6 Risks and benefits..................................................................................................45 4 Population..........................................................................................................................46 4.1 Inclusion criteria ....................................................................................................46 4.2 Exclusion criteria...................................................................................................47 5 Treatment...........................................................................................................................50 5.1 Study treatment......................................................................................................50 5.1.1 Investigational and control drugs ..........................................................50 5.1.2 Additional treatment..............................................................................51 5.2 Treatment arms ......................................................................................................51 5.3 Treatment assignment and randomization .............................................................52 5.4 Treatment blinding.................................................................................................53 5.5 Treating the patient ................................................................................................54 5.5.1 Patient numbering, ................................................................................54 Novartis Confidential Page 3 Clinical Trial Protocol v03 (Clean) Protocol No. CLJN452A2202 5.5.2 Dispensing the study drug.....................................................................55 5.5.3 Handling of study and additional treatment ..........................................55 5.5.4 Instructions for prescribing and taking study treatment........................55 5.5.5 Permitted dose adjustments and interruptions of study treatment ........56 5.5.6 Rescue medication ................................................................................60 5.5.7 Concomitant medication .......................................................................60 5.5.8 Prohibited medication ...........................................................................61 5.5.9 Emergency breaking of assigned treatment code..................................62 5.6 Study completion and discontinuation...................................................................63 5.6.1 Study completion and post-study treatment..........................................63 5.6.2 Discontinuation of study treatment .......................................................63 5.6.3 Withdrawal of informed consent...........................................................64 5.6.4 Loss to follow-up ..................................................................................65 5.6.5 Early study termination by the sponsor.................................................65 6 Visit schedule and assessments .........................................................................................65 6.1 Information to be collected on screening failures..................................................81 6.2 Patient demographics/other baseline characteristics .............................................81 6.2.1 Demographic Information.....................................................................81 6.2.2 Medical history......................................................................................81 6.2.3 Alcohol history and assessments...........................................................82 6.2.4 Smoking history ....................................................................................82 6.2.5 Prior and concomitant medications.......................................................82 6.2.6 Liver evaluation ....................................................................................82 6.2.7 Other baseline characteristics................................................................83 6.2.8 Screening visit 2 – additional assessments............................................84 6.3 Treatment exposure and compliance .....................................................................84 6.4 Efficacy..................................................................................................................84 6.4.1 Magnetic Resonance Imaging...............................................................85 6.4.2 Liver Function Tests .............................................................................85 6.4.3 Coagulation tests ...................................................................................85 6.4.4 Markers of liver fibrosis........................................................................86 6.4.5 NAFLD fibrosis score ...........................................................................86 6.4.6 Fasting Lipids........................................................................................86 86 86 6.4.9 Liver Biopsy..........................................................................................87 Novartis Confidential Page 4 Clinical Trial Protocol v03 (Clean) Protocol No. CLJN452A2202 6.4.10 Appropriateness of efficacy assessments ..............................................87 6.5 Safety .....................................................................................................................88 6.5.1 Physical examination ............................................................................88 6.5.2 Vital signs..............................................................................................88 6.5.3 Anthropometric assessments.................................................................88 6.5.4 Laboratory evaluations..........................................................................89 6.5.5 Electrocardiogram (ECG) .....................................................................90 6.5.6 Pregnancy and assessments of fertility .................................................90 6.5.7 Appropriateness of safety measurements..............................................91