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Statistical Analysis Plan I8K-MC-JPDA (Version 3)

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Statistical Analysis Plan I8K-MC-JPDA (Version 3) Statistical Analysis Plan I8K-MC-JPDA (Version 3) A Randomized, Double-Blind, Placebo-Controlled, 2-Part Phase 2 Study to Evaluate the Safety and Efficacy of LY3337641 in Adult Subjects with Rheumatoid Arthritis: The RAjuvenate Study NCT02628028 Approval Date: 01-Sep-2017 I8K-MC-JPDA Statistical Analysis Plan Version 3 Page 1 1. Statistical Analysis Plan: I8K-MC-JPDA: A Randomized, Double-Blind, Placebo- Controlled, 2-Part Phase 2 Study to Evaluate the Safety and Efficacy of LY3337641 in Adult Subjects with Rheumatoid Arthritis: The RAjuvenate Study Confidential Information The information contained in this Statistical Analysis Plan (SAP) is confidential and the information contained within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly and Company or its subsidiaries. This document and its associated attachments or appendices are subject to United States Freedom of Information Act Exemption 4. LY3337641 Rheumatoid Arthritis Study I8K-MC-JPDA is a 2-part Phase 2, randomized, double-blind, placebo-controlled trial in subjects with rheumatoid arthritis. In Part A, subjects will be dosed with 5, 10, or 30 mg of LY3337641 or placebo for 4 weeks. Following a safety analysis, Part B will enroll subjects to be dosed with the planned doses of 5, 10, or 30 mg of LY3337641 or placebo for 12 weeks. Eli Lilly and Company Indianapolis, Indiana USA 46285 Protocol I8K-MC-JPDA Phase 2 Statistical Analysis Plan electronically signed and approved by Lilly: 14 September 2016 SAP Version 2 electronically signed and approved by Lilly on date provided below. 01 March 2017 SAP Version 3 electronically signed and approved by Lilly on date provided below. Approval Date: 01-Sep-2017 GMT LY3337641 I8K-MC-JPDA Statistical Analysis Plan Version 3 Page 2 2. Table of Contents Section Page 1. Statistical Analysis Plan: I8K-MC-JPDA: A Randomized, Double- Blind, Placebo-Controlled, 2-Part Phase 2 Study to Evaluate the Safety and Efficacy of LY3337641 in Adult Subjects with Rheumatoid Arthritis: The RAjuvenate Study ....................................................................1 2. Table of Contents................................................................................................................2 3. Revision History .................................................................................................................7 4. Study Objectives .................................................................................................................8 4.1. Objectives and Endpoints for Part A...............................................................................8 4.2. Objectives and Endpoints for Part B...............................................................................8 5. Study Design.....................................................................................................................10 5.1. Overview of Study Design ...........................................................................................10 5.2. Determination of Sample Size ......................................................................................12 5.3. Method of Treatment Assignment ................................................................................13 6. A Priori Statistical Methods ..............................................................................................14 6.1. General Statistical Considerations ................................................................................14 6.1.1. Analysis Population .............................................................................................14 6.1.2. Baseline Definition ..............................................................................................15 6.1.3. Missing Data Imputation......................................................................................15 6.1.3.1. Non-Responder Imputation (NRI)...................................................................15 6.1.3.2. Modified Last-Observation-Carried-Forward (mLOCF) .................................15 6.2. Treatment Group Comparability...................................................................................16 6.2.1. Subject Disposition ..............................................................................................16 6.2.2. Important Protocol Deviations..............................................................................16 6.2.3. Subject Characteristics and Demographics ...........................................................21 6.2.4. Previous and Concomitant Therapy......................................................................21 6.2.5. Pre-existing Conditions and Medical History .......................................................22 6.2.6. Treatment Compliance .........................................................................................22 6.3. Primary and Secondary Analyses .................................................................................22 6.3.1. Primary Efficacy Analyses...................................................................................22 6.3.2. Additional Analyses on the Primary Efficacy Measure.........................................24 6.3.3. Secondary Analyses .............................................................................................24 6.3.3.1. ACR50, ACR70, ACR90, ACRN, and Hybrid ACR .......................................24 6.3.3.2. DAS28-hsCRP ...............................................................................................25 6.3.4. Tertiary/Exploratory Analyses..............................................................................26 6.3.4.1. Morning Joint Stiffness Duration....................................................................27 LY3337641 I8K-MC-JPDA Statistical Analysis Plan Version 3 Page 3 6.3.4.2. Patient’s Assessment of Sexual Function (VAS).............................................27 6.3.4.3. SF-36..............................................................................................................27 6.3.4.4. Functional Assessment of Chronic Illness Therapy - Fatigue Scores (FACIT-F) ..............................................................................28 6.3.4.5. Biomarkers.....................................................................................................28 6.3.4.6. Autoantibodies and Immunoglobulins.............................................................29 6.3.4.7. Dose-Response Relationship...........................................................................29 6.3.4.7.1. Trend Test ................................................................................................29 6.3.4.7.2. Dose-Response Curve Characterization.....................................................29 6.3.4.8. Exposure-Response Relationship ....................................................................30 6.4. Safety Analyses............................................................................................................30 6.4.1. Exposure to the Drug ...........................................................................................30 6.4.2. Adverse Events ....................................................................................................30 6.4.2.1. Serious Adverse Events ..................................................................................32 6.4.2.2. Other Significant Adverse Events ...................................................................32 6.4.3. Clinical Laboratory Evaluations ...........................................................................32 6.4.4. Vital Signs and Body Weight ...............................................................................33 6.4.5. Special Safety Topics...........................................................................................34 6.4.5.1. Abnormal Hepatic Tests .................................................................................34 6.4.5.2. Rash ...............................................................................................................35 6.4.5.3. Potential Myelosuppressive Events.................................................................35 6.4.5.4. Lymphocyte Subset Cell Counts.....................................................................38 6.4.5.5. Renal Function Effects ...................................................................................38 6.4.5.6. Infections, Including Potential Opportunistic Infections..................................39 6.4.5.7. Allergic Reactions/Hypersensitivities .............................................................40 6.4.5.8. Gastrointestinal (GI) Perforation, Ulceration, Hemorrhage, or Obstruction ...........................................................................41 6.5. Other Analyses.............................................................................................................41 6.5.1. Subgroup Analyses ..............................................................................................41 6.5.2. Analysis for Japan Submission.............................................................................41 6.5.3. Development Safety Update Report (DSUR)........................................................42 6.5.4. Clinical Trial Registry Analyses...........................................................................42 6.5.5. Analyses for the Optional Long-Term Extension Period.......................................42 6.6. Interim Analyses ..........................................................................................................43
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