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Statistical Analysis Plan STATISTICAL ANALYSIS PLAN NCT Number: NCT03259334 Study Title: A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group Efficacy and Safety Study of SHP647 as Induction Therapy in Subjects with Moderate to Severe Ulcerative Colitis (FIGARO UC 301) Study Number: SHP647-301 SAP Version and Date: Version 3.0: 04 Nov 2020 STATISTICAL ANALYSIS PLAN SHP647 PHASE 3 A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel group Efficacy and Safety Study of SHP647 as Induction Therapy in Subjects with Moderate to Severe Ulcerative Colitis (FIGARO UC 301) PROTOCOL IDENTIFIER: SHP647-301 Study Sponsor(s): Shire Human Genetic Therapies, Inc. ("Shire"), 300 Shire Way, Lexington, MA 02421 USA Author: , PPD Protocol: V1 (06 Jul 2017); Amendment 1, 05 Sep 2018; Amendment 2, 11 Nov 2019 SAP Version #: 3.0 SAP Date: For non-commercial04 Nov 2020 use only Status: Final Shire CONFIDENTIAL Page 2 SHP647-301 Statistical Analysis Plan v 3.0 SHP647 04 Nov 2020 REVISION HISTORY Version Issue Date Summary of Changes 1.0 30 Aug 2019 Final 2.0 13 Aug 2020 Incorporated Protocol Amendment 2 Updates. - Added Hypersensitivity AEs. - Changed study treatment name. - Changed sample size calculation. - Changed the term ‘dimension’ to ‘domain’ for IBDQ Domain Scores. - Updated Prior medication definition to remove restriction for stop date. Due to the early discontinuation of the study before full enrollment, previously planned supplementary and subgroup analyses were removed. - Removed Per-protocol Set and Completers Set. - Removed supplementary analyses for efficacy endpoints (per-protocol, completer, missing data assumptions, etc). - Removed subgroup for efficacy endpoints beyond the actual randomization factors. Updated PCI percentage summary definition. Updated skip logic for Patient-reported UC signs and symptom data in Section 12.3.5. Added Section 12.5.2 Missing Date of Ulcerative Colitis Diagnoses. Added Section 7.5.3 Pregnancy Test and Follicle-stimulating Hormone Test. For non-commercialAdded Section 7.5.4 Contraception use only Check. Added Section 7.5.5 Stool Microbiology. Added Section 7.5.6 Physical Examination. Added Section 10.1 Coronavirus. Updated Appendix 3 Rescue Therapy for UC. Moved Smoking history from Section 5.2 to Section 5.3. Minor editorial and formatting changes. 3.0 04 Nov 2020 Updated text in Section 6.1.1 and Section 6.2.1. Minor editorial and formatting changes. Shire CONFIDENTIAL Page 3 SHP647-301 Statistical Analysis Plan v 3.0 SHP647 04 Nov 2020 TABLE OF CONTENTS REVISION HISTORY.....................................................................................................................2 TABLE OF CONTENTS.................................................................................................................3 LIST OF TABLES...........................................................................................................................6 LIST OF FIGURES .........................................................................................................................6 LIST OF APPENDIX ......................................................................................................................6 ABBREVIATIONS .........................................................................................................................7 1. INTRODUCTION ....................................................................................................................9 2. OBJECTIVES, ESTIMAND(S), AND ENDPOINTS ...........................................................10 2.1 Objectives.................................................................................................................10 2.1.1 Primary Objective .............................................................................................10 2.1.2 Key Secondary Objectives ................................................................................10 2.1.3 Other Secondary Objectives..............................................................................10 2.1.4 Exploratory Objective(s)...................................................................................10 2.2 Estimand(s)...............................................................................................................11 2.3 Endpoints..................................................................................................................14 2.3.1 Primary Endpoint ..............................................................................................14 2.3.2 Key Secondary Endpoints.................................................................................14 2.3.3 Other Secondary Endpoints ..............................................................................14 2.3.4 Exploratory Endpoints ......................................................................................15 3. STUDY DESIGN ...................................................................................................................17 3.1 General Description..................................................................................................17 3.2 Randomization .........................................................................................................19 3.3 Blinding....................................................................................................................20 3.4 SampleFor Size and non-commercial Power Considerations...................................................................20 use only 4. STATISTICAL ANALYSIS SETS........................................................................................22 4.1 Screened Set .............................................................................................................22 4.2 Randomized Set........................................................................................................22 4.3 Safety Set..................................................................................................................22 4.4 Full Analysis Set ......................................................................................................22 5. STUDY SUBJECTS...............................................................................................................23 5.1 Disposition of Subjects.............................................................................................23 5.2 Demographic and Other Baseline Characteristics....................................................23 Shire CONFIDENTIAL Page 4 SHP647-301 Statistical Analysis Plan v 3.0 SHP647 04 Nov 2020 5.3 Smoking history .......................................................................................................25 5.4 Medical History........................................................................................................25 5.5 Prior Procedures and Medication .............................................................................25 5.6 Concomitant Therapies, Procedures and Medications .............................................26 5.7 Exposure to Investigational Product ........................................................................26 5.8 Measurements of Treatment Compliance.................................................................26 5.9 Protocol Deviations..................................................................................................27 6. EFFICACY ANALYSES .......................................................................................................28 6.1 Analyses of Primary Efficacy Endpoint(s)...............................................................28 6.1.1 Sensitivity Analyses of Primary Efficacy Endpoint..........................................29 6.2 Analyses of Key Secondary Efficacy Endpoint(s)...................................................29 6.2.1 Sensitivity Analyses of Key Secondary Efficacy Endpoints ............................30 6.3 Analyses of Other Secondary Efficacy Endpoints ...................................................30 6.3.1 Sensitivity Analyses of Other Secondary Efficacy Endpoint(s) .......................33 6.4 Multiplicity Adjustment ...........................................................................................33 6.5 Analyses of Exploratory Endpoint(s).......................................................................34 6.6 Subgroup Analyses...................................................................................................36 7. SAFETY ANALYSIS ............................................................................................................37 7.1 Adverse Events.........................................................................................................37 7.1.1 Adverse Events of Special Interest and other Potential Risks ..........................37 7.1.1.1 Hypersensitivity .....................................................................................38 7.2 Clinical Laboratory Data..........................................................................................38 7.3 Vital Signs ................................................................................................................41 7.4 Electrocardiogram (ECG).........................................................................................42 7.5 Other Safety Data .....................................................................................................43 7.5.1 Targeted Neurological Assessment...................................................................43
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