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Statistical Analysis Plan Title: A Randomized, International, Multicenter, Parallel Group, Double-Blind, Placebo- Controlled Study to Evaluate the Efficacy and Safety of Actovegin 12-Week Treatment Given First Intravenously and Subsequently Orally in Subjects With Peripheral Arterial Occlusive Disease Fontaine Stage IIB NCT Number: NCT03469349 SAP Approve Date: 11 November 2019 Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information or company confidential information (CCI). This may include, but is not limited to, redaction of the following: Named persons or organizations associated with the study. Proprietary information, such as scales or coding systems, which are considered confidential information under prior agreements with license holder. Other information as needed to protect confidentiality of Takeda or partners, personal information, or to otherwise protect the integrity of the clinical study. 1.0 TITLE PAGE STATISTICAL ANALYSIS PLAN STUDY NUMBER: Actovegin-3001 A Randomized, International, Multicenter, Parallel Group, Double-Blind,Blind, P Placebo- Controlled Study to Evaluate the Efficacy and Safety of Actovegin 12-Week12-2-Wee Treatment Given First Intravenously and Subsequently Orally in Subjects withwithth PeripheralPerPe Arterial Occlusive Disease Fontaine Stage IIBB PHASE 3 Version: 1.00 ( (Final)FinalFina ) Date: 11 Novemberovemberb 2019 Prepared by: PPD PPD Based on: Protocolcoll Version:VersVe Amendment 4 Protocolotocoltocol Date:D 19 Feb. 2019 Property of Takeda: For n rcial use only and subject to the applicable Terms of Use Actovegin-3001 Page 2 of 23 Statistical Analysis Plan (Final V1.0) 11NOV2019 1.1 Approval Signatures Electronic signatures can be found on the last page of this document. Study Title: A Randomized, International, Multicenter, Parallel Group, Double-ubleble- Blind, Placebo-Controlled Study to Evaluate the Efficacy andnd SafetSafSafety of Actovegin 12-Week Treatment Given First Intravenouslyy and Subsequently Orally in Subjects with Peripheral Arterialrialal OccOcOcclusive Disease Fontaine Stage IIB Reviewers/Approvals: ct to the applicable Terms of Use PPD Prope Actovegin-3001 Page 3 of 23 Statistical Analysis Plan (Final V1.0) 11NOV2019 PPD Property of Takeda: For non-commercial use only and subject to the applicable Ter se Actovegin-3001 Page 4 of 23 Statistical Analysis Plan (Final V1.0) 11NOV2019 2.0 TABLE OF CONTENTS 1.0 TITLE PAGE ..................................................................................................................1 1.1 Approval Signatures ..................................................................................................2 2.0 TABLE OF CONTENTS.................................................................................................4 3.0 LIST OF ABBREVIATIONS..........................................................................................6 4.0 OBJECTIVES .................................................................................................................7 4.1 Primary Objectives ....................................................................................................7 4.2 Secondary Objectives.................................................................................................7 4.3 Safety Objectives.......................................................................................................7 4.4 Study Design .............................................................................................................7 5.0 ANALYSIS ENDPOINTS...............................................................................................8 5.1 Primary Endpoint.......................................................................................................8 5.2 Secondary Endpoints .................................................................................................8 5.3 Additional Endpoints: Safety .....................................................................................9 6.0 DETERMINATION OF SAMPLE SIZE.........................................................................9 7.0 METHODS OF ANALYSIS AND PRESENTATION...................................................10 7.1 General Principles....................................................................................................10 7.1.1 Study Definitions ...............................................................................................11 7.1.2 Definition of Study Days....................................................................................11 7.1.3 Definition of Study Visit Windows ....................................................................11 7.1.4 Conventions for Missing Adverse Event Dates...................................................11 7.1.5 Conventions for Missing Concomitant Medication Dates...................................12 7.2 Analysis Sets ...........................................................................................................12 7.3 Disposition of Subjects ............................................................................................13 7.4 Demographic and Other Baseline Characteristics .....................................................14 7.5 Medical History and Concurrent Medical Conditions ...............................................14 7.6 Prior and Concomitant Medications, Concomitant Procedures .................................14 7.7 Study Drug Exposure and Compliance.....................................................................15 7.8 Efficacy Analysis.....................................................................................................16 7.8.1 Primary Efficacy Endpoint(s).............................................................................16 7.8.2 Secondary Efficacy Endpoint(s).........................................................................16 7.8.3 Additional Efficacy Endpoint(s).........................................................................17 7.9 Pharmacokinetic/Pharmacodynamic Analysis ..........................................................17 Property of Takeda:7.9.1 PharmacokinetFor non-commercialic Analysis ................................ use only and subject.................................................. to the applicable Terms17 of Use 7.9.2 Pharmacodynamic Analysis ...............................................................................17 Actovegin-3001 Page 5 of 23 Statistical Analysis Plan (Final V1.0) 11NOV2019 7.10 Other Outcomes.......................................................................................................17 7.11 Safety Analysis........................................................................................................18 7.11.1 Adverse Events ..................................................................................................18 7.11.2 Clinical Laboratory Evaluations .........................................................................19 7.11.3 Vital Signs .........................................................................................................20 7.11.4 12-Lead ECGs ...................................................................................................20 7.11.5 Other Observations Related to Safety.................................................................21 7.12 Interim Analysis ......................................................................................................21 7.13 Changes in the Statistical Analysis Plan...................................................................21 8.0 REFERENCES..............................................................................................................21 9.0 APPENDIX...................................................................................................................22 LIST OF IN-TEXT TABLES Table 6 Sample Sizes Under Different Values of Power....................................................9 LIST OF IN-TEXT FIGURES Figure 4.4 Schematic of Study Design ..................................................................................7 LIST OF APPENDICES Appendix A Schedule of Study Procedures............................................................................21 Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use Actovegin-3001 Page 6 of 23 Statistical Analysis Plan (Final V1.0) 11NOV2019 3.0 LIST OF ABBREVIATIONS ACD absolute claudication distance AE adverse event ALT alanine aminotransferase ANCOVA analysis of covariance ANOVA analysis of variance AST aspartate aminotransferase BMI body mass index BUN blood urea nitrogen ECG electrocardiogram eCRF electronic case report form FAS full analysis set GGT -glutamyl transferase IC intermittent claudication ICD initial claudication distance ICH International Conference on Harmonisation IMP investigational medicinal product IP investigational product IV intravenous LFT liver function tests LDH lactate dehydrogenase LLN lower limit of normal MedDRA Medical Dictionary for Regulatory Activities MMRM mixed model for repeated measures PAD peripheral arterial disease PD pharmacodynamics PK pharmacokinetics PPS per-protocol set QOL quality-of-life PRO patient-reported outcome SAE serious adverse event SAF safety set SAP statistical analysis plan SF-36 36-item Short Form Survey TID 3 times daily TLGs tables, listings, and graphs ULN upper limit
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