A Phase 3, Multicenter, Investigator-blind, Randomized, Parallel Group Study to Investigate the Safety and Efficacy of Fidaxomicin Oral Suspension or Tablets Taken q12h, and Vancomycin Oral Liquid or Capsules Taken q6h, for 10 Days in Pediatric Subjects with Clostridium difficile-associated Diarrhea The SUNSHINE Study ISN/Protocol 2819-CL-0202 ClinicalTrials.gov Identifier: NCT02218372 Date of Protocol Version 3.0: 21 Jul 2015 Sponsor: Astellas Pharma Europe B.V. Sylviusweg 62 2333 BE Leiden The Netherlands Sponsor: APEB ISN/Protocol 2819-CL-0202 EudraCT number 2013-000508-40 - CONFIDENTIAL - A Phase 3, Multicenter, Investigator-blind, Randomized, Parallel Group Study to Investigate the Safety and Efficacy of Fidaxomicin Oral Suspension or Tablets Taken q12h, and Vancomycin Oral Liquid or Capsules Taken q6h, for 10 Days in Pediatric Subjects with Clostridium difficile-associated Diarrhea The SUNSHINE Study ISN/Protocol 2819-CL-0202 Version 3.0 Incorporating Substantial Amendment 2 [See Attachment 1] 21 July 2015 EudraCT 2013-000508-40 Sponsor: Astellas Pharma Europe B.V. (APEB) Sylviusweg 62 2333 BE Leiden The Netherlands Protocol History: Version 1.0 [17Sep2013] Version 1.1 Incorporating Non-Substantial Amendment 1 [05Jun2014] Version 2.0 Incorporating Substantial Amendment 1 [21Nov2014] Investigator: Investigator information is on file at Astellas -------------------------------------------------------------------------------------------------------------------------------------- This confidential document is the property of the Sponsor. No unpublished information contained in this document may be disclosed without prior written approval of the Sponsor. 21 Jul 2015 Astellas Page 1 of 116 Version 3.0 Incorporating Substantial Amendments 1 & 2 Sponsor: APEB ISN/Protocol 2819-CL-0202 EudraCT number 2013-000508-40 - CONFIDENTIAL - Table of Contents I. SIGNATURES ······················································································ 8 II. CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························10 III. LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················11 List of Abbreviations·····················································································11 Definition of Key Study Terms ·········································································13 IV. SYNOPSIS··························································································15 V. FLOW CHART AND SCHEDULE OF ASSESSMENTS ·································22 Flow Chart·································································································22 Table 1: Schedule of Assessments······································································23 1 INTRODUCTION·················································································26 1.1 Background ····················································································26 1.2 Non-clinical and Clinical Data ······························································31 1.2.1 Non-Clinical Data ·······································································31 1.2.2 Clinical Data ·············································································31 Table 2: Summary of Fidaxomicin Clinical Studies·················································31 1.2.2.1 Phase 1 Studies ··········································································33 1.2.2.2 Phase 2A Study ··········································································34 1.2.2.3 Phase 3 Studies ··········································································35 1.2.2.4 Phase 2A Pediatric Study·······························································35 1.3 Summary of Key Safety Information for Study Drugs ···································36 1.3.1 Fidaxomicin ··············································································36 1.3.2 Vancomycin··············································································36 1.4 Risk-Benefit Assessment·····································································36 2 STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ··································38 2.1 Study Objectives ··············································································38 2.1.1 Primary ···················································································38 2.1.2 Secondary ················································································38 2.2 Study Design and Dose Rationale···························································38 2.2.1 Study Design·············································································38 2.2.2 Dose Rationale···········································································40 2.3 Endpoints·······················································································40 21 Jul 2015 Astellas Page 2 of 116 Version 3.0 Incorporating Substantial Amendments 1 & 2 Sponsor: APEB ISN/Protocol 2819-CL-0202 EudraCT number 2013-000508-40 - CONFIDENTIAL - 2.3.1 Primary Endpoint········································································40 2.3.2 Secondary Endpoints····································································41 2.3.3 Exploratory Endpoints ··································································42 3 STUDY POPULATION··········································································43 3.1 Selection of Study Population ·······························································43 3.2 Inclusion Criteria··············································································43 3.3 Exclusion Criteria ·············································································44 4 TREATMENT(S)··················································································44 4.1 Identification of Investigational Product(s) ················································44 4.1.1 Test Drug(s)··············································································44 4.1.2 Comparative Drug(s)····································································45 4.2 Packaging and Labeling ······································································45 4.3 Study Drug Handling ·········································································46 4.4 Blinding ························································································46 4.4.1 Unblinding for Subject Safety Reasons···············································47 4.4.2 Blinding Method·········································································47 4.4.3 Retention of the Assignment Schedule and Procedures for Treatment Code Breaking ··················································································47 4.4.4 Breaking the Treatment Code for Emergency ·······································47 4.4.5 Breaking the Treatment Code by the Sponsor ·······································47 4.5 Assignment and Allocation ··································································48 5 TREATMENTS AND EVALUATION························································48 5.1 Dosing and Administration of Study Drug(s) and Other Medication(s)················48 5.1.1 Dose/Dose Regimen and Administration Period ····································48 Table 3A: Weight-based Dosing Instruction of the Fidaxomicin Oral Suspension··············48 Table 3B: Weight-based Dosing Instruction of the Vancomycin Oral Liquid ····················48 5.1.2 Increase or Reduction in Dose of the Study Drug(s) ································49 5.1.3 Previous and Concomitant Treatment (Medication and Non-Medication Therapy) ··················································································49 5.1.3.1 Prohibited Medication and Restricted Medication ··································49 5.1.4 Treatment Compliance··································································50 5.2 Demographics and Baseline Characteristics ···············································50 5.2.1 Demographics············································································50 5.2.2 Medical History··········································································50 21 Jul 2015 Astellas Page 3 of 116 Version 3.0 Incorporating Substantial Amendments 1 & 2 Sponsor: APEB ISN/Protocol 2819-CL-0202 EudraCT number 2013-000508-40 - CONFIDENTIAL - 5.2.3 Diagnosis of the Target Disease, Severity, and Duration of Disease··············50 5.2.4 Rotavirus ·················································································51 5.3 Efficacy Assessment··········································································51 5.4 Safety Assessment ············································································52 5.4.1 Vital Signs················································································52 5.4.2 Adverse Events ··········································································52 5.4.2.1 Adverse Events of Possible Hepatic Origin ··········································52 5.4.3 Laboratory Assessments································································52 Table 4 Clinical Laboratory Tests to be Performed·················································53 5.4.4 Physical Examination ···································································54 5.4.5 Electrocardiogram (ECG) ······························································54 5.4.6 CDAD Signs and Symptoms···························································54