A Phase 4, Double-Blind, Randomized, Placebo-controlled Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Mirabegron in Male Subjects with OAB Symptoms while taking the Alpha Blocker Tamsulosin for BPH ISN/Protocol 178-MA-3016 ClinicalTrials.gov Identifier: NCT02656173 Date of Protocol: 10 May 2016 Sponsor: Astellas Pharma Inc. 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan Sponsor: API ISN/Protocol 178-MA-3016 CONFIDENTIAL A Phase 4, Double-Blind, Randomized, Placebo-controlled Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Mirabegron in Male Subjects with OAB Symptoms while taking the Alpha Blocker Tamsulosin for BPH Protocol for Phase 4 Study of Mirabegron for Overactive Bladder ISN/Protocol 178-MA-3016 Version 4.0/ 10 May 2016 Sponsor: Astellas Pharma Inc. (API) 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo Prepared on May 10, 2016 (Version 4.0) 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 No unpublished information contained in this document may be disclosed without prior written approval of the Sponsor. 10 May 2016 Astellas Page 1 of 94 Sponsor: API ISN/Protocol 178-MA-3016 CONFIDENTIAL Table of Contents I. SIGNATURES ······················································································· 7 II. CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL ···························· 10 III. LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ·················· 12 IV. SYNOPSIS ··························································································· 15 V. FLOW CHART AND SCHEDULE OF ASSESSMENTS ································· 24 VI. ACCEPTABLE RANGE OF SCHEDULE OF ASSESSMENTS ························ 27 1 INTRODUCTION ·················································································· 30 1.1 Background ····················································································· 30 1.2 Non-clinical and Clinical Data ······························································· 31 1.3 Summary of Key Safety Information for Study Drugs ···································· 32 1.4 Risk-Benefit Assessment ······································································ 32 1.4.1 Foreseeable Risks with Mirabegron ··················································· 32 1.4.1.1 Japanese Labeling ·································································· 32 1.4.1.2 Korean Labeling ···································································· 36 1.4.1.3 Clinically significant adverse drug reactions with mirabegron treatment ············································································· 37 1.4.2 Foreseeable Risks with Tamsulosin ··················································· 38 1.4.2.1 Japanese Labeling ·································································· 38 1.4.2.2 Korean Labeling ···································································· 39 1.4.3 Potential Risks with Combined Treatment ············································ 40 1.4.4 Potential Benefits ········································································· 41 2 STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ·································· 41 2.1 Study Objectives ··············································································· 41 2.2 Study Design and Dose Rationale ··························································· 41 2.2.1 Study Design ·············································································· 41 2.2.2 Dose Rationale ············································································ 42 2.3 Endpoints ························································································ 42 2.3.1 Primary Endpoint ········································································· 42 2.3.2 Secondary Endpoints····································································· 42 2.3.3 Exploratory Endpoints ··································································· 43 2.3.4 Safety Endpoints·········································································· 43 3 STUDY POPULATION ··········································································· 43 3.1 Selection of Study Population ································································ 43 3.2 Inclusion Criteria ··············································································· 43 3.3 Exclusion Criteria ·············································································· 44 10 May 2016 Astellas Page 2 of 94 Sponsor: API ISN/Protocol 178-MA-3016 CONFIDENTIAL 4 TREATMENT(S) ··················································································· 46 4.1 Identification of Investigational Product(s) ················································· 47 4.1.1 Test Drug(s) ··············································································· 47 4.1.2 Comparative Drug(s)····································································· 48 4.1.3 Drug(s) for Screening Period ··························································· 48 4.2 Packaging and Labeling ······································································· 48 4.2.1 Packaging ·················································································· 48 4.2.2 Labeling ··················································································· 49 4.3 Study Drug Handling ·········································································· 49 4.4 Blinding ························································································· 49 4.4.1 Blinding Method·········································································· 49 4.4.2 Confirmation of the Indistinguishability of the Study Drugs ······················· 50 4.4.3 Retention of the Assignment Schedule and Procedures for Treatment Code Breaking ············································································ 50 4.4.4 Breaking the Treatment Code for Emergency ········································ 50 4.4.5 Breaking the Treatment Code by the Sponsor ········································ 50 4.5 Assignment and Allocation ··································································· 50 5 TREATMENTS AND EVALUATION ························································ 51 5.1 Dosing and Administration of Study Drug(s) and Other Medication(s) ················ 51 5.1.1 Dose/Dose Regimen and Administration Period ····································· 51 5.1.2 Increase or Reduction in Dose of the Study Drug(s) ································ 51 5.1.3 Previous and Concomitant Treatment (Medication and Non-Medication Therapy) ··················································································· 51 5.1.3.1 Prior Treatment ····································································· 51 5.1.3.2 Concomitant Treatment ···························································· 51 5.1.4 Treatment Compliance··································································· 52 5.1.5 Restrictions During the Study ·························································· 53 5.2 Demographics and Baseline Characteristics ················································ 53 5.2.1 Demographics ············································································· 53 5.2.2 Medical History ··········································································· 54 5.2.3 Diagnosis of the Target Disease, Severity, and Duration of Disease ·············· 54 5.3 Efficacy Assessments ·········································································· 54 5.3.1 Micturition Diary ········································································· 54 5.3.2 Overactive Bladder Symptom Score (OABSS) ······································ 54 5.3.3 Overactive Bladder Questionnaire (OAB-q) ········································· 54 5.3.4 International Prostate Symptom Score (IPSS and IPSS [QoL]) ··················· 54 5.4 Safety Assessment ············································································· 55 10 May 2016 Astellas Page 3 of 94 Sponsor: API ISN/Protocol 178-MA-3016 CONFIDENTIAL 5.4.1 Vital Signs ················································································· 55 5.4.2 Adverse Events ··········································································· 55 5.4.2.1 Adverse Events of Possible Hepatic Origin ····································· 55 5.4.3 Laboratory Assessments ································································· 55 5.4.4 Measurement of Residual Urine Volume ············································· 57 5.4.5 Measurement of Uroflowmetry ························································· 57 5.5 Adverse Events and Other Safety Aspects ·················································· 57 5.5.1 Definition of Adverse Events (AEs) ··················································· 57 5.5.1.1 Treatment-Emergent Adverse Events (TEAEs) ································ 58 5.5.2 Definition of Serious Adverse Events ················································· 58 5.5.3 Criteria for Causal Relationship to the Study Drug ·································· 59 5.5.4 Criteria for Defining the Severity of an Adverse Event ····························· 59