Sponsor: API ISN/Protocol <8825-CL-0101> ‐ CONFIDENTIAL ‐ Gabapentin Enacarbil Post-marketing Clinical Study Protocol - A Randomized, Double-blind, Placebo-controlled, Parallel-group Study in Subjects With Restless Legs Syndrome - ISN/Protocol 8825-CL-0101 Version 3.0 13 January 2017 (Translation from Japanese) Sponsor: Astellas Pharma Inc.(API) 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo This document is the property of the Sponsor. Unpublished information in this document must not be disclosed without prior written agreement of the Sponsor. 13 January 2017 Astellas Page 1 of 105 Sponsor: API ISN/Protocol <8825-CL-0101> ‐ CONFIDENTIAL ‐ Table of Contents I SIGNATURE ······················································································· 8 II CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL ···························· 9 III LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERM ··················· 10 IV SYNOPSIS·························································································· 13 V FLOW CHART AND SCHEDULE OF ASSESSMENTS································· 20 1 INTRODUCTION ················································································ 24 1.1 Background···················································································· 24 1.2 Nonclinical and Clinical Data ······························································· 25 1.2.1 Nonclinical Data ········································································ 25 1.2.2 Clinical Data············································································· 26 1.3 Summary of Key Safety Information for the Study Drug································ 34 1.4 Risk Benefit Assessment····································································· 34 1.4.1 Risk Assessment ········································································ 34 1.4.2 Benefit Assessment ····································································· 35 2 STUDY OBJECTIVES, DESIGN, AND ENDPOINTS···································· 35 2.1 Study Objectives ·············································································· 35 2.2 Study Design and Dose Rationale ·························································· 36 2.2.1 Study Design ············································································ 36 2.2.2 Dose Rationale ·········································································· 36 2.3 Endpoints ······················································································ 37 2.3.1 Primary Endpoint ······································································· 37 2.3.2 Secondary Endpoints ··································································· 37 2.3.3 Safety Endpoints ········································································ 37 3 STUDY POPULATION ········································································· 38 3.1 Selection of Study Population······························································· 38 3.2 Inclusion Criteria ············································································· 38 3.3 Exclusion Criteria············································································· 40 4 TREATMENT ····················································································· 42 4.1 Identification of Study Drug································································· 42 4.1.1 Test Drug················································································· 42 13 January 2017 Astellas Page 2 of 105 Sponsor: API ISN/Protocol <8825-CL-0101> ‐ CONFIDENTIAL ‐ 4.1.2 Comparative Drug ······································································ 42 4.1.3 Study drug for the run-in period and study drug for the follow-up period ······· 42 4.2 Packaging and Labeling······································································ 43 4.3 Study Drug Handling········································································· 48 4.4 Blinding························································································ 48 4.4.1 Blinding Method ········································································ 48 4.4.2 Confirmation of the Indistinguishability of the Study Drugs ······················ 48 4.4.3 Retention of the Assignment Schedule and Procedures for Treatment Code Breaking·················································································· 48 4.4.4 Breaking the Treatment Code for Emergency ······································· 49 4.4.5 Breaking the Treatment Code by the Sponsor ······································· 49 4.5 Assignment and Allocation·································································· 50 5 TREATMENTS AND EVALUATION ······················································· 50 5.1 Dosing and Administration of Study Drug and Other Medications····················· 50 5.1.1 Dose, Dosage Regimen, and Administration Period································ 50 5.1.2 Increase or Reduction in Dose of the Study Drug··································· 51 5.1.3 Previous and Concomitant Treatment (Medication and Non-medication Therapy)·················································································· 51 5.1.3.1 Previous Treatment (Medications and Non-medication Therapies)········· 51 5.1.3.2 Concomitant Treatment (Medication and Non-medication Therapy) ······· 52 5.1.4 Treatment Compliance ································································· 53 5.1.5 Emergency Procedures and Management of Overdose····························· 53 5.1.6 Criteria for Continuation of Treatment ··············································· 53 5.1.7 Restrictions During the Study ························································· 53 5.2 Demographics and Baseline Characteristics··············································· 55 5.2.1 Demographics ··········································································· 55 5.2.2 Medical History ········································································· 55 5.2.3 Diagnosis of the Target Disease, Severity, and Duration of Disease ············· 55 5.3 Efficacy Assessment·········································································· 55 5.4 Safety Assessment ············································································ 56 5.4.1 Vital Signs ··············································································· 56 5.4.2 Adverse Events·········································································· 56 5.4.3 Laboratory Assessments································································ 56 5.4.4 Physical Examination··································································· 57 13 January 2017 Astellas Page 3 of 105 Sponsor: API ISN/Protocol <8825-CL-0101> ‐ CONFIDENTIAL ‐ 5.4.5 Imaging··················································································· 57 5.4.6 Other······················································································ 57 5.5 Adverse Events and Other Safety Aspects················································· 57 5.5.1 Definition of Adverse Events (AEs) ·················································· 57 5.5.2 Definition of Serious Adverse Events (SAEs)······································· 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 ···························· 60 5.5.5 Reporting of Serious Adverse Events (SAEs) ······································· 60 5.5.6 Follow-up of Adverse Events·························································· 61 5.5.7 Monitoring of Common Serious Adverse Events ··································· 61 5.5.8 Procedure in Case of Pregnancy······················································· 61 5.5.9 Emergency Procedures and Management of Overdose····························· 62 5.5.10 Supply of New Information Affecting the Conduct of the Study ················· 62 5.5.11 Deviations from the Protocol and Other Actions Taken to Avoid Life- Threatening Risks to Subjects ························································· 62 5.6 Test Drug Concentration····································································· 63 5.7 Other Measurements, Assessments or Methods··········································· 63 5.8 Total Amount of Blood Collected ·························································· 63 6 DISCONTINUATION ··········································································· 64 6.1 Discontinuation of Individual Subjects····················································· 64 6.2 Discontinuation of the Site ·································································· 66 6.3 Discontinuation of the Study ································································ 66 7 STATISTICAL METHODOLOGY··························································· 66 7.1 Sample Size···················································································· 66 7.2 Analysis Sets ·················································································· 67 7.2.1 Full Analysis Set (FAS) ································································ 67 7.2.2 Per Protocol Set (PPS)·································································· 67 7.2.3 Safety Analysis Set (SAF) ····························································· 67 7.3