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Study Protocol 2017N317982_00 CONFIDENTIAL 2018N388745_00 GlaxoSmithKline group of companies 206899 TITLE PAGE Protocol Title: A Phase IIa Single-Center, Open-Label Study Evaluating the Pharmacokinetics of Repeat Oral Doses of Gepotidacin (GSK2140944) in Adult Female Participants With Uncomplicated Urinary Tract Infection (Acute Cystitis) Protocol Number: 206899 Short Title: Phase IIa Pharmacokinetic Study of Oral Gepotidacin (GSK2140944) in Participants With Uncomplicated Urinary Tract Infection (Acute Cystitis) Compound Number: GSK2140944 Sponsor Name and Legal Registered Address: GlaxoSmithKline Research & Development Limited 980 Great West Road Brentford Middlesex, TW8 9GS UK Sponsor Contact Address: GlaxoSmithKline 1250 South Collegeville Road PO Box 5089 Collegeville, PA 19426-0989 USA Medical Monitor Name and Contact Information can be found in the Study Reference Manual Regulatory Agency Identifying Number: IND 111885 Approval Date: 10-MAY-2018 Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved. Unauthorized copying or use of this information is prohibited. 1 2018N388745_00 PPD PPD 2017N317982_00 CONFIDENTIAL 2018N388745_00 206899 TABLE OF CONTENTS PAGE 1. SYNOPSIS...............................................................................................................6 2. SCHEDULE OF ACTIVITIES ...................................................................................8 3. INTRODUCTION....................................................................................................11 3.1. Study Rationale ..........................................................................................11 3.2. Background ................................................................................................11 3.3. Benefit/Risk Assessment ............................................................................13 3.3.1. Risk Assessment .........................................................................14 3.3.2. Benefit Assessment .....................................................................17 3.3.3. Overall Benefit:Risk Conclusion...................................................17 4. OBJECTIVES AND ENDPOINTS...........................................................................18 5. STUDY DESIGN ....................................................................................................19 5.1. Overall Design ............................................................................................19 5.2. Number of Participants ...............................................................................22 5.3. Participant and Study Completion...............................................................22 5.4. Scientific Rationale for Study Design ..........................................................22 5.5. Dose Justification........................................................................................23 6. STUDY POPULATION ...........................................................................................24 6.1. Inclusion Criteria.........................................................................................24 6.2. Exclusion Criteria........................................................................................25 6.3. Lifestyle Restrictions...................................................................................27 6.3.1. Meals and Dietary Restrictions ....................................................27 6.3.2. Caffeine and Alcohol....................................................................28 6.3.3. Activity .........................................................................................28 6.4. Screen Failures...........................................................................................28 7. TREATMENTS.......................................................................................................28 7.1. Treatments Administered............................................................................28 7.2. Dose Modification .......................................................................................29 7.3. Method of Treatment Assignment ...............................................................29 7.4. Blinding.......................................................................................................29 7.5. Preparation/Handling/Storage/Accountability ..............................................29 7.6. Treatment Compliance................................................................................30 7.7. Concomitant Therapy..................................................................................30 7.7.1. Permitted Medications and Nondrug Therapies ...........................30 7.7.2. Prohibited Medications and Nondrug Therapies...........................30 7.8. Treatment after the End of the Study ..........................................................31 8. DISCONTINUATION CRITERIA.............................................................................31 8.1. Discontinuation of Study Treatment ............................................................31 8.1.1. Liver Chemistry Stopping Criteria ................................................32 8.1.2. QTc Stopping Criteria ..................................................................34 8.1.3. Temporary Discontinuation ..........................................................34 8.1.4. Rechallenge.................................................................................34 8.1.4.1. Study Treatment Restart or Rechallenge....................34 3 2017N317982_00 CONFIDENTIAL 2018N388745_00 206899 8.2. Withdrawal from the Study..........................................................................35 8.3. Lost to Follow-Up........................................................................................35 9. STUDY ASSESSMENTS AND PROCEDURES .....................................................36 9.1. Efficacy Assessments.................................................................................39 9.1.1. Therapeutic Response Evaluation ...............................................39 9.1.2. Bacteriology Samples ..................................................................39 9.1.2.1. Microbiological Outcome and Response.....................40 9.1.3. Clinical Evaluation .......................................................................43 9.2. Adverse Events...........................................................................................45 9.2.1. Time Period and Frequency for Collecting AE and SAE Information...................................................................................45 9.2.2. Method of Detecting AEs and SAEs.............................................46 9.2.3. Follow-up of AEs and SAEs.........................................................46 9.2.4. Regulatory Reporting Requirements for SAEs .............................46 9.2.5. Adverse Events of Special Interest ..............................................47 9.2.6. Cardiovascular and Death Events................................................47 9.2.7. Pregnancy ...................................................................................47 9.3. Treatment of Overdose...............................................................................47 9.4. Safety Assessments ...................................................................................48 9.4.1. Physical Examinations.................................................................48 9.4.2. Vital Signs....................................................................................48 9.4.3. Electrocardiograms......................................................................48 9.4.4. Clinical Safety Laboratory Assessments ......................................49 9.5. Pharmacokinetics .......................................................................................49 9.5.1. Blood and Urine Samples ............................................................49 9.5.2. Cervical, Rectal, and Pharyngeal Swab Specimens.....................50 9.6. Pharmacodynamics ....................................................................................50 9.6.1. Pharmacokinetics/Pharmacodynamics ........................................50 9.6.2. Microbiome Assessments ............................................................50 9.7. Genetics .....................................................................................................51 9.8. Biomarkers .................................................................................................51 9.9. Health Economics or Medical Resource Utilization and Health Economics..................................................................................................51 10. STATISTICAL CONSIDERATIONS........................................................................51 10.1. Sample Size Determination ........................................................................51 10.2. Populations for Analyses ............................................................................52 10.3. Statistical Analyses.....................................................................................52 10.3.1. Pharmacokinetic Analyses...........................................................52 10.3.2. Safety Analyses...........................................................................53 10.3.3. Exploratory Analyses ...................................................................54 10.3.4. Interim Analyses ..........................................................................55
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