Statistical Analysis Plan: IT001-301 Study Title: A prospective, Phase 3, randomized, multi-center, double-blind study of the efficacy, tolerability and safety of PF-03709270 with probenecid versus oral ciprofloxacin for treatment of uncomplicated urinary tract infections in adult women. Study Number: IT001-301 Study Phase: Phase 3 Product Name: sulopenem etzadroxil/probenecid (PF -03709270/probenecid) Indication: Uncomplicated urinary tract infection Study Statistician: Michael Zelasky Study Clinician: Steven I. Aronin, M.D. Sponsor: Iterum Therapeutics International Limited 20 Research Parkway, Suite A Old Saybrook, CT 06475 Final SAP Date: September 30, 2019 Revised SAP Date: March 11, 2020 Protocol Version January 6, 2020 (amendment 2) Confidentiality Statement This document is strictly confidential. It was developed by Iterum Therapeutics US Limited should not be disclosed to a third party, with the exception of regulatory agencies and study audit personnel. Reproduction, modification or adaptation, in part or in total, is strictly forbidden without prior written approval by Iterum Therapeutics US Limited Sulopenem Iterum Therapeutics US Limited Statistical Analysis Plan: IT001-301 19 March 2020 TABLE OF CONTENTS TABLE OF CONTENTS ............................................................................................................ 3 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................. 5 1 INTRODUCTION............................................................................................................. 7 2 STUDY DESIGN ............................................................................................................... 7 3 STUDY OBJECTIVES ..................................................................................................... 7 3.1 Primary Objective ................................................................................................. 7 3.2 Secondary Objectives ........................................................................................... 7 4 DEFINITION OF ANALYSIS POPULATIONS ........................................................... 8 4.1 Intent-to-Treat (ITT) ............................................................................................ 8 4.2 Modified Intent-to-Treat (MITT) ....................................................................... 8 4.3 Microbiological Modified Intent-to-Treat (micro-MITT or m-MITT) ......... 8 4.3.1 Susceptible (micro-MITTS or m-MITTS) ............................................................. 8 4.3.2 Resistant (micro-MITTR or m-MITTR) ............................................................... 8 4.4 Clinical Evaluable (CE) ......................................................................................... 8 4.5 Microbiological Evaluable (ME) ....................................................................... 10 4.5.1 Susceptible (ME-S) ................................................................................................ 10 4.5.2 Resistant (ME-R).................................................................................................. 11 4.6 Safety ..................................................................................................................... 11 4.7 Determination of Inclusion in Analysis Populations ................................... 11 5 DEFINITION OF ENDPOINTS ................................................................................... 11 5.1 Overall Response ................................................................................................... 11 5.2 Microbiologic Response ........................................................................................ 12 5.2.1 Baseline Pathogens ................................................................................................ 12 5.2.2 Post-Baseline Pathogens ....................................................................................... 13 5.3 Patient-Determined Clinical Response (Clinical Response) ............................. 14 5.4 Investigator-Determined Clinical Response: ...................................................... 14 5.5 Patient Symptom Assessment Questionnaire (PSAQ) ................................. 15 5.6 Safety Endpoint Measures ................................................................................. 15 6 STATISTICAL METHODS .......................................................................................... 16 6.1 Sample Size ........................................................................................................... 16 6.2 Randomization ...................................................................................................... 17 6.3 Visit Windows........................................................................................................ 17 6.4 Microbiology Data ................................................................................................ 17 Confidential 3 Sulopenem Iterum Therapeutics US Limited Statistical Analysis Plan: IT001-301 19 March 2020 6.5 Handling of Missing Data ..................................................................................... 18 6.6 Comments on Statistical Analysis........................................................................ 20 7 STATISTICAL ANALYSES ......................................................................................... 20 7.1 Patient Disposition ................................................................................................ 20 7.2 Demographics and Baseline Characteristics ...................................................... 21 7.2.1 Baseline Microbiology .................................................................................. 21 7.3 Prior and Concomitant Medications ................................................................... 22 7.4 Study Drug Exposure ........................................................................................... 22 7.5 Efficacy Analyses .................................................................................................. 22 7.5.1 Primary Efficacy Analysis .................................................................................... 23 7.5.2 Additional Hypothesis Testing of the Primary Efficacy Endpoint ................... 24 7.5.3 Additional Analyses of the Primary Efficacy Endpoint .................................... 25 7.5.4 Secondary Efficacy Analysis ................................................................................ 27 7.5.5 Additional Efficacy Analyses ............................................................................... 27 7.6 Interim Analysis .................................................................................................... 32 7.7 Safety Analyses ...................................................................................................... 33 7.7.1 Adverse Events ...................................................................................................... 33 7.7.1.1 Diarrhea Episodes ................................................................................................. 34 7.7.2 Laboratory Values ................................................................................................ 35 7.7.3 Physical Examinations .......................................................................................... 36 7.7.4 Vital Signs .............................................................................................................. 36 7.8 Protocol Deviations ............................................................................................... 37 8 DIFFERENCES WITH ANALYSES SPECIFIED IN THE PROTOCOL............... 37 9 REFERENCES ................................................................................................................ 38 Appendix A: Schedule of Activities ............................................................................. 39 Appendix B: Criteria for Safety Values of Potential Clinical Concern ........................ 40 Appendix C: Method for Determination of Creatinine Clearance ................................ 41 Appendix D: Microbiology Rules ................................................................................. 42 Appendix E: Inclusion of OpGen (PCR) Data for Exploratory Analysis ..................... 43 Confidential 4 Sulopenem Iterum Therapeutics US Limited Statistical Analysis Plan: IT001-301 19 March 2020 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS AE Adverse Event BMI Body Mass Index CE Clinical Evaluable CFU Colony Forming Unit CI Confidence Interval CRF Case Report Form CSR Clinical Study Report EOT End of Treatment Visit ESBL Extended-Spectrum β-Lactamases FDA Food and Drug Administration FV Final Visit GCP Good Clinical Practice IA Interim Analysis ITT Intent-to-Treat IWRS Interactive Web Response System m-MITT Microbiological Modified Intent-to-Treat m-MITTR Microbiological Modified Intent-to-Treat Resistant m-MITTS Microbiological Modified Intent-to-Treat Susceptible ME Microbiological Evaluable MedDRA Medical Dictionary for Regulatory Activities MG Milligram MIC Minimum Inhibitory Concentration micro-MITT Microbiological Modified Intent-to-Treat MITT Modified Intent-to-Treat NDA New Drug Application Confidential 5 Sulopenem Iterum Therapeutics US Limited Statistical Analysis Plan: IT001-301 19 March 2020 PD Pharmacodynamic PK Pharmacokinetic PO Orally PSAQ Patient Symptom Assessment Questionnaire SAE serious adverse event