Effect of Meropenem-Vaborbactam Vs Piperacillin-Tazobactam on Clinical

Supplementary Online Content 1

Kaye KS, Bhowmick T, Metallidis S, et al. Effect of meropenem- vaborbactam vs piperacillin-tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection. JAMA. doi:10.1001/jama.2018.0438

Study Protocol

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Clinical Study Protocol

A PHASE 3, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY STUDY TO EVALUATE THE EFFICACY, SAFETY, AND TOLERABILITY OF CARBAVANCE (MEROPENEM/RPX7009) COMPARED TO PIPERACILLIN/TAZOBACTAM IN THE TREATMENT OF COMPLICATED URINARY TRACT INFECTIONS, INCLUDING ACUTE PYELONEPHRITIS, IN ADULTS

Protocol Number: REMPEX-505 Amended Protocol Dated: 14 JAN 2016, Version 4.0 Amended Protocol Dated: 02 APR 2015, Version 3.0 Amended Protocol Dated: 06 AUG 2014, Version 2.0 Original Protocol Dated: 06 MAY 2014, Version 1.0

Phase 3 Investigational Product Carbavance™ (Meropenem/RPX7009)

US IND # 120040 EudraCT #2014-000545-78

Rempex Pharmaceuticals, a wholly-owned subsidiary of

Sponsor: Rempex Pharmaceuticals, Inc. A wholly owned subsidiary of The Medicines Company 8 Sylvan Way Parsippany, NJ 07054

GCP Statement This study is to be performed in full compliance with the protocol, Good Clinical Practices (GCP), and applicable regulatory requirements. All required study documentation will be archived as required by regulatory authorities.

Confidentiality Statement This document is confidential. It contains proprietary information belonging to Rempex Pharmaceuticals, Inc. (Rempex). Any viewing or disclosure of such information that is not authorized in writing by Rempex is strictly prohibited. Such information may be used solely for the purpose of reviewing or performing this study.

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1 PROTOCOL REVISION HISTORY Date/Version Description 0$<9HUVLRQ 2ULJLQDOSURWRFRO $8*9HUVLRQ $PHQGHGSURWRFRO $359HUVLRQ $PHQGHGSURWRFRO -$19HUVLRQ $PHQGHGSURWRFRO

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2 SPONSOR SIGNATURE A Phase 3, Multi-Center, Randomized, Double-Blind, Double-Dummy Study to Evaluate the Efficacy, Safety, and Tolerability of Carbavance (Meropenem/RPX7009) Compared to Piperacillin/Tazobactam in the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis, in Adults

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3 ADDITIONAL KEY CONTACTS FOR THE STUDY

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INVESTIGATOR’S PROTOCOL AGREEMENT AND SIGNATURE PAGE

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5 TABLE OF CONTENTS 1 PROTOCOL REVISION HISTORY ...... 2 2 SPONSOR SIGNATURE ...... 3 3 ADDITIONAL KEY CONTACTS FOR THE STUDY ...... 4 INVESTIGATOR’S PROTOCOL AGREEMENT AND SIGNATURE PAGE ...... 7 4 SYNOPSIS ...... 8 5 TABLE OF CONTENTS ...... 25 LIST OF IN-TEXT TABLES ...... 28 6 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...... 29 7 INTRODUCTION ...... 32 7.1 Carbavance (Meropenem/RPX7009) ...... 32 7.2 Microbiology ...... 33 7.2.1 Susceptibility Testing ...... 33 7.3 Nonclinical Pharmacology and Toxicology ...... 33 7.3.1 Mechanism of Action ...... 33 7.3.2 Metabolism and Excretion ...... 33 7.4 Overview of Clinical Pharmacology ...... 34 7.4.1 Justification of Carbavance (Meropenem/RPX7009) Dose Selection for Registration Clinical Program ...... 36 7.5 Overview of Clinical Safety ...... 37 7.6 Benefits and Risks Conclusions ...... 39 8 STUDY OBJECTIVES...... 40 9 OVERALL STUDY DESIGN ...... 41 9.1 Study Design ...... 41 9.1.1 Data Safety Monitoring Board ...... 42 9.2 Rationale for Study Design ...... 42 10 SELECTION OF STUDY POPULATION ...... 43 10.1 Inclusion Criteria ...... 43 10.2 Exclusion Criteria ...... 45 10.3 Prior and Concomitant Medications and Treatments ...... 47 10.3.1 Permitted Non-antibacterial Treatment ...... 48 10.3.2 Permitted Antibacterial Treatments ...... 48 10.3.3 Permitted Anti-infective Adjunctive Therapies and Procedures ...... 48 10.3.4 Concomitant Medication Precautions and Exclusions ...... 48 10.4 Randomization and Treatment Group Assignment...... 48 10.5 Blinding ...... 49 11 STUDY DRUG ...... 50 11.1 Description of Study Drugs ...... 51 11.1.1 Carbavance (Meropenem/RPX7009) ...... 51 11.1.2 Piperacillin/Tazobactam ...... 51 11.1.3 Levofloxacin ...... 51 11.2 Study Drug Administration ...... 51 11.2.1 Dosing in Subjects with Renal Insufficiency ...... 52 11.3 Study Drug Labeling and Packaging ...... 52

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11.4 Study Drug Storage Conditions...... 53 11.5 Receipt of Supplies ...... 53 11.6 Study Drug Accountability ...... 53 11.7 Study Drug Handling and Return ...... 53 12 STUDY ASSESSMENTS AND PROCEDURES ...... 54 12.1 Screening (Day -1 or Day 1 Pre-randomization) ...... 54 12.2 Treatment Period (Day 1 to Day 10) (Up to Day 14 for Subjects with Bacteremia) ...55 12.2.1 Study Day 1 Pre-Dose ...... 55 12.2.2 Study Day 1 Post-Dose ...... 56 12.2.3 Study Day 3 ...... 56 12.2.4 End of Treatment ...... 57 12.2.4.1 End of Intravenous Treatment (EOIVT) Visit (for Subjects Switching to Oral Step-Down Therapy Only) ...... 57 12.2.4.2 End of Treatment (EOT) Visit ...... 58 12.3 Follow-up Period ...... 59 12.3.1 Test-of-Cure (TOC) ...... 59 12.3.2 Late Follow-up (LFU) ...... 59 12.3.3 Early Termination ...... 60 12.4 Study Interventions/Procedures ...... 60 12.4.1 Informed Consent ...... 60 12.4.2 Medical History ...... 61 12.4.3 Prior and Concomitant Medications ...... 61 12.4.4 Physical Examination ...... 61 12.4.5 Vital Signs...... 61 12.4.6 Assessment of Signs and Symptoms ...... 61 12.4.7 12-Lead ECG ...... 62 12.4.8 Pharmacokinetic Sampling ...... 63 12.4.9 Clinical Laboratory Assessments ...... 63 12.4.10 Microbiology Assessments ...... 63 12.4.11 Hospitalization Assessments ...... 65 13 SUBJECT AND STUDY DISCONTINUATION ...... 66 13.1 Screening Failures ...... 66 13.2 Withdrawal from Study Drug ...... 66 13.3 Withdrawal from Study ...... 66 13.4 Study Site Discontinuation ...... 67 14 SAFETY ASSESSMENTS ...... 68 14.1 Adverse Events ...... 68 14.2 Adverse Drug Reaction ...... 69 14.3 Unexpected Adverse Drug Reaction ...... 69 14.4 Assessment and Reporting of Adverse Events by the Investigator ...... 69 14.5 Serious Adverse Events...... 71 14.6 Serious Adverse Event Reporting – Procedures for Investigators ...... 71 14.7 Pregnancy Reporting ...... 72 14.8 Expedited Reporting ...... 73 15 EFFICACY EVALUATION ...... 74 15.1 Study Endpoints ...... 74 15.1.1 Primary Endpoint for Food and Drug Administration ...... 74 15.1.2 Primary Endpoint for European Medicines Agency ...... 74 15.1.3 Secondary Endpoints ...... 74

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15.1.4 Exploratory Endpoints ...... 75 15.2 Efficacy Assessments ...... 75 15.2.1 Clinical Outcome ...... 75 15.2.2 Microbiologic Outcome...... 76 15.2.3 Overall Response ...... 77 16 PHARMACOKINETIC ASSESSMENTS ...... 79 17 DATA MANAGEMENT ...... 80 18 STATISTICAL METHODS AND DATA ANALYSIS ...... 81 18.1 Analysis Populations ...... 81 18.2 Disposition, Demographics, Baseline Characteristics, and Exposure ...... 82 18.3 Efficacy Analysis ...... 82 18.4 Safety Analysis ...... 82 18.5 Pharmacokinetic Analysis ...... 83 18.6 Sample Size Justification ...... 83 19 REGULATORY AND ADMINISTRATIVE ASPECTS ...... 84 19.1 Compliance with Regulatory Requirements ...... 84 19.2 Institutional Review Board/Independent Ethics Committee ...... 84 19.3 Informed Consent ...... 84 19.4 Confidentiality ...... 84 19.5 Compensation, Insurance, and Indemnity ...... 85 19.6 Protocol Amendment ...... 85 19.7 Electronic Case Report Forms ...... 85 19.8 Data Quality Assurance ...... 85 19.9 Source Document Maintenance ...... 85 19.10 Study Monitoring Requirements ...... 86 19.11 Study File Management ...... 86 19.12 Study Completion ...... 86 19.13 Audits ...... 86 19.14 Retention of Records ...... 87 19.15 Disclosure of Data ...... 87 19.16 Financial Disclosure ...... 87 19.17 Publication Policy...... 87 20 REFERENCES ...... 88 APPENDIX 1: STATISTICAL ANALYSIS POPULATIONS...... 89 APPENDIX 2: SIGNS AND SYMPTOMS ...... 90 APPENDIX 3: STUDY SCHEMA...... 91 APPENDIX 4: COMMON TOXICITY CRITERIA TABLE...... 92

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LIST OF IN-TEXT TABLES

Table 1. Schedule of Procedures ...... 22 Table 2. Comparison Across Clinical Pharmacology Studies of RPX7009 Pharmacokinetic Parameters (Mean ±SD) Following Single- and Multiple-Dose Administration of RPX7009 2 g Alone and in Combination with Meropenem (Preliminary Data) ...... 35 Table 3. Preliminary Mean (±Standard Deviation) Meropenem Pharmacokinetic Parameters Following Single and Multiple Doses of Meropenem Administered Alone or in Combination with RPX7009 as 3-Hour Infusions to Healthy Volunteers in Rempex-501 ...... 36 Table 4 Clinical Studies with RPX7009 Alone or in Combination with Meropenem ...... 37 Table 5. Criteria for Clinical Outcome ...... 76 Table 6. Criteria for Microbiologic Outcome ...... 77 Table 7. Overall Response at End of Intravenous Treatment (EOIVT) Visit ...... 78 Table 8. Overall Response at Test-of-Cure (TOC) Visit ...... 78

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Table 2. Comparison Across Clinical Pharmacology Studies of RPX7009 Pharmacokinetic Parameters (Mean ±SD) Following Single- and Multiple-Dose Administration of RPX7009 2 g Alone and in Combination with Meropenem (Preliminary Data) Study 402 Rempex-501 Alone Alone w/ Meropenem 1 g Alone w/ Meropenem 2 g Parameter Singlea Lasta Singleb Firstc Lastc Singleb Firstc Lastc (N=6) (N=6) (N=8) (N=8) (N=7) (N=8) (N=8) (N=8) & PJ/ PD[ G $8& PJāK/ +DOI/LIH K 9 / VV 3ODVPD &OHDUDQFH /K D7KHVLQJOHGRVHRI53;ZDVDGPLQLVWHUHGRQ'D\DQGWKHODVWGRVHRI53;IROORZLQJPXOWLSOHGRVH DGPLQLVWUDWLRQZDVRQ'D\ E7KHVLQJOHGRVHRI53;ZDVDGPLQLVWHUHGRQHLWKHU'D\RU'D\GHSHQGLQJRQZKHWKHUWKHVXEMHFWZDV UDQGRPL]HGWRUHFHLYH53;ILUVWRUPHURSHQHPILUVW F7KHILUVWGRVHRIPXOWLSOHGRVHDGPLQLVWUDWLRQRIPHURSHQHP53;ZDVRQ'D\DQGWKHODVWGRVHRIHYHU\ KRXUGRVHDGPLQLVWUDWLRQZDVRQ'D\ G$8& YDOXHVDUHSURYLGHGIRUVLQJOHGRVHVDQG$8& 7ODVW YDOXHVDUHSURYLGHGIRUWKHODVWGD\RI PXOWLSOH GRVLQJ $8& DUHD XQGHU WKH FRQFHQWUDWLRQWLPH FXUYH IURP WLPH WR LQILQLW\ $8& 7ODVW DUHD XQGHU WKH FRQFHQWUDWLRQWLPH FXUYH IURP WLPH WR WKH ODVW UHFRUGHG PHDVXUHPHQW &PD[ PD[LPXP SODVPD FRQFHQWUDWLRQ 6' VWDQGDUGGHYLDWLRQ9VV VWHDG\VWDWHYROXPHRIGLVWULEXWLRQZ ZLWK

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Table 3. Preliminary Mean (±Standard Deviation) Meropenem Pharmacokinetic Parameters Following Single and Multiple Doses of Meropenem Administered Alone or in Combination with RPX7009 as 3-Hour Infusions to Healthy Volunteers in Rempex-501 Meropenem 1 g Meropenem 2 g w/ RPX7009 w/ RPX7009 w/ RPX7009 Alone Alone Alone Parameter 1g 2g 2g Singlea Firstb Lastb Singlea Firstb Lastb Singlea Firstb Lastb (N=9) (N=5) (N=5) (N=14) (N=7) (N=7) (N=14) (N=8) (N=8) & PJ/ PD[ $8&F PJā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Table 4 Clinical Studies with RPX7009 Alone or in Combination with Meropenem

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Number of VXEMHFWV VXEMHFWV VXEMHFWV VXEMHFWV Subjects

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11.1 Description of Study Drugs

11.1.1 Carbavance (Meropenem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

11.1.2 Piperacillin/Tazobactam 3LSHUDFLOOLQWD]REDFWDPIRULQMHFWLRQLVDZKLWHWRRIIZKLWHSRZGHUFRQVLVWLQJRISLSHUDFLOOLQDQG WD]REDFWDPDVWKHLUVRGLXPVDOWVSDFNDJHGLQYLDOV (DFKSLSHUDFLOOLQWD]REDFWDPJ JSLSHUDFLOOLQJWD]REDFWDP VLQJOHGRVHYLDOFRQWDLQV DQ DPRXQW RI GUXJ VXIILFLHQW IRU ZLWKGUDZDO RI SLSHUDFLOOLQ VRGLXP HTXLYDOHQW WR J RI SLSHUDFLOOLQDQGWD]REDFWDPVRGLXPHTXLYDOHQWWRJRIWD]REDFWDP

11.1.3 Levofloxacin /HYRIOR[DFLQZLOOEHSURYLGHGWRVLWHVDVILOPFRDWHGPJDQGPJWDEOHWV

11.2 Study Drug Administration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11.5 Receipt of Supplies 8SRQUHFHLSWRIWKHVWXG\GUXJ V WKHSKDUPDFLVWRUGHVLJQDWHGXQEOLQGHGVWXG\VLWHSHUVRQQHO ZLOOYLVXDOO\LQVSHFWWKHVKLSPHQWDQGYHULI\WKHGUXJLQIRUPDWLRQTXDQWLW\DQGFRQGLWLRQRIWKH NLWVUHFHLYHG5HFHLSWRIVKLSPHQWPXVWEHFRQILUPHGWKURXJKWKH,:56

11.6 Study Drug Accountability

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12 STUDY ASSESSMENTS AND PROCEDURES

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14.5 Serious Adverse Events

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14.6 Serious Adverse Event Reporting – Procedures for Investigators

Initial Reports

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14.8 Expedited Reporting

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15 EFFICACY EVALUATION

15.1 Study Endpoints

15.1.1 Primary Endpoint for Food and Drug Administration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

15.1.2 Primary Endpoint for European Medicines Agency 7KHSULPDU\HIILFDF\HQGSRLQWIRUWKLVVWXG\IRUWKH(XURSHDQ0HGLFLQHV$JHQF\ (0$ ZLOOEH WKH SURSRUWLRQ RI VXEMHFWV LQ WKH FRSULPDU\ P0,77 DQG 0LFURELRORJLF (YDOXDEOH 0( 3RSXODWLRQVZKRDFKLHYHDPLFURELRORJLFRXWFRPHRI(UDGLFDWLRQDWWKH72&YLVLW $ PLFURELRORJLF RXWFRPH RI (UDGLFDWLRQ LV GHILQHG DV WKH GHPRQVWUDWLRQ WKDW WKH EDFWHULDO SDWKRJHQ V IRXQGDWEDVHOLQHLVUHGXFHGWR &)8P/RIXULQH

15.1.3 Secondary Endpoints 7KHVHFRQGDU\HQGSRLQWVIRUWKLVVWXG\DUHWKHIROORZLQJ x 3URSRUWLRQRIVXEMHFWVLQWKHP0,773RSXODWLRQZLWKRYHUDOOVXFFHVVDWERWKWKH(2,97DQG 72&YLVLWV x 3URSRUWLRQRIVXEMHFWVLQWKHP0,77DQG0(3RSXODWLRQVZLWKDPLFURELRORJLFRXWFRPHRI (UDGLFDWLRQ WR &)8P/ RI XULQH IRU )'$ DQG &)8P/ RI XULQH IRU (0$ DW 'D\(2,97(2772&DQG/)8 x 3URSRUWLRQRIVXEMHFWVZLWKD FOLQLFDORXWFRPHRI&XUHLQWKHP0,77&OLQLFDO(YDOXDEOH &( DQG0(3RSXODWLRQVDW'D\(2,97(2772&DQG/)8 x 3HUSDWKRJHQPLFURELRORJLFRXWFRPHLQWKHP0,77DQG0(3RSXODWLRQVDW'D\(2,97 (2772&DQG/)8 x 3KDUPDFRNLQHWLFFKDUDFWHUL]DWLRQRISODVPDH[SRVXUHRIPHURSHQHPDQG53;DQG x 6DIHW\ DQG WROHUDELOLW\ SURILOH RI &DUEDYDQFH PHURSHQHP53; E\ LQFLGHQFH DQG VHYHULW\RIDGYHUVHHYHQWVDQG6$(VYLWDOVLJQVFOLQLFDOODERUDWRU\WHVWV(&*VDQGSK\VLFDO H[DPLQDWLRQVLQWKH6DIHW\3RSXODWLRQ

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15.1.4 Exploratory Endpoints 7KHH[SORUDWRU\HQGSRLQWVIRUWKLVVWXG\DUHWKHIROORZLQJ x ,QFLGHQFHRIWUHDWPHQWHPHUJHQWQHZLQIHFWLRQV x /HQJWKRIKRVSLWDOVWD\ x /HQJWKRILQWHQVLYHFDUHXQLW ,&8 VWD\ x 3URSRUWLRQRIVXEMHFWVZLWKLQIHFWLRQUHODWHG,&8UHDGPLVVLRQ x /HQJWKRI,&8VWD\IRUVXEMHFWVZLWKLQIHFWLRQUHODWHG,&8UHDGPLVVLRQ x $OOFDXVHPRUWDOLW\ x 7LPHWRRUDOVZLWFK LIFOLQLFDOO\LQGLFDWHG x GD\DOOFDXVHDQGLQIHFWLRQUHODWHGKRVSLWDOUHDGPLVVLRQ x 5HODSVHUHFXUUHQFHUDWHVRIF87,RU$3DWWKH/)8YLVLWDQG x 6XEMHFWGLVSRVLWLRQ GLVFKDUJHVWDWXV

15.2 Efficacy Assessments

15.2.1 Clinical Outcome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Table 5. Criteria for Clinical Outcome Category Criteria Cure $W(2,97WKHFRPSOHWHUHVROXWLRQRUVLJQLILFDQWLPSURYHPHQWRIWKHEDVHOLQHVLJQVDQG V\PSWRPVRIF87,RU$3$W(2772&DQG/)8WKHFRPSOHWHUHVROXWLRQRUVLJQLILFDQW LPSURYHPHQW RI WKH EDVHOLQH VLJQV DQG V\PSWRPV RI F87, RU $3 VXFK WKDW QR IXUWKHU DQWLPLFURELDOWKHUDS\LVZDUUDQWHG 6\PSWRP UHVROXWLRQ GRHV QRW QHFHVVDULO\ LQFOXGH EDVHOLQH V\PSWRPV DVVRFLDWHG ZLWK DQDWRPLF DEQRUPDOLWLHV WKDW SUHGLVSRVH WR F87, VXFK DV V\PSWRPV DVVRFLDWHG ZLWK WKH SUHVHQFHRIDQLQGZHOOLQJXULQDU\FDWKHWHUThis outcome category will be used only at EOIVT, EOT, TOC, and LFU visits. Improvement /HVVHQLQJ LQFRPSOHWH UHVROXWLRQ RU QR ZRUVHQLQJ RI EDVHOLQH FOLQLFDO VLJQV DQG V\PSWRPVRIF87,RU$3EXWFRQWLQXHG,9WKHUDS\LVZDUUDQWHGThis outcome category will be used only at Day 3 and EOIVT visits. Failure 6XEMHFWVZKRH[SHULHQFHDQ\one RIWKHIROORZLQJ x $WDQ\VWXG\YLVLWZRUVHQLQJRIEDVHOLQHFOLQLFDOVLJQVDQGV\PSWRPVRIF87,RU$3 RUWKHGHYHORSPHQWRIQHZFOLQLFDOVLJQVDQGV\PSWRPVRILQIHFWLRQVXIILFLHQWWRVWRS VWXG\GUXJDQGLQLWLDWHQRQVWXG\DQWLPLFURELDO x $W(2772&DQG/)8YLVLWVSHUVLVWHQFHLQFRPSOHWHUHVROXWLRQRIEDVHOLQHFOLQLFDO VLJQVDQGV\PSWRPVRILQIHFWLRQ x :LWKGUDZDO IURP WKH VWXG\ GXH WR DQ DGYHUVH HYHQW RU GXH WR ODFN RI FOLQLFDO LPSURYHPHQWRU x 'HDWKRIWKHVXEMHFWGXULQJWKHVWXG\ ,QGHWHUPLQDWH &OLQLFDORXWFRPHFDQQRWEHGHWHUPLQHG $3 DFXWH S\HORQHSKULWLV F87, FRPSOLFDWHG XULQDU\ WUDFW LQIHFWLRQ (2,97 (QG RI ,QWUDYHQRXV 7UHDWPHQW (27 (QGRI7UHDWPHQW,9 LQWUDYHQRXV/)8 /DWH)ROORZXS72& 7HVWRI&XUH

15.2.2 Microbiologic Outcome 7KHPLFURELRORJLFRXWFRPHRI(UDGLFDWLRQLQWKHP0,77DQG0(3RSXODWLRQVDWWKH72&YLVLW ZLOOEHXVHGDVWKHSULPDU\HQGSRLQWIRUWKH(0$IRUWKLVVWXG\7KHFULWHULDIRUPLFURELRORJLF RXWFRPHDUHGHILQHGLQ7DEOH

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Table 6. Criteria for Microbiologic Outcome Category Criteria Eradication x (UDGLFDWLRQLV WKHGHPRQVWUDWLRQWKDWWKHEDFWHULDOSDWKRJHQ V IRXQGDWEDVHOLQHLV UHGXFHGWR &)8P/RQXULQHFXOWXUHIRU)'$RU &)8P/IRU(0$ x $1' D QHJDWLYH EORRG FXOWXUH IRU DQ RUJDQLVP WKDW LV LGHQWLILHG DV D XURSDWKRJHQ LIUHSHDWHGDIWHUSRVLWLYHDWEDVHOLQHEORRGFXOWXUH Persistence x 3HUVLVWHQFHLVWKHGHPRQVWUDWLRQWKDWRQHRUPRUHRIWKHEDFWHULDOSDWKRJHQ V IRXQG DWEDVHOLQHUHPDLQVFRQWLQXRXVO\SUHVHQWDWt&)8P/RQXULQHFXOWXUHIRU)'$ RUt&)8P/IRU(0$ x 25 D FRQWLQXRXVO\ SRVLWLYH EORRG FXOWXUH ZLWK DQ RUJDQLVP WKDW LV LGHQWLILHG DV D XURSDWKRJHQ Recurrence x 5HFXUUHQFH LV WKH LVRODWLRQRIWKH VDPH EDVHOLQHEDFWHULDOSDWKRJHQ V IURPFXOWXUH DIWHUDUHVSRQVHRI(UDGLFDWLRQ x 25DSRVLWLYHEORRGFXOWXUHZLWKWKHVDPHEDVHOLQHRUJDQLVPWKDWZDVLGHQWLILHGDVD XURSDWKRJHQDIWHUDUHVSRQVHRI(UDGLFDWLRQ Indeterminate x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Table 7. Overall Response at End of Intravenous Treatment (EOIVT) Visit Clinical Microbiologic Outcome Outcome Eradication Persistence RecurrenceD Indeterminate Cured 6XFFHVV )DLOXUH )DLOXUH 6XFFHVVEDVHGRQ SUHVXPHGHUDGLFDWLRQ Improvement 6XFFHVV )DLOXUH )DLOXUH 6XFFHVVEDVHGRQ SUHVXPHGHUDGLFDWLRQ Failure )DLOXUH )DLOXUH )DLOXUH )DLOXUHEDVHGRQ SUHVXPHGSHUVLVWHQFH Indeterminate )DLOHGLIFOLQLFDO )DLOXUH )DLOXUH )DLOHGLIFOLQLFDO RXWFRPHDW'D\ RXWFRPHDW'D\ IDLOHGRWKHUZLVH IDLOHGRWKHUZLVH ,QGHWHUPLQDWH ,QGHWHUPLQDWH D )RUDQRXWFRPHRI5HFXUUHQFHVXEMHFWVPXVWKDYHGRFXPHQWHGSULRUHUDGLFDWLRQ LH'D\ 7KHDOJRULWKPIRURYHUDOOUHVSRQVHDWWKH72&YLVLWLVVXPPDUL]HGLQ7DEOH

Table 8. Overall Response at Test-of-Cure (TOC) Visit Clinical Microbiologic Outcome Outcome Eradication Persistence RecurrenceD Indeterminate Cured 6XFFHVV )DLOXUH )DLOXUH 6XFFHVVEDVHGRQ SUHVXPHGHUDGLFDWLRQ Failure )DLOXUH )DLOXUH )DLOXUH )DLOXUHEDVHGRQ SUHVXPHGSHUVLVWHQFH Indeterminate )DLOHGLIFOLQLFDO )DLOXUH )DLOXUH )DLOHGLIFOLQLFDO RXWFRPHDWDQ\HDUOLHU RXWFRPHDWDQ\HDUOLHU YLVLWLVIDLOHG YLVLWLVIDLOHG 2WKHUZLVH 2WKHUZLVH ,QGHWHUPLQDWH ,QGHWHUPLQDWH D )RUDQRXWFRPHRI5HFXUUHQFHVXEMHFWVPXVWKDYHGRFXPHQWHGHUDGLFDWLRQDWDQ\SULRUWLPHSRLQW

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18 STATISTICAL METHODS AND DATA ANALYSIS

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19.14 Retention of Records

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APPENDIX 1: STATISTICAL ANALYSIS POPULATIONS

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APPENDIX 2: SIGNS AND SYMPTOMS

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REMPEX 505 Carbavance (Meropenem/RPX7009) $3+$6(08/7,&(17(55$1'20,=(''28%/(%/,1''28%/('800<678'<72(9$/8$7(7+(()),&$&< 6$)(7<$1'72/(5$%,/,7<2)&$5%$9$1&( 0(523(1(053; &203$5('723,3(5$&,//,17$=2%$&7$0,1 7+(75($70(172)&203/,&$7('85,1$5<75$&7,1)(&7,216,1&/8',1*$&87(3<(/21(3+5,7,6,1$'8/76

Objectives To assess the efficacy of Carbavance Screening (meropenem/RPX7009) administered Day -1 to Day 1 by intravenous (IV) infusion in subjects with cUTI or AP. Treatment with IV Study Drug To assess the safety and tolerability of Day 1 through Day 5 (up to Day 10**) Carbavance (meropenem/RPX7009) administered by IV infusion in subjects EOIVT* with cUTI or AP. ≥15 doses (Day 5 up to Day 10**) To assess the population PK of FDA primary endpoint meropenem and RPX7009 in subjects EOT* with cUTI or AP. Day 10**

Follow-up*** Day 15 up to Day 26 Carbavance (meropenem/RPX7009) Subjects with 2 g/2 g q8h via IV infusion over 3 hours cUTI or AP AND ≥15 doses of IV with or 100 mL NS via IV infusion over Study Drug without 30 minutes Transition to oral TOC*** LFU*** bacteremia step-down Day 15 up to Day 19 Day 22 up Requiring therapy** if EMA Primary Endpoint to Day 26 more than 5 Randomization Piperacillin/tazobactam 4.5 g (4 g clinically indicated days of IV piperacillin/0.5 g tazobactam) q8h via IV and criteria met treatment infusion over 30 minutes AND 250 mL NS via IV infusion over 3 hours *If EOIVT and EOT occur on the same day, visit activities will be combined. **Subjects who are unable to receive levofloxacin based on prescribing information or have baseline urinary pathogen(s) resistant to levofloxacin and cannot remain in the hospital for a total of 10 days of IV treatment, with Medical Monitor approval, one of the following oral antibiotics can be selected: trimethoprim/sulfamethoxazole, cefdinir, cefixime or cefpodoxime. ***Subjects with bacteremia may receive treatment up to 14 days. For subjects with bacteremia, the visit window for the TOC visit is Day 15 to Day 23 and the visit window for the LFU visit is Day 22 to Day 30. AP = acute pyelonephritis; cUTI = complicated urinary tract infection; EMA = European Medicines Agency; EOIVT = End of Intravenous Treatment; EOT = End of Treatment (IV + oral); FDA = Food and Drug Administration; IV = intravenous; LFU = Late Follow-up; NS = normal saline; PK = pharmacokinetic; q8h = Every 8 hours; TOC = Test-of-Cure -$19HUVLRQ 4.0 3DJHRI

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