Clinical trial NCT02168946
Conditions: Urinary Tract Infection Complicated Acute Pyelonephritis Hospital Acquired Bacterial Pneumonia Ventilator-associated Bacterial Pneumonia Bacteremia Abdominal Infection
Sponsor: Rempex (a wholly owned subsidiary of Melinta Therapeutics, Inc.)
Start date: 2014-07-01; Completion date: 2017-07-21
Enrollment: 77 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Vabomere™, (meropenem-vaborbactam) is being compared to the Best Available Therapy in the treatment of adults with selected serious infections due to Carbapenem Resistant Enterobacteriaceae

Detailed description:
In the current era of increased resistance to extended spectrum cephalosporins and penicillin/beta-lactamase inhibitor combinations, carbapenem antimicrobial agents are frequently the antibiotics of "last defense" for the most resistant pathogens in serious infections. However, the recent dissemination of serine carbapenemases (e.g. KPC) in Enterobacteriaceae within many hospitals worldwide now poses a considerable threat to carbapenems and other members of the beta-lactam class of antimicrobial agents.

Infections caused by Carbapenem-Resistant Enterobacteriaceae (CRE) are associated with high mortality rates and have limited treatment options. The loss of the carbapenem class of antimicrobial agents for treatment of Enterobacteriaceae (the most frequently occurring pathogens in the hospital setting), Acinetobacter baumannii, and Pseudomonas aeruginosa represents a critical setback in modern patient care.

As a result of the current lack of an optimal treatment for patients who have infections due to a CRE, physicians manage these patients with the limited anti-infective options available, including aminoglycosides, polymyxin B, colistin, tigecycline, or various combinations of these. There are limited efficacy data available for many of these therapies when used to treat serious CRE infections, particularly in combination, but with limited or no alternative therapies currently available, such treatments have become the Best Available Therapy despite the toxicities associated with many of them.

Vaborbactam is a novel beta-lactamase inhibitor that has inhibitory activity against many serine beta-lactamases and was optimized for inhibition of the KPC beta-lactamase and the potentiation of carbapenems against Enterobacteriaceae. Vaborbactam is being developed for use with meropenem (a broad spectrum injectable carbapenem antibiotic) to address the challenges of treatment of serious infections caused by pathogens increasingly resistant to available treatments.

Vabomere, (meropenem-vaborbactam) administered as a fixed combination by intravenous (IV) infusion, is being developed to treat serious gram-negative infections, such as complicated urinary tract infections (cUTI), acute pyelonephritis (AP), hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), and bacteremia, including those infections caused by bacteria resistant to currently available carbapenems.

Arms: arm 1: Vabomere (meropenem 2g plus vaborbactam 2g) IV q8h, for up to 14 days arm 2: Subjects will receive Best Available Therapy (IV antibiotics)
Interventions: intervention 1: Vabomere intervention 2: Best Available Therapy
Intervention descriptions: intervention 1: Vabomere for IV injection, administered as a 2 g/2 g dose intervention 2: Antibiotic(s) chosen by Investigator

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
 
A PHASE 3, MULTI-CENTER, RANDOMIZED, OPEN-LABEL STUDY OF 
CARBAVANCE (MEROPENEM/RPX7009) VERSUS BEST AVAILABLE THERAPY IN 
SUBJECTS WITH SELECTED SERIOUS INFECTIONS DUE TO 
CARBAPENEM-RESISTANT ENTEROBACTERIACEAE  
Protocol Number: REMPEX-506 
Amendment 2 Protocol Dated: 24 APR 2015, Version 3.0 
Amendment 1 Protocol Dated: 22 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 # 2014-000546-30 
 
 
 
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. 
 


REMPEX PHARMACEUTICALS, INC. 
 
Carbavance™ (Meropenem/RPX7009) 
CONFIDENTIAL 
Clinical Study Protocol: REMPEX-506 
24 APR 2015, Version 3.0 
Page 2 of 116 
1 
PROTOCOL REVISION HISTORY 
 
Date/Version 
Description 
06 May 2014/Version 1.0 
Original Protocol 
22 Aug 2014/Version 2.0 
Protocol incorporating Amendment 1 
24 Apr 2015/Version 3.0 
Protocol incorporating Amendment 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


REMPEX PHARMACEUTICALS, INC. 
 
Carbavance™ (Meropenem/RPX7009) 
CONFIDENTIAL 
Clinical Study Protocol: REMPEX-506 
24 APR 2015, Version 3.0 
Page 3 of 116 
2 
SPONSOR—SIGNATURE PAGE  
A Phase 3, Multi-Center, Randomized, Open-Label Study of Carbavance 
(Meropenem/RPX7009) Versus Best Available Therapy in Subjects with Selected Serious 
Infections Due to Carbapenem-Resistant Enterobacteriaceae 
Sponsor 
Rempex Pharmaceuticals, Inc. 
A wholly owned subsidiary of 
The Medicines Company 
8 Sylvan Way 
Parsippany, NJ 07054 
 
Sponsor Representative 
 
 
 
 
 
 
 
Signature 
Date 
Principal Investigator 
and Clinical Site 
Keith Kaye, MD, MPH 
Wayne State University 
University Health Center  
4201 St. Antoine, Suite 2B 
Detroit, MI 48201 
 
 
 
 
 
 
 
 
 


REMPEX PHARMACEUTICALS, INC. 
 
Carbavance™ (Meropenem/RPX7009) 
CONFIDENTIAL 
Clinical Study Protocol: REMPEX-506 
24 APR 2015, Version 3.0 
Page 4 of 116 
3 
ADDITIONAL KEY CONTACTS FOR THE STUDY 
 
Sponsor Medical Monitors 
Elizabeth Alexander, MD, MSc 
Director, Health Sciences Infectious 
Disease Care 
The Medicines Company  
8 Sylvan Way 
Parsippany, NJ 07054 
 
 
 
 
Jeffery Loutit, MBChB 
Vice President and Chief Medical Officer, 
Health Sciences Infectious Disease Care 
8 Sylvan Way 
Parsippany, NJ 07054 
 
 
 
 
Medpace US Medical Monitors 
Brian Murphy, MD, MPH, AAHIVS 
5375 Medpace Way 
Cincinnati, OH 45227 
 
 
  
 
Medpace Outside US Medical 
Monitor 
Anibal Calmaggi, MD (Latin America) 
Calle 19 – 130, City Bell (1896)  
Buenos Aires, Argentina 
 
 
 
 
Markus Heep, MD (Europe, UK and Israel) 
Medpace Germany GmbH 
Theresienhoehe 30 
80339 München, Germany 
 
    
 


REMPEX PHARMACEUTICALS, INC. 
 
Carbavance™ (Meropenem/RPX7009) 
CONFIDENTIAL 
Clinical Study Protocol: REMPEX-506 
24 APR 2015, Version 3.0 
Page 5 of 116 
 
Clinical Laboratory 
Medpace Reference Laboratories 
5365 Medpace Way 
Cincinnati, OH 45227 
  
 
Microbiology Laboratory 
JMI Laboratories 
345 Beaver Kreek Centre, Suite A 
North Liberty, IA 52317 
 
 
Bioanalytical Laboratory and  
Pharmacokinetic Analysis  
MicroConstants, Inc. 
9050 Camino Santa Fe 
San Diego, CA 92121 
 
 
Electrocardiogram Laboratory 
Chris Werremeyer 
ERT 
1818 Market Street, Suite 1000 
Philadelphia, PA 19103 
 
 
 
Safety  
Medpace Clinical Safety 
Medpace Serious Adverse Event hotline – US: 
  
 
  
 
 
Medpace Serious Adverse Event hotline 
– Europe: 
 
 
  
Biostatistics, Data Management 
and Medical Writing 
Medpace, Inc.  
5375 Medpace Way 
Cincinnati, OH 45227 
 
 


REMPEX PHARMACEUTICALS, INC. 
 
Carbavance™ (Meropenem/RPX7009) 
CONFIDENTIAL 
Clinical Study Protocol: REMPEX-506 
24 APR 2015, Version 3.0 
Page 6 of 116 
Interactive Web Response System 
(IWRS) 
Medpace, Inc.  
5375 Medpace Way 
Cincinnati, OH 45227 
 
 
Investigational Product 
Distribution 
Bill Karosen 
Clinical Supply Chain Manager 
The Medicines Company 
8 Sylvan Way  
Parsippany, NJ 07054 
 
 
 


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Carbavance™ (Meropenem/RPX7009) 
CONFIDENTIAL 
Clinical Study Protocol: REMPEX-506 
24 APR 2015, Version 3.0 
Page 7 of 116 
INVESTIGATOR’S PROTOCOL AGREEMENT AND SIGNATURE PAGE 
Protocol Number:  Rempex-506 (Version 3.0, Dated 24-Apr-2015) 
Protocol Title:  
A Phase 3, Multi-Center, Randomized, Open-Label Study of Carbavance 
(Meropenem/RPX7009) Versus Best Available Therapy in Subjects with 
Selected Serious Infections Due to Carbapenem-Resistant 
Enterobacteriaceae 
The Investigator’s Protocol Agreement and Signature Page must be signed by the Principal Investigator. 
The original or a copy must be kept on file at the Sponsor or the Sponsor’s designee and the Investigator 
must retain the original or a copy. The completed Investigator’s Protocol Agreement and Signature Page 
signifies review and acceptance of the protocol by the Principal Investigator prior to initiation of the study.  
By my signature, I confirm that my staff and I have carefully read and understand this protocol, and agree 
to comply with the conduct and terms of the study specified herein. In particular, I/we have agreed to the 
following: 
• 
Abide by all obligations stated on Form FDA 1572, Good Clinical Practice (GCP), or local authority 
regulatory requirements. 
• 
Maintain confidentiality and assure security of the Sponsor’s confidential documents such as the 
protocol, Case Report Forms, Investigator’s Brochure, final study reports, manuscript drafts, 
unpublished data, correspondence, etc.  
• 
Assure access by the Sponsor or monitors to original documents, data, and records. 
• 
Obtain Independent Ethics Committee (IEC)/Institutional Review Board (IRB) approval of study, any 
amendments to the study, and periodic re-approval as required, unless performed by Sponsor. 
• 
Keep the IEC/IRB informed of adverse events and periodically report the status of the study to them as 
required by local regulations and IEC/IRB requirements. 
• 
Have read the Investigator’s Brochure and are familiar with the results of the pharmacologic and 
toxicologic tests concerning Carbavance™ (meropenem/RPX7009) and acknowledge the probable 
risks of the study. 
• 
Obtain written informed consent/assent from each participant or his/her legal representative. 
• 
Make prompt reports of serious adverse events to the Sponsor or the Sponsor’s designee as detailed in 
Section 14.6 of this protocol. 
• 
Cooperate fully with any study-related GCP audit as performed by the Sponsor’s designated quality 
assurance group and agree to comply with the principles of the Declaration of Helsinki. 
• 
Abide by stipulations regarding data disclosure (Section 19.14). 
 
 
 
 
Signature of Investigator 
 
 
Date 
 


REMPEX PHARMACEUTICALS, INC. 
 
Carbavance™ (Meropenem/RPX7009) 
CONFIDENTIAL 
Clinical Study Protocol: REMPEX-506 
24 APR 2015, Version 3.0 
Page 8 of 116 
4 
SYNOPSIS 
Title 
A Phase 3, Multi-Center, Randomized, Open-Label Study of Carbavance 
(Meropenem/RPX7009) Versus Best Available Therapy in Subjects with Selected 
Serious Infections Due to Carbapenem-Resistant Enterobacteriaceae 
Indications 
Subjects with serious infections, specifically 
complicated urinary tract infection (cUTI) or 
acute pyelonephritis (AP), complicated 
intra-abdominal infections (cIAI), 
hospital-acquired bacterial pneumonia 
(HABP), ventilator-associated bacterial 
pneumonia (VABP), and bacteremia, known 
or suspected to be caused by 
carbapenem-resistant Enterobacteriaceae 
(CRE). 
US Investigational New 
Drug # 120040 
EudraCT # 2014-000546-30 
Study Duration 
First subject enrolled: Third quarter 2014 
Last subject enrolled: First quarter 2016 
Number of Global Sites: 
Approximately 50 sites  
Study 
Objectives 
The objectives of this study are: 
• 
To evaluate the safety, tolerability and efficacy of Carbavance™ (meropenem/ 
RPX7009) in treatment of subjects with selected serious infections, suspected 
or known to be due to CRE; and 
• 
To assess the pharmacokinetics (PK) of meropenem and RPX7009 in subjects 
with selected serious infections, suspected or known to be due to CRE. 
Rationale  
 
 
Beta-lactam antimicrobials are considered to be among the most useful classes of 
antimicrobial agents for treatment of bacterial infections. In particular, the 
development of broad-spectrum cephalosporin and carbapenem antimicrobials have 
represented a key advancement in replacing other classes of drugs with toxicities 
and limited spectra of activity against pathogens.  
In the current era of increased resistance to extended spectrum cephalosporins and 
penicillin/beta-lactamase inhibitor combinations, carbapenem antimicrobial agents 
are frequently the antibiotics of “last defense” for the most resistant pathogens in 
serious infections. However, the recent dissemination of serine carbapenemases 
(e.g., Klebsiella pneumoniae carbapenemase [KPC]) in Enterobacteriaceae within 
many United States and global hospitals now poses a considerable threat to 
carbapenem and other members of the beta-lactam class of antimicrobial agents.  
Infections caused by CRE are associated with high mortality rates and have limited 
treatment options. The loss of the carbapenem class of antimicrobial agents for 
treatment of Enterobacteriaceae (the most frequently occurring pathogens in the 
hospital setting), Acinetobacter baumannii, and Pseudomonas aeruginosa 
represents a critical setback in modern patient care. 
As a result of the current lack of an optimal treatment for patients who have 
infections due to a CRE, physicians manage these patients with the limited 
anti-infective options available, including aminoglycosides, polymyxin B, colistin, 
tigecycline, or various combinations of these. There are limited efficacy data 
available for many of these therapies when used to treat serious CRE infections, 
particularly in combination, but with limited or no alternative therapies currently 


REMPEX PHARMACEUTICALS, INC. 
 
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CONFIDENTIAL 
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24 APR 2015, Version 3.0 
Page 9 of 116 
available, such treatments have become the Best Available Therapy (BAT) despite 
the toxicities associated with many of them. 
Meropenem is a broad-spectrum injectable carbapenem antibiotic used to treat a 
wide variety of infections. The spectrum of action includes many gram-positive 
bacteria, gram-negative bacteria, and anaerobic bacteria, and it is approved in many 
countries around the world at doses up to 2 g every 8 hours (q8h). Three-hour 
infusions of meropenem are commonly used to treat organisms with higher 
minimum inhibitory concentrations (MICs), such as Pseudomonas aeruginosa, to 
maximize the time above the MIC. 
RPX7009 is a novel beta-lactamase inhibitor that has inhibitory activity against 
many serine beta-lactamases and was optimized for inhibition of the KPC 
beta-lactamase and the potentiation of carbapenems against Enterobacteriaceae. 
RPX7009 is being developed for use with meropenem to address the challenges of 
treatment of serious infections caused by pathogens increasingly resistant to 
available treatments.  
Carbavance, the combination of meropenem and RPX7009 administered as a fixed 
combination by intravenous (IV) infusion, is being developed to treat serious 
gram-negative infections, such as cUTI, AP, cIAI, HABP, VABP, and bacteremia, 
including those infections caused by bacteria resistant to currently available 
carbapenems. 
Study Design  
 
 
This is a Phase 3, multi-center, randomized, open-label study of Carbavance 
(meropenem/RPX7009) versus BAT in the treatment of subjects with selected 
serious infections, specifically cUTI or AP, cIAI, HABP, VABP, and bacteremia, 
suspected or known to be caused by CRE. 
Approximately 150 subjects will be enrolled in a 2:1 ratio of Carbavance to BAT, 
respectively. 
The Treatment Arms in the study are as follows: 
• 
Treatment Arm A: Subjects (n = 100) will receive Carbavance (meropenem 2 g 
plus RPX7009 2 g) IV q8h, with each dose infused for 3 hours for up to 14 days. 
NOTE: Dose adjustments will be required for subjects with renal insufficiency. 
• 
Treatment Arm B: Subjects (n = 50) will receive BAT with IV antibiotics chosen 
from the following list, either in combination or alone, for up to 14 days: 
carbapenem (meropenem, ertapenem, or imipenem), tigecycline, colistin, 
aminoglycoside (amikacin, tobramycin, or gentamicin), polymyxin B, and 
ceftazidime-avibactam. 
Subjects (or subjects’ legal representatives) providing informed consent, meeting all 
study eligibility criteria including those criteria for their particular site of infection 
(e.g., cUTI or AP, cIAI, HABP, VABP, and bacteremia), and who have either a 
known CRE infection or a suspected CRE infection (based on colonization with a 
KPC-producing Enterobacteriaceae organism [which may be determined through 
rapid diagnostic tests, active surveillance cultures, or other documentation of CRE 
colonization] in the past 90 days, or prior infection due to a CRE pathogen that was 
treated within the past 90 days) will be randomized to receive Carbavance 
(meropenem/RPX7009) or BAT.  


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Any isolated bacterial pathogen will be identified by genus and species. The local 
laboratory will culture each subject sample for pathogen identification, 
quantification, and susceptibility testing. Isolated pathogens collected at the time 
points listed in the Schedule of Procedures and cultured at the local laboratory will 
be sent to the central laboratory for confirmation of identification and testing results.  
Day 1 is defined as the first day of study drug administration (Carbavance 
[meropenem/RPX7009] or BAT). Subsequent study days are defined by the number 
of calendar days thereafter. The planned total duration of IV study drug therapy is 
up to 14 days. A subject assessed as a clinical cure must receive 5 days of study 
drug therapy, and a subject assessed as a clinical failure must receive 3 days of 
study drug therapy. 
End of Treatment (EOT) will be the day on which the final dose of study drug is 
administered (+1 day). The Test of Cure (TOC) visit and Late Follow-up (LFU) visit 
will occur at the time points listed in the Schedule of Procedures. 
An independent Data Safety Monitoring Board (DSMB) will review accumulated 
safety data for this study and Rempex-505 when the total combined enrollment in 
both trials is approximately 25% (250 subjects) and 50% (500 subjects). They will 
also review serious adverse events on an ongoing basis. They will make 
recommendations to the Sponsor based on this safety data. Further details regarding 
the data safety monitoring guidelines will be included in the DSMB Charter, which 
is the governing document of the DSMB. 
In order to ensure unbiased assessment of outcomes between treatment arms 
subjects will not be informed what treatment arm they are assigned. Efforts should 
be made to keep subjects treatment naïve throughout the course of the study. At each 
site a Blinded Investigator (BI) will be assigned to assess each subject’s baseline 
status and Outcome Assessment during the EOT and TOC visits. A blinded 
adjudication committee will also be formed to independently evaluate clinical 
outcome data in cases where the Principal Investigator (PI) and BI’s assessment of 
outcome differ. Further details regarding the blinded adjudication committee will be 
included in a Blinded Adjudication Committee Charter, which is the governing 
document of the committee.  
Number of 
Subjects 
The study will enroll approximately 150 subjects with serious infections, of whom 
a proportion will have CRE infections across the following indications: cUTI or AP, 
cIAI, HABP, VABP, and bacteremia. Hospital acquired bacterial pneumonia and 
VABP will be stratified separately. Subjects will be stratified at randomization based 
on their presenting indication (cUTI/AP, cIAI, HABP, VABP, or bacteremia) and 
by region (North America vs. Europe vs. Asia Pacific vs. Rest of World). 
Enrollment will continue until at least 45 subjects (30 Carbavance [meropenem/ 
RPX7009], 15 BAT) with cUTI or AP are documented to have a CRE organism at 
baseline and until at least 30 subjects with cIAI with a documented CRE organism 
at baseline (20 Carbavance [meropenem/RPX7009], 10 BAT) are enrolled.  Once 
the specified number of subjects are enrolled in the cUTI and/or cIAI indications, 
data from these subjects may be submitted to regulatory agencies in support of a 
marketing application, and the enrollment of additional subjects into the specific 
indication(s) where enrollment was met may be stopped. 


REMPEX PHARMACEUTICALS, INC. 
 
Carbavance™ (Meropenem/RPX7009) 
CONFIDENTIAL 
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24 APR 2015, Version 3.0 
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Inclusion 
Criteria: 
 
Subjects must meet all of the following criteria in order to be eligible for the study: 
1. Willingness to comply with all study activities and procedures and to provide 
signed, written informed consent prior to any study procedures. If a subject is 
unable to provide informed consent due to their medical condition, the subject’s 
legal representative will be provided with study information in order for consent 
to be obtained.  
2. Hospitalized male or female, 18 years of age. 
3. Weight 185 kg. 
4. Have a confirmed diagnosis of a serious infection, specifically cUTI or AP, 
cIAI, HABP, VABP, and bacteremia, requiring administration of IV 
antibacterial therapy (See inclusion number 7 for criteria for all indications). 
5. The following must be satisfied:  
For known CRE infection:  
• 
Have a known CRE infection based on evidence from CRE culture or other 
phenotypic or molecular testing within 72 hours prior to Day 1, alone or as 
a single isolate of a polymicrobial infection; 
• 
Have received no more than 24 hours of an antimicrobial agent to which 
the known CRE is susceptible prior to enrollment,  
OR 
• 
Have documented clinical evidence of failure (i.e., clinical deterioration or 
failure to improve) after at least 48 hours of treatment with an antimicrobial 
agent to which the known CRE is susceptible.   
For suspected CRE infection: 
• 
Have a suspected CRE infection based on evidence from CRE culture 
(KPC-producing, if known) or other phenotypic or molecular testing, alone 
or as a single isolate of a polymicrobial infection, from any source within 
90 days prior to Day 1; 
• 
Have received no more than 24 hours of empiric antimicrobial therapy for 
gram negative organisms prior to enrollment. 
6. Expectation, in the opinion of the Investigator, that the subject’s infection will 
require treatment with IV antibiotics for a minimum of 7 days. 
7. Expectation that subjects with an estimated creatinine clearance <10 ml/min 
(Cockcroft-Gault) will receive hemodialysis at least 2 times per week. 
 


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Carbavance™ (Meropenem/RPX7009) 
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Page 12 of 116 
8. Diagnosis with either cUTI or AP, cIAI, HABP, VABP, and bacteremia as 
defined below:  
Complicated Urinary Tract Infection 
Expectation, in the judgment of the Investigator, that any indwelling urinary 
catheter or instrumentation (including nephrostomy tubes and/or indwelling 
stents) will be removed or replaced (if removal is not clinically acceptable) 
before or as soon as possible, but not longer than 12 hours, after randomization, 
AND: 
Indication 
At least ONE of the 
following: 
AND at least TWO of 
the following signs or 
symptoms: 
AND at least ONE 
of the following: 
cUTI 
• Indwelling urinary catheter; 
• Neurogenic bladder with 
presence or history of urine 
residual volume of 100 mL; 
• Obstructive uropathy (e.g., 
nephrolithiasis, tumor, 
fibrosis) that is expected to 
be medically or surgically 
treated within 48 hours 
post-randomization; 
• Azotemia due to intrinsic 
renal disease; 
• Urinary retention in men due 
to previously diagnosed 
benign prostatic hypertrophy 
• Chills, rigors, or 
fever* (oral or 
tympanic temperature 
38°C [100.4°F] or 
rectal/core temperature 
38.3°C [100.9°F]); 
• Elevated WBC count 
(>10,000/mm3) or left 
shift (>15% immature 
PMNs); 
• Nausea or vomiting; 
• Dysuria, increased 
urinary frequency, or 
urinary urgency; 
• Lower abdominal pain 
or pelvic pain 
 
• Positive LCE on 
urinalysis; 
• WBC count 
10 cells/mm3 in 
unspun urine;  
• WBC count 
10 cells/hpf in 
urine sediment 
cUTI = complicated urinary tract infection; hpf = high-power field; LCE = leukocyte esterase; 
PMN = polymorphonuclear leukocyte; WBC = white blood cell. 
Acute Pyelonephritis 
Expectation, in the judgment of the Investigator, that any indwelling urinary 
catheter or instrumentation (including nephrostomy tubes and/or indwelling 
stents) will be removed or replaced (if removal is not clinically acceptable) 
before or as soon as possible, but not longer than 12 hours, after randomization, 
AND: 
Indication 
Presence of an ascending tract infection including 
at least TWO of the following signs or symptoms: 
AND at least ONE of the 
following: 
AP 
• Chills, rigors, or fever* (oral or tympanic 
temperature 38°C [100.4°F] or rectal/core 
temperature 38.3°C [100.9°F]); 
• Elevated WBC count (>10,000/mm3), or left shift 
(>15% immature PMNs); 
• Nausea or vomiting; 
• Dysuria, increased urinary frequency, or urinary 
urgency; 
• Flank pain;  
• Costo-vertebral angle tenderness on physical 
examination 
• Positive LCE on 
urinalysis; 
• WBC count 
10 cells/mm3 in unspun 
urine;  
• WBC count 10 cells/hpf 
in urine sediment 
AP = acute pyelonephritis; hpf = high-power field; LCE = leukocyte esterase; PMN = polymorphonuclear 
leukocyte; WBC = white blood cell. 


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Complicated Intra-Abdominal Infection (cIAI)  
Patients may be enrolled approximately 24 hours before or 96 hours after the 
surgical procedure when the following conditions are met:  
• 
Expectation, in the judgment of the investigator, that operative 
drainage/debridement/removal (including open laparotomy, percutaneous 
drainage, or laparoscopic surgery) of any intra-abdominal collection or 
other potential source of intra-abdominal infection will be performed; 
• 
Expectation that cultures from the aforementioned procedure (including 
open laparotomy, percutaneous drainage, or laparoscopic surgery) will be 
sent for microbiological evaluation, including gram stain, culture and 
susceptibility testing, and Carbavance susceptibility testing AND:    
 
Indication 
At least ONE of the following either on intra-
operative visualization of infection (e.g. pus 
within the abdominal cavity) OR supportive 
radiographic imaging: 
AND at least ONE of the 
following: 
cIAI 
• Intra-abdominal abscess, including splenic or 
hepatic abscess; 
• Appendicitis or diverticulitis with peritonitis, 
perforation or abscess;  
• Perforation of stomach or intestine, associated 
with peritonitis, abscess or fecal contamination;  
• Cholecystitis or cholangitis with perforation, 
abscess or progression beyond the gallbladder wall 
or biliary tract.   
• Chills, rigors, or fever* 
(oral or tympanic 
temperature 38°C 
[100.4°F] or rectal/core 
temperature 38.3°C; 
• Hypotension, systolic BP 
<90 mmHg;  
• Abdominal pain or 
tenderness; 
• Nausea or vomiting; 
• Abdominal mass on 
clinical examination; 
• Altered mental status.  
BP = blood pressure; cIAI = complicated intra-abdominal infection. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Hospital Acquired Bacterial Pneumonia  
Indication 
All of the following: 
AND signs or 
symptoms evidenced by 
at least TWO of the 
following: 
AND at least ONE of 
the following: 
HABP  
 
• The onset of symptoms 
>48 hours after admission 
or <7 days after discharge 
from an inpatient acute or 
chronic care facility (e.g., 
LTAC, rehabilitation 
center, hospital, or skilled 
nursing home); 
OR  
• Admission from LTAC or 
rehabilitation center, or 
admission from home 
<7 days after discharge 
from an LTAC or 
rehabilitation center; 
• New or evolving infiltrate 
on chest x-ray obtained 
within 48 hours prior to 
randomization  
 
• A new onset of cough 
(or worsening of 
baseline cough); 
• Auscultatory findings 
consistent with 
pneumonia/ pulmonary 
consolidation (e.g., 
rales, dullness on 
percussion, bronchial 
breath sounds, or 
egophony); 
• Dyspnea, tachypnea, 
or respiratory rate 
greater than 25/min;  
• Hypoxemia (O2 
saturation <90% or 
pO2 <60 mmHg while 
breathing room air, or 
worsening of the 
O2sat/FiO2); 
OR The following 
criterion ALONE: 
• New onset need for 
mechanical ventilation 
  
• Fever* (oral or 
tympanic temperature 
38°C [100.4°F] or 
rectal/core 
temperature 38.3°C 
[100.9°F]) OR 
hypothermia 
(rectal/core 
temperature <35°C 
[<95°F]); 
• Elevated total 
peripheral WBC 
count 
(>10,000/mm3);  
• >15% immature 
neutrophils (bands) 
regardless of total 
peripheral WBC 
count;  
• Leukopenia (total 
WBC <4,500/mm3); 
• Procalcitonin 
>0.25 μg/mL 
HABP = hospital-acquired bacterial pneumonia; LTAC = long-term acute care; WBC = white blood cell. 
Ventilator Associated Bacterial Pneumonia  
Indication 
All of the following: 
AND signs or 
symptoms evidenced 
by at least TWO of the 
following: 
AND at least ONE of the 
following: 
VABP 
• The onset of symptoms 
>48 hours after receiving 
ventilatory support via an 
endotracheal (or 
nasotracheal) tube; 
• Require ventilatory 
support; 
• New or evolving infiltrate 
on chest x-ray obtained 
within 48 hours prior to 
randomization and 
>48 hours after 
intubation 
• Auscultatory findings 
consistent with 
pneumonia/ 
pulmonary 
consolidation (e.g., 
rales, dullness on 
percussion, bronchial 
breath sounds, or 
egophony); 
• An acute change in 
the ventilator support 
system to enhance 
oxygenation, as 
determined by a 
worsening oxygen 
saturation/FiO2 ratio; 
• Increased suctioning; 
• Tracheal aspirate 
change to purulence 
• Fever* (oral or 
tympanic temperature 
38°C [100.4°F] or 
rectal/core temperature 
38.3°C [100.9°F]) 
OR hypothermia 
(rectal/core temperature 
<35°C [<95°F]); 
• Elevated total 
peripheral WBC count 
(>10,000/mm3);  
• >15% immature 
neutrophils (bands) 
regardless of total 
peripheral WBC count;  
• Leukopenia (total WBC 
<4,500/mm3);  
• Procalcitonin 
>0.25 μg/mL 
VABP = ventilator-associated bacterial pneumonia; WBC = white blood cell. 


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Bacteremia 
Indication 
All of the following: 
AND at least ONE of the following: 
Bacteremia • Isolation of a CRE from 
at least 1 blood culture  
• Fever* (oral or tympanic temperature 38°C 
[100.4°F] or rectal/core temperature 38.3°C 
[100.9°F]) OR hypothermia (rectal/core 
temperature <35°C [<95°F]); 
• Elevated total peripheral WBC count 
(>10,000/mm3); 
• >15% immature neutrophils (bands) regardless of 
total peripheral WBC count (>10,000/mm3); 
• Leukopenia (total WBC <4,500/mm3); 
• Tachycardia >100 bpm; 
• Tachypnea >20 breaths/min; 
• Hypotension, systolic <90 mmHg 
CRE = carbapenem-resistant Enterobacteriaceae; WBC = white blood cell. 
9. Female subjects of childbearing potential, including those who are less than 
2 years post-menopausal, must agree to, and comply with, using 2 highly 
effective methods of birth control (i.e., condom plus spermicide, combined 
oral contraceptive, implant, injectable, indwelling intrauterine device, 
sexual abstinence, or a vasectomized partner) while participating in this 
study. In addition, all women of childbearing potential must agree to 
continue to use 2 forms of birth control throughout the study and for at least 
30 days after administration of the last dose of study drug. 
* Evidence of fever within 24 hours of the screening visit is acceptable if observed 
and documented by a health care provider. 
Exclusion 
Criteria  
 
Subjects who meet any of the following exclusion criteria will not be enrolled in the 
study: 
1. History of any significant hypersensitivity or severe allergic reaction to any 
beta-lactam antibiotics (e.g., cephalosporins, penicillins, carbapenems, or 
monobactams). 
2. Known or suspected likely infection with New Delhi metallo- (NDM), 
Verona integron-encoded metallo- (VIM), or imipenemase-metallo-beta-
lactamases or oxacillinase- (OXA)-beta-lactamases (i.e., Class B or Class D 
beta-lactamases). 
3. For subjects to be enrolled with the primary indication of cUTI or AP, any 
of the following urologic conditions: 
a. Likely to receive ongoing antibacterial drug prophylaxis after 
treatment of cUTI (e.g., subjects with vesico-ureteral reflux); 
b. Suspected or confirmed prostatitis; 
c. Requirement for bladder irrigation with antibiotics or for antibiotics 
to be administered directly via urinary catheter; 
d. Previous or planned cystectomy or ileal loop surgery; 
e. Uncomplicated urinary tract infection (for example, female subjects 
with urinary frequency, urgency or pain or discomfort without 
systemic symptoms or signs of infection); 
f. Complete, permanent obstruction of the urinary tract; 


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g. Suspected or confirmed perinephric or renal corticomedullary 
abscess; 
h. Polycystic kidney disease; or 
i. 
Any recent history of trauma to the pelvis or urinary tract. 
4. For subjects to be enrolled with the primary indication of cIAI, any of the 
following conditions:  
a. Incomplete drainage of suspected or known intra-abdominal 
source; 
b. Likely to receive ongoing antibacterial drug prophylaxis or chronic 
suppressive therapy after intravenous treatment of cIAI; 
c. Source of infection thought to be related to or involving a 
non-removable 
prosthesis 
(e.g. 
intra-abdominal 
mesh) 
or 
implantable device, line (e.g. peritoneal catheter) or stent (e.g. 
biliary stent);   
d. Uncomplicated intra-abdominal infection, such as simple 
appendicitis, simple cholecystitis or gangrenous cholecystitis 
without rupture; 
e. Patients with infected necrotizing pancreatitis or pancreatic 
abscess;   
f. Patients whose surgery will include staged abdominal repair or 
“open abdomen” technique, or marsupialization (i.e. patients who 
undergo a surgical procedure where fascial closure is performed are 
eligible. The skin incision may be left open for purposes of wound 
management as long as fascial closure is accomplished);   
g. Patients in whom the intra-abdominal process is deemed not likely 
to be infectious in origin (e.g. bowel obstruction, ischemic bowel 
without perforation, traumatic bowel perforation within past 
12 hours, perforated gastroduodenal ulcer within 24 hours); or 
h. Non-intra-abdominal infection (e.g. infection or abscess of the 
abdominal wall without extension into the intra-abdominal cavity). 
5. For subjects to be enrolled with the primary indication of HABP or VABP, 
any of the following conditions:  
a. Diagnosis of ventilator-associated tracheobronchitis; or  
b. Inability to obtain proper respiratory specimens for culture. 
6. For subjects to be enrolled with the indication of bacteremia unrelated to 
cUTI or AP, cIAI, HABP, and VABP, any of the following: 
a. Unverified CRE infection; or 
b. Source of infection thought to be related to or involving a 
non-removable or implantable device or line. 


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7. Evidence of immediately life-threatening disease where in the opinion of 
the Investigator, the subject is unlikely to survive more than 72 hours from 
randomization.  
8. Acute Physiology and Chronic Health Evaluation (APACHE) II score >30. 
An APACHE II score is only required if calculated. 
9. Known or suspected endocarditis, meningitis, or osteomyelitis. 
10. Irremovable or implantable device or line thought to be the potential source 
of infection. 
11. Evidence of significant hepatic, hematological, or immunologic disease or 
dysfunction determined by any of the following: 
a. Known fulminant viral hepatitis; 
b. Patients meeting Hy’s criterion of ALT or AST >3 × upper limit of 
normal (ULN) AND total bilirubin >2 × ULN AND no other 
explanation such as hepatitis or acute liver injury, etc.; 
c. Manifestations of end-stage liver disease, such as ascites or hepatic 
encephalopathy; or 
d. Human immunodeficiency virus with either a CD4 count 
<200 cells/mm3 at the last measurement, or current diagnosis of 
another Acquired Immune Deficiency Syndrome-defining illness. 
12. Women who are pregnant or breastfeeding. 
13. Require the use of inhaled antibiotics. 
14. Participation in any study involving administration of an investigational 
agent or device within 30 days prior to randomization into this study or 
previous participation in the current study. 
15. Previous participation in a study of RPX7009. 
16. Any condition that, in the opinion of the Investigator, would compromise 
the safety of the subject or the quality of the data. 
Microbiology 
Accurate microbiologic results are critical to successfully meet the study objectives. 
All specimens will be sent to the local laboratory for culture and susceptibility 
testing per institutional standards. For all carbapenem-resistant gram-negative 
organisms, the MIC to carbapenems will be captured in the electronic Case Report 
Form (eCRF). Susceptibility to Carbavance as determined by Kirby-Bauer disk 
methodology will be captured at baseline. If the resistance mechanism for each 
carbapenem-resistant organism cultured during the study is known, it should be 
captured in source documents.  
Any isolated bacteria deemed to be contributory to the infectious process will be 
designated a pathogen by the PI and identified by genus and species. The local 
laboratory will culture each sample for organism identification, quantification (when 
applicable), and susceptibility testing per institutional standards. CRE isolates at 
baseline, and all post-baseline isolates cultured at the local laboratory and designated 
as pathogens by the PI will be sent to the central laboratory (Medpace Reference 
Laboratory [MRL]) for confirmation of identification and susceptibility testing 
results. 
All subjects must have a specimen sample from the site of infection (i.e., blood, 
urine, intra-abdominal fluid/tissue, or respiratory secretion) and two sets of blood 
samples from two separate venipuncture sites collected immediately prior to the first 


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dose of study drug (or for cIAI specimens, 96 hours before or 24 hours after the first 
dose of study drug), and submitted to the local microbiology laboratory for culture 
and susceptibility testing. When it is not possible to collect specimens for culture 
immediately prior to the first dose of study drug, cultures that have been obtained 
no more than 72 hours (or 96 hours for cIAI) prior to the first dose of study drug are 
acceptable. The results of this culture will determine whether the subject meets the 
criteria for the Microbiological CRE Modified Intent-to-Treat (mCRE-MITT) 
Population or the Microbiological Modified Intent-to-Treat (m-MITT) Population. 
Kirby-Bauer disks for Carbavance (meropenem/RPX7009) susceptibility testing 
will be provided by the Sponsor for baseline testing. Susceptibility testing for BAT 
and other antimicrobials will be done per each institution’s standard procedures. In 
instances where susceptibility testing indicates resistance to the study drug but the 
subject is clinically improving, the subject should remain on study drug at the 
Investigator’s discretion. 
If the screening sample for culture is taken per standard of care before the subject 
(or the subject’s legal representative) signs informed consent, that isolate may be 
used for baseline and sent to the central laboratory once consent is obtained as long 
as the sample was collected no more than 72 hours before (or 96 hours for cIAI 
specimens) the first dose of study drug. 
Urine Specimens 
For subjects with cUTI or AP, urine samples will be collected by clean-catch 
midstream, from a newly-inserted Foley catheter (no bag specimens allowed), 
bladder needle aspiration, or ureter aspiration. 
CRE isolates at baseline, and all post-baseline isolates cultured at the local 
laboratory and designated as pathogens by the PI will be sent to the central 
laboratory for confirmation of identification and susceptibility testing results.  
The baseline urine cultures must grow at least one defined bacterial pathogen at 
concentration of 105 CFU/mL. Up to 2 isolated pathogens will be allowed per 
baseline urine culture provided they are at concentrations of 105 CFU/mL of urine. 
The baseline urine samples submitted for culture must have a microscopic 
evaluation (e.g., gram stain) and a dipstick analysis performed by the local 
microbiology laboratory.  
For all post-baseline urine cultures, only pathogens at concentrations of 103 
CFU/mL of urine will be sent to the central laboratory.  Up to 2 isolated pathogens 
will be allowed per post-baseline urine culture provided they are at concentrations 
of 103 CFU/mL. 
For both baseline and post-baseline cultures - if a subject grows 3 or more bacterial 
organisms in the urine, the urine culture will be considered contaminated. An 
organism will not be considered a contaminant if the organism also grows in a 
concurrently obtained blood culture.  Isolates from contaminated samples should not 
be sent to the central lab. 
culture.  Isolates from contaminated samples should not be sent to the central lab. 
Intra-abdominal Cultures  
For subjects with cIAI, acceptable specimens should include at least one intra-
abdominal culture obtained during the time of surgical (or percutaneous) 


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intervention. The specimen must be collected within approximately 96 hours before 
or 24 hours after of the first dose of study drug (preferably prior to study drug 
administration). Baseline specimens should be sent for gram stain, pathogen 
identification and susceptibility testing at the local laboratory. Isolates from the 
baseline specimen will also be sent to the central laboratory for confirmatory testing. 
Post-baseline specimens should be collected as clinically indicated and sent to the 
local laboratory for testing. Isolates from all post-baseline specimens should be sent 
to the central laboratory for confirmatory testing. 
To be considered adequate, a specimen should consist of at least 1mL of fluid or 
tissue representative of the material associated with the clinical infection.  
Gram stains will be conducted per institutional standards and gram stain data should 
be captured in source documents. If any intra-abdominal culture is performed 
(including cultures taken on swab), pathogens exhibiting significant growth on 
cultures identified by the site laboratory’s routine procedures should be sent to the 
central lab, even if from a specimen that does not meet the aforementioned adequacy 
criteria.   
Respiratory Tract Specimens 
For subjects with HABP or VABP, acceptable specimens should include at least 
one positive pretreatment sample obtained by Protected Specimen Brush (PSB) with 
bronchial alveolar lavage (BAL) or mini-BAL, non-bronchoscopic-BAL (NBBAL), 
or Protected Endotracheal Catheter obtained prior to randomization and treatment. 
Non-ventilated subjects may have specimens obtained via deep expectoration or 
expectorated/induced sputum.  
All specimens should be sent for gram stain, quantitative culture, pathogen 
identification and susceptibility testing.  
To be adequate, respiratory samples from expectorated or induced sputum should 
show <10 squamous epithelial cells and >25 polymorphonuclear neutrophils per 
100x field. Colony counts 103 CFU/mL are considered the threshold for identifying 
pathologic bacteria from PSB and the CombiCath® NBBAL, 104 CFU/mL for 
bronchoscopic BAL or the BALCath NBBAL, and 106 CFU/mL for endotracheal 
aspirate specimens.  
Gram stains will be conducted per institutional standards, and gram stain data should 
be captured in source documents. Colony counts are not expected to be performed 
on expectorated or induced sputum. If the sputum is cultured, all pathogens 
exhibiting significant growth identified by the site laboratory’s routine procedures 
should be sent to the central lab, even if from a specimen that does not meet the 
specimen adequacy criteria described above. 
Blood and Other Tissue Specimens 
Two sets of samples from 2 separate venipuncture sites are required for blood 
cultures in all study participants. If a blood culture is positive at baseline, daily blood 
cultures will be collected until the first negative blood culture (culture reading at 
24 hours or more).  
Additional blood cultures, including blood cultures taken during fever spikes (oral 
or tympanic temperature 38°C [100.4°F] or rectal/core temperature 38.3°C 
[100.9°F]) may also be collected at the Investigator’s discretion.  


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Isolated pathogens (e.g., considered not to be a contaminant by the PI) from each 
individual positive blood culture will be sent to the central lab. 
If a tissue sample (e.g., kidney biopsy) is collected to determine target pathogen, it 
should be obtained 72 hours prior to first dose of study drug. The isolated pathogen 
should be shipped to the central laboratory for confirmation and susceptibility 
testing. In the event that pre-randomization urine and blood cultures are negative 
and the subject has a positive tissue culture, the isolated pathogen may qualify as a 
defined baseline CRE pathogen.  
Duration of 
Treatment and 
Trial 
Participation 
The duration of study participation for each subject is approximately 29 days 
(~4 weeks), with a maximum duration of study participation of 31 days: 
• 
Screening (and Randomization) Period, 1 day; 
• 
Treatment Period, 7-14 days (final dose day of study drug is EOT); and 
• 
Follow-up Period, 5-16 days (including TOC and LFU visits). 
Investigational 
Product/Dose/ 
Route/Regimen 
Subjects will receive a dosage regimen of Carbavance (meropenem/RPX7009) 
consisting of 2 g meropenem plus 2 g RPX7009 via 3-hour IV infusion q8h. Dose 
adjustments 
are 
permitted 
based 
on 
estimated 
creatinine 
clearance 
(Cockcroft-Gault) for subjects with renal insufficiency. 
Subjects will receive infusions every 8 hours (±2 hours). Infusions that fall outside 
of the q8h dosing (± 2 hours) will be captured as protocol deviations. 
Reference 
Therapy, 
Dose/Route 
Subjects will receive BAT, with IV antibiotics, either alone or in combination, 
chosen from the following: carbapenem (meropenem, ertapenem, or imipenem), 
tigecycline, colistin, aminoglycoside (amikacin, tobramycin, or gentamicin), 
polymyxin B, and ceftazidime-avibactam. Ceftazidime-avibactam may also be used 
as BAT, but may not be given in combination with other BAT agents, with the 
exception of concurrent aminoglycoside therapy for either 72 hours/pending 
susceptibility testing in patients with cIAI, HABP, VABP and bacteremia, similar 
to Carbavance (see Concomitant Antibiotics below). Details for dose and frequency 
of administration of BAT (as well as warnings, precautions, and contraindications) 
can be found in the referenced summaries of product characteristics for the specific 
antibacterials selected by the Investigator as BAT. Investigators will be instructed 
to select only country-approved therapies.  
Concomitant 
Antibiotics 
Subjects with cUTI or AP who are randomized to Carbavance (meropenem/ 
RPX7009) or to BAT, and receive ceftazidime-avibactam should receive 
Carbavance (meropenem/RPX7009) or ceftazidime-avibactam alone, respectively. 
Subjects with cIAI, HABP, VABP, or bacteremia who are randomized to 
Carbavance (meropenem/RPX7009) or to BAT and are treated with 
ceftazidime-avibactam should receive Carbavance (meropenem/RPX7009) or 
ceftazidime-avibactam alone, respectively. However, if the Investigator believes it 
is medically necessary, subjects may receive supportive aminoglycoside therapy in 
conjunction with Carbavance (meropenem/RPX7009) or ceftazidime-avibactam 
until culture information is available or for the first 72 hours, whichever is the 
shorter. Aminoglycoside treatment should be discontinued once the subject’s 
organism is shown to be susceptible to Carbavance (meropenem/RPX7009) or 
ceftazidime-avibactam and the subject is clinically improving. The use of an 
aminoglycoside beyond 72 hours in subjects with a pathogen(s) susceptible to 
Carbavance (meropenem/RPX7009) or ceftazidime-avibactam will be considered a 
treatment failure. 


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Subjects in both treatment arms may receive coverage (e.g., vancomycin or 
linezolid) for gram-positive organisms, as deemed necessary by the Investigator.  
Subjects with cIAI randomized to the BAT treatment arm may receive 
metronidazole. 
Inhaled antibiotics are not permitted.  
Bladder irrigation with antibiotics or antibiotics administered directly via a urinary 
catheter are not permitted.   
Intra-abdominal irrigation with antibiotics or antibiotics administered through a 
peritoneal dialysis catheter or other intra-abdominal catheter are not permitted. 
Analysis 
Populations 
The Intent-to-Treat (ITT) Population will include all subjects screened and 
randomized to study drug (Carbavance [meropenem/RPX7009] or BAT). 
The Modified Intent-to-Treat (MITT) Population will include subjects who meet the 
ITT criteria and receive at least 1 dose of study drug as randomized.   
The Safety Population will include subjects who meet the ITT criteria and receive 
at least one dose of study drug, based on the actual treatment received. 
The PK Population will include subjects who meet the MITT criteria and have at 
least one plasma PK sample drawn. 
The m-MITT Population will include subjects who meet the MITT criteria and have 
a baseline gram negative bacterial pathogen(s). 
The mCRE-MITT Population (i.e., Primary Efficacy Population) will include 
subjects who meet the m-MITT criteria and who have a baseline Enterobacteriaceae 
that is confirmed to be meropenem-resistant.  
The Clinical Evaluable (CE) Population will include subjects who meet the MITT 
criteria, as well as the following criteria:  
• 
Have no key inclusion or exclusion violations;  
• 
Obtain a clinical outcome (cure, improvement, or failure) at EOT and a clinical 
outcome of cure or failure at TOC, unless criteria for failure were met at an 
earlier time point; 
• 
Receive 80% of expected IV doses for the completed treatment duration, miss 
no more than 1 IV dose in the first 48 hours of treatment, and miss no more than 
2 consecutive IV doses overall; and  
• 
Receive 3 days of study drug if classified as a failure on clinical outcome, or 
receive 5 days of study drug if classified as a cure on clinical outcome. 
The Microbiological Evaluable (ME) Population will include subjects who meet the 
m-MITT criteria, as well as the following criteria: 
• 
Have no key inclusion or exclusion violations;  
• 
Obtain a clinical outcome (cure, improvement, or failure) and a microbiological 
outcome (eradication or persistence) at EOT and an overall outcome of cure or 
failure at TOC, unless criteria for failure were met at an earlier time point; 
• 
Receive 80% of expected IV doses for the completed treatment duration, miss 
no more than 1 IV dose in the first 48 hours of treatment, and miss no more than 
2 consecutive IV doses overall; and  


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• 
Receive 3 days of study drug if classified as a failure on overall outcome, or 
receive 5 days of study drug if classified as a cure on overall outcome. 
The CRE Microbiological Evaluable (CRE-ME) Population will include subjects 
who meet the ME criteria and who have a baseline Enterobacteriaceae that is 
confirmed to be meropenem-resistant. 
Efficacy 
Assessments 
 
Efficacy Assessments for cUTI or AP 
Primary Endpoint 
The primary endpoint for cUTI or AP is defined differently by the EMA and 
FDA. The primary endpoint for the EMA is proportion of subjects in the 
mCRE-MITT Population that demonstrate microbiological eradication (See 
table below). The primary endpoint for the FDA is the proportion of subjects in 
the mCRE-MITT Population who demonstrate a response of overall success at 
the TOC visit (See table below). 
To meet the primary endpoint for EMA and FDA, a subject’s gram-negative 
antimicrobial therapy to treat the baseline infection cannot be altered (other than 
dose adjustment or modification of BAT based on susceptibility of baseline 
pathogen within the first 72 hours after first dose of study drug) after 
randomization due to concerns of microbiological failure, clinical failure, or 
tolerability AND the following at TOC: 
Parameter 
Analysis for EMA 
Analysis for FDA 
Outcome measure 
Microbiological 
eradicationa) 
Overall Success (Clinical 
cureb) and microbiological 
eradicationa)) 
Efficacy time point(s) 
TOCc) 
TOCc) 
a) 
Microbiological eradication is defined as the demonstration that the bacterial pathogen(s) found 
at baseline is reduced to <103 CFU/mL of urine for EMA and <104 CFU/mL of urine for FDA. 
b) 
Clinical cure is defined as complete resolution or significant improvement of the baseline signs 
and symptoms of cUTI or AP such that no further surgical intervention or antimicrobial therapy 
is warranted. 
c) 
The TOC visit occurs 7 days (±2 days) post-EOT (Day 12 to Day 23). 
CFU = colony-forming unit; EMA = European Medicines Agency; EOT = End of Treatment; 
FDA = Food and Drug Administration; TOC = Test of Cure. 


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Secondary Endpoints 
• 
The all-cause mortality rate in the mCRE-MITT and m-MITT Populations 
at Day 28; 
• 
Proportion of subjects in the m-MITT and ME Populations who demonstrate 
a response of overall success at the TOC visit; 
• 
Proportion of subjects in the mCRE-MITT, m-MITT, CE, CRE-ME, and 
ME Populations with a clinical outcome of cure at Day 3, EOT, TOC, and 
LFU;  
• 
Proportion of subjects in the mCRE-MITT, m-MITT, CRE-ME, and ME 
Populations with a microbiological outcome of eradication at Day 3, EOT, 
TOC, and LFU; 
• 
 Relapse/recurrence rates of baseline cUTI or AP at the LFU visit; and 
• 
Per-pathogen outcome in the mCRE-MITT, m-MITT, CRE-ME, and ME 
Populations at Day 3, EOT, TOC, and LFU. 
Efficacy Assessments for cIAI 
Primary Endpoint 
The primary endpoint for cIAI for both the EMA and the FDA is the proportion 
of patients with a clinical outcome of cure in the mCRE-MITT population at the 
test of cure (TOC) visit. To meet the primary endpoint, subjects’ gram-negative 
antimicrobial therapy to treat the baseline infection cannot be altered (other than 
dose adjustment or modification of BAT based on susceptibility of baseline 
pathogen within the first 72 hours after first dose of study drug) after 
randomization due to concerns of microbiological failure, clinical failure, or 
tolerability. In addition, subjects cannot require any unplanned surgical or 
radiologic intervention after randomization until TOC due to concerns of 
microbiologic failure or clinical failure.    
 
Secondary Endpoints 
• 
The all-cause mortality rate in the mCRE-MITT and m-MITT Populations 
at Day 28; 
• 
Proportion of subjects in the m-MITT and ME Populations who demonstrate 
a response of overall success at the TOC visit; 
• 
Proportion of subjects in the mCRE-MITT, m-MITT, CE, CRE-ME, and 
ME Populations with a clinical outcome of cure at Day 3, EOT, TOC, and 
LFU;  
• 
Proportion of subjects in the mCRE-MITT, m-MITT, CE, CRE-ME, and 
ME Populations with a clinical outcome of cure at TOC, where the use of 
an aminoglycoside beyond 72 hours in subjects with a pathogen susceptible 
to Carbavance (meropenem/RPX7009) is assigned to failure;  
• 
Relapse/recurrence rates of baseline cIAI at the LFU visit; and  


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• 
Per-pathogen outcome in the mCRE-MITT, m-MITT, CRE-ME, and ME 
Populations at Day 3, EOT, TOC, and LFU. 
Efficacy Assessments for HABP and VABP 
Primary Endpoint 
The primary endpoint for HABP and VABP is the all-cause mortality rate in the 
mCRE-MITT Population at Day 28 for all subjects with HABP and VABP, 
combined with all subjects with bacteremia (not related to cUTI/AP or 
HABP/VABP). 
Secondary Endpoints 
• 
The all-cause mortality rate in the mCRE-MITT and m-MITT Populations 
at Day 28;  
• 
The proportion of subjects in the mCRE-MITT Population who demonstrate 
a clinical outcome of cure at the TOC visit. 
A clinical outcome of cure is defined as: 
o A subject whose gram-negative antimicrobial therapy to treat the 
baseline infection is not altered (other than dose adjustment or 
modification of BAT based on susceptibility of baseline pathogen 
within the first 72 hours after first dose of study drug) after 
randomization due to concerns of microbiological failure, clinical 
failure, or tolerability AND  
o Complete resolution or significant improvement of the baseline signs 
and symptoms of HABP and VABP such that no further surgical 
intervention or antimicrobial therapy is warranted; 
• 
Proportion of subjects in the mCRE-MITT, m-MITT, CE, CRE-ME, and 
ME Populations with a clinical outcome of cure at Day 3, EOT, TOC, and 
LFU; 
• 
Proportion of subjects in the mCRE-MITT, m-MITT, CE, CRE-ME, and 
ME Populations with a clinical outcome of cure at TOC, where the use of 
an aminoglycoside beyond 72 hours in subjects with a pathogen susceptible 
to Carbavance (meropenem/RPX7009) is assigned to failure; 
• 
Per-pathogen outcome in the mCRE-MITT, m-MITT, CRE-ME, and ME 
Populations at Day 3, EOT, TOC, and LFU; 
• 
Relapse/recurrence rates of baseline bacterial pneumonia at the LFU visit; 
• 
Total ventilator days measured from time of randomization; 
• 
Change in the partial pressure arterial oxygen to fraction of inspired oxygen 
(PaO2:FiO2) ratio from baseline to Day 3, Day 7, and EOT; and 
• 
Time (days) to extubation in subjects who are on the ventilator at baseline 
(i.e., Day 1). 
 
 
 
 


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Efficacy Assessments for Bacteremia 
Primary Endpoint 
The primary endpoint for bacteremia is the all-cause mortality rate in the 
mCRE-MITT Population at Day 28 for all subjects with HABP and VABP, 
combined with all subjects with bacteremia (not related to cUTI/AP or 
HABP/VABP). 
Secondary Endpoints 
• 
The all-cause mortality rate in the mCRE-MITT and m-MITT Populations 
at Day 28;  
• 
The proportion of subjects in the mCRE-MITT Population who 
demonstrate a response of overall success at the TOC visit. 
For subjects whose gram-negative antimicrobial therapy to treat the baseline 
infection is not altered (other than dose adjustment or modification of BAT 
based on susceptibility of baseline pathogen within the first 72 hours after 
first dose of study drug) after randomization due to concerns of 
microbiological failure, clinical failure, or tolerability, a response of success 
is defined by clearance of bacteremia (microbiological eradication) and a 
clinical assessment of cure.  
Clearance of bacteremia (microbiological eradication) is defined as the 
demonstration that bacterial pathogens) found at baseline is absent with 
repeat culture. 
Clinical assessment of cure is defined as complete resolution or significant 
improvement of the baseline signs and symptoms of bacteremia, such that 
no further surgical intervention or antimicrobial therapy is warranted; 
• 
Proportion of subjects in the m-MITT, CRE-ME, and ME Populations 
who demonstrate a response of overall success at the TOC visit;  
• 
Proportion of subjects in the mCRE-MITT, m-MITT, CE, CRE-ME, and 
ME Populations with a clinical outcome of cure at Day 3, EOT, TOC, and 
LFU; 
• 
Proportion of subjects in the mCRE-MITT, m-MITT, CE, CRE-ME, and 
ME Populations with a clinical outcome of cure at TOC, where the use of 
an aminoglycoside beyond 72 hours in subjects with a pathogen 
susceptible to Carbavance (meropenem/RPX7009) is assigned to failure; 
• 
Proportion of subjects in the mCRE-MITT, m-MITT, CRE-ME, and ME 
Populations with a microbiological outcome of eradication at Day 3, EOT, 
TOC, and LFU;  
• 
Relapse/recurrence rates of baseline bacteremia at the LFU visit;  
• 
Per-pathogen outcome in the mCRE-MITT, m-MITT, CRE-ME, and ME 
Populations at Day 3, EOT, TOC, and LFU; and 
• 
Time to bacterial clearance in mCRE-MITT, m-MITT, CRE-ME, and ME 
Populations. 


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Exploratory analyses will be conducted based on subject evaluability and may 
include clinical and microbiological responses in various analysis populations at 
EOT, TOC, and LFU. 
Safety 
Assessments 
The following will be assessed to determine the safety of Carbavance 
(meropenem/RPX7009): 
• 
Assessment of adverse events from Day 1 through LFU visit (or, if applicable, 
early termination visit); and 
• 
Changes from baseline in physical examination findings, electrocardiograms 
(ECGs), safety laboratory test results, and vital signs will be evaluated. 
Data Analysis 
 
Sample Size Justification 
Due to the infeasibility of recruiting a large number of subjects infected with CRE 
pathogens, no formal power calculations have been performed for this study. The 
sample size is based on practical considerations.  
Criteria for Outcome Measures 
Study populations are as follows: ITT, MITT, Safety Population, m-MITT, 
mCRE-MITT (i.e., Primary Efficacy Population), CE, ME, and CRE-ME. Please 
refer to the Statistical Analysis Populations diagram provided in Appendix 1. 
Efficacy 
The efficacy analyses will be descriptive summaries of the proportion of subjects in 
the mCRE-MITT Population at the TOC visit with a response of success defined 
according to primary indication. A descriptive summary of all-cause mortality for 
subjects with HABP, VABP, and bacteremia will be provided. Two-sided, exact 
binomial 95% confidence intervals for the true proportion of responses of success 
for the primary efficacy endpoint will be reported. 
Exploratory analyses will be conducted based on subject evaluability and may 
include clinical and microbiological responses in various analysis populations at 
EOT, TOC, and LFU. 
Pharmacokinetics 
Pharmacokinetic characterization, evaluation of plasma PK, and exposures of 
meropenem and RPX7009 in treated subjects will be performed. Analysis of the PK 
data will be described in a separate Statistical Analysis Plan. 
A pharmacodynamic analysis will be conducted to link meropenem and RPX7009 
exposures in each subject with clinical and microbiological outcomes. 
Safety 
All subjects who receive at least 1 dose of study drug (i.e., the MITT Population) 
will be included in the safety analyses and analyzed based on actual treatment 
received. Adverse events will be collected throughout the study duration. 
Treatment-emergent adverse events (TEAEs) will be tabulated by National Cancer 
Institute Common Terminology Criteria for Adverse Events Grade. The number and 
percentage of subjects in each treatment group reporting at least 1 occurrence of a 
TEAE for each unique System Organ Class and Preferred Term will be tabulated. 
Treatment-emergent adverse events will also be tabulated by severity and by the 
relationship to study drug in treatment groups as assessed by the Investigator. The 
number and percentage of subjects in each treatment group reporting at least 
1 occurrence of a serious adverse event will be tabulated. The number and 
percentage of subjects (in each treatment group) prematurely discontinuing study 


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drug treatment due to a TEAE will be tabulated by System Organ Class and 
Preferred Term.  
Safety laboratory data will be presented by change from baseline. The number and 
percentage of subjects with laboratory, vital sign, ECG, or physical examination 
abnormalities at baseline, subsequent visits, or early termination from the study will 
be tabulated by treatment group. The results of all laboratory test results, physical 
examination findings, ECGs, and vital signs will be presented in data listings. 


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Table 1. 
Schedule of Procedures 
 
Screening 
Treatment 
Follow-Up 
 
Early 
Terminatione 
Day 
 
Assessment/Procedure 
-1 or 1a 
1a 
2 
3 
4 
5 
6  
7 
8-14 
 
EOTb 
(+1 day) 
 TOCc  
EOT + 7 
(±2) days 
LFUd  
EOT + 14 
(±2) days 
Pre 
Dose 
Post 
Dose 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographicsf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and weightg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical examinationg 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Limited physical examinationg 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Chest x-ray, MRI, or CT scanp 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Assessment of signs & symptoms 
(Unblinded)h 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of signs & symptoms (Blinded)q 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
Assessment of clinical outcome (Unblinded) 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
Assessment of clinical outcome (Blinded)q 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Vital signsi 
X 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
Randomization to treatment arm 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testj 
X 
X 
 
 
 
 
 
 
 
 
Xj 
 
 
Xj 
Screening laboratoriesk (Local laboratory) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyl (Central laboratory) 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
Serum chemistryl (Central laboratory) 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
Urinalysisl (Central laboratory) 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
Pharmacokinetic samplingm 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
12-lead electrocardiogram 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Blood culturen 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Infection-site specific sample for cultureo 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
Study drug administration  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Assessment of adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Footnotes appear on the following page.  
 
 


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a. Screening/baseline procedures may be performed up to 24 hours prior to the first dose of study drug. All screening procedures must be completed PRIOR to randomization and the first 
dose of study drug (Day 1). The date of the first dose of study drug will be considered Day 1, and subsequent study days are defined by calendar days thereafter. 
b. All subjects will be assessed on their last day of treatment (any time from Day 7 to Day 14). The EOT visit activities should occur within 24 hours of last dose of study drug. If EOT is on 
Day 7, visit activities will be combined. If a subject’s treatment is changed after 72-hours post-randomization, EOT procedures will be performed and the subject will complete further 
visits as planned. 
c. The TOC visit will occur 7 days (±2 days) after EOT, between Day 12 and Day 23. Any subject receiving treatment for less than 7 days should have a TOC visit on Day 12 (+2 days). 
d. The LFU visit will occur 14 days (±2 days) after EOT, between Day 19 to Day 30. The LFU visit should be performed in-house (with limited physical examination) if at all possible. If 
not possible, a phone call to assess the subject’s wellbeing may be substituted. Any subject receiving treatment for less than 7 days should receive an LFU visit on Day 19 (+2 days). For 
outpatient subjects with an LFU visit occurring before Day 28, a phone call to assess survival will be made on Day 28.  
e. Subjects are expected to complete all study visits. In circumstances where a subject discontinues the study early, early termination visit procedures are required. 
f. Demographic data will be collected, including name, sex, age, race, weight, and alcohol use. 
g. Height will be taken at screening only. A limited, symptom-based, physical examination will be performed at indicated visits. If a subject does not display symptoms, no limited physical 
examination needs to be performed. 
h. Assessment of signs and symptoms will include assessments to classify as new onset, continuing (increased, decreased, no change), or resolved (returned to pre-infection state) 
indication-based symptoms as outlined in the protocol.  
i. Vital signs include blood pressure, heart rate, respiratory rate, and temperature. Vital signs should be captured at approximately the same time as the Signs and Symptoms assessment.  
j. A urine and serum pregnancy test will be performed before the first dose of study drug in women of childbearing potential, however, only urine results are required to initiate treatment. 
A urine and serum pregnancy test will be performed as part of EOT/early termination procedures. 
k. Screening laboratories will be processed/analyzed by the local laboratory within 48 hours of randomization and include: AST, ALT, total bilirubin, creatinine, WBC count with 
differentials, platelet count, and LCE in urine. 
l. Laboratory samples will be collected, processed, and sent to the central laboratory for analysis. Hematology includes complete blood count (with red blood cell count, total WBC count 
with differential counts, platelet count, hemoglobin, and hematocrit). Serum chemistry includes creatinine, estimated creatinine clearance, blood urea nitrogen, AST, ALT, alkaline 
phosphatase, total bilirubin, uric acid, lipase, amylase, albumin, total protein, glucose, sodium, potassium, chloride, carbon dioxide, calcium, and phosphorus. Urinalysis includes dipstick 
analysis of protein, glucose, ketones, bilirubin, blood, nitrites, LCE, and urobilinogen; microscopic evaluation for red blood cells, WBCs, bacteria, and casts; specific gravity; and pH. 
m. For subjects randomized to Carbavance (meropenem/RPX7009) only: Day 1 plasma PK samples will be collected within 30 minutes and 2 to 3 hours after the end of the first infusion. 
Day 3 and Day 5 plasma PK samples will be collected within 30 minutes after the end of one of that day’s infusions. 
n. Blood cultures are required from all study participants at baseline. All subjects with bacteremia will have daily blood cultures collected until the first negative blood culture (culture 
reading at 24 hours or more). Subsequent blood cultures may be collected at the Investigator’s discretion, but are not required. Isolates from each positive culture will be sent to the 
central laboratory.  
o. An adequate and appropriate infection site-specific specimen based upon diagnosis (e.g., cUTI or AP, cIAI, HABP, or VABP) should be obtained immediately prior to the first dose of 
study drug (or for cIAI, 96 hours before or 24 hours after the first dose of study drug) and submitted to the local microbiology laboratory for culture and susceptibility testing. If the 
screening sample for culture is taken per standard of care before the subject or the subject’s legal representative signs informed consent, that isolate may be used for baseline and sent to 
the central laboratory once consent is obtained as long as the sample was collected within 72 hours (96 hours for cIAI) of the first dose of study drug. Additional samples for culture 
should also be collected at the specified time points. If at any point in the study a subject fails while on therapy, an adequate and appropriate specimen should be obtained prior to the 
initiation of a new treatment.  When bacteremia is a subject’s primary index infection, daily blood cultures will be collected until the first negative blood culture (culture reading at 
24 hours or more). When cIAI is the subject’s baseline infection, post-baseline samples should be collected as clinically indicated. 
p. A chest x-ray, MRI, or CT scan done within 48 hours of enrollment is acceptable. 
q.  The Blinded Investigator will be responsible for establishing a baseline level of health and performing outcome assessments independent of the unblinded staff per the Blinded 
Adjudication Charter. 
 
ALT = alanine aminotransferase; AP = acute pyelonephritis; AST = aspartate aminotransferase; CT = computed tomography; cUTI = complicated urinary tract infection; cIAI = complicated 
intra-abdominal infection; EOT = End of Treatment; HABP = hospital-acquired bacterial pneumonia; LCE = leukocyte esterase; LFU = Late Follow-up; MRI = magnetic resonance imaging; 
PK = pharmacokinetic; TOC = Test of Cure; VABP = ventilator-associated bacterial pneumonia; WBC = white blood cell. 


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5 
TABLE OF CONTENTS 
1 
PROTOCOL REVISION HISTORY ....................................................................................... 2 
2 
SPONSOR—SIGNATURE PAGE......................................................................................... 3 
3 
ADDITIONAL KEY CONTACTS FOR THE STUDY ............................................................ 4 
INVESTIGATOR’S PROTOCOL AGREEMENT AND SIGNATURE PAGE ................................ 7 
4 
SYNOPSIS ............................................................................................................................. 8 
5 
TABLE OF CONTENTS ...................................................................................................... 30 
6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 36 
7 
INTRODUCTION ................................................................................................................. 39 
7.1 
Overview of the Current Treatment of Infections due to CRE ................................... 39 
7.2 
Carbavance (Meropenem/RPX7009) ......................................................................... 42 
7.3 
Microbiology ................................................................................................................ 43 
7.3.1 
Susceptibility Testing ............................................................................................ 43 
7.4 
Nonclinical Pharmacology and Toxicology ................................................................. 43 
7.4.1 
Mechanism of Action............................................................................................. 43 
7.4.2 
Metabolism and Excretion .................................................................................... 43 
7.5 
Overview of Clinical Pharmacology ............................................................................ 43 
7.5.1 
Rempex 402 and Rempex 501 – Single and Multiple-Ascending Dose 
Studies in Healthy Volunteers .............................................................................. 43 
7.5.2 
Rempex 503 – Randomized, Open-label Study of the Pulmonary 
Pharmacokinetics of Meropenem and RPX7009 (Carbavance) in Healthy 
Volunteers ............................................................................................................. 46 
7.5.3 
Rempex 504- A Phase 1, Open-Label, Single-dose Study to Determine the 
Safety and Pharmacokinetics of Carbavance in Subjects With Renal 
Insufficiency (Including Subjects on Standard Hemodialysis) ............................. 47 
7.6 
Justification of Carbavance Dose Selection for Registration Clinical Program ......... 48 
7.7 
Overview of Clinical Safety ......................................................................................... 48 
7.7.1 
Rempex 402 and Rempex 501 – Single and Multiple-Ascending Dose 
Studies in Healthy Volunteers .............................................................................. 48 
7.7.2 
Rempex 503 – Randomized, Open-label Study of the Pulmonary 
Pharmacokinetics of Meropenem and RPX7009 (Carbavance) in Healthy 
Volunteers ............................................................................................................. 49 
7.7.3 
Rempex 504 – Open-label Study of the Safety and PK of a Single Dose of 
Meropenem and RPX7009 (Carbavance) in Volunteers with Varying 
Degrees of Renal Insufficiency or Normal Renal Function, and in Patients 
with Hemodialysis ................................................................................................. 50 
7.8 
Benefits and Risks Conclusions ................................................................................. 51 
8 
STUDY OBJECTIVES ......................................................................................................... 52 


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9 
OVERALL STUDY DESIGN ............................................................................................... 53 
9.1 
Study Design ............................................................................................................... 53 
9.1.1 
Blinding ................................................................................................................. 54 
9.1.1.1 
Subject Treatment Bias .................................................................................. 54 
9.1.1.2 
Blinded Investigator (BI) ................................................................................. 54 
9.2 
Independent Monitoring Committees ......................................................................... 55 
9.2.1 
Data Safety Monitoring Board .............................................................................. 55 
9.2.2 
Blinded Adjudication Committee........................................................................... 55 
9.3 
Rationale for Study Design ......................................................................................... 55 
10 
SELECTION OF STUDY POPULATION ............................................................................ 56 
10.1 
Inclusion Criteria ......................................................................................................... 56 
10.2 
Exclusion Criteria ........................................................................................................ 60 
10.3 
Prior and Concomitant Treatment .............................................................................. 62 
10.3.1 
Permitted Non-antibacterial Treatment ................................................................ 62 
10.3.2 
Permitted Antibacterial Treatments ...................................................................... 62 
10.3.3 
Permitted Anti-infective Adjunctive Therapies and Procedures ........................... 63 
10.3.4 
Concomitant Medication Precautions and Exclusions ......................................... 63 
10.4 
Randomization and Treatment Group Assignment .................................................... 63 
10.5 
Subject Numbering ..................................................................................................... 64 
11 
STUDY DRUGS ................................................................................................................... 65 
11.1 
Description of Carbavance (Meropenem/RPX7009) .................................................. 65 
11.1.1 
Administration of Carbavance (Meropenem/RPX7009) ....................................... 65 
11.1.2 
Dosing in Subjects with Renal Insufficiency ......................................................... 66 
11.2 
Description of Best Available Therapy ....................................................................... 66 
11.3 
Carbavance (Meropenem/RPX7009) Labeling and Packaging ................................. 67 
11.4 
Study Drug Storage Conditions .................................................................................. 67 
11.5 
Receipt of Supplies ..................................................................................................... 67 
11.6 
Study Drug Accountability........................................................................................... 67 
11.7 
Carbavance (Meropenem/RPX7009) Handling and Return ...................................... 67 
12 
STUDY ASSESSMENTS AND PROCEDURES................................................................. 68 
12.1 
Screening (Day -1 or Day 1 Pre-randomization) ........................................................ 68 
12.2 
Treatment Period (Day 1 up to Day 14) ..................................................................... 69 
12.2.1 
Day 1 Pre-Dose .................................................................................................... 69 
12.2.2 
Study Day 1 Post-Dose ........................................................................................ 70 
12.2.3 
Day 3 ..................................................................................................................... 70 
12.2.4 
Day 5 ..................................................................................................................... 71 


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12.2.5 
Day 7 ..................................................................................................................... 71 
12.2.6 
End of Treatment (EOT) ....................................................................................... 71 
12.3 
Follow-up Period ......................................................................................................... 72 
12.3.1 
Test of Cure (TOC) Visit (7 days [±2 days] post-EOT) ........................................ 72 
12.3.2 
Late Follow-Up (LFU) Visit (14 days [±2 days] post-EOT) ................................... 73 
12.3.3 
Early Termination .................................................................................................. 73 
12.4 
Study Interventions/Procedures ................................................................................. 74 
12.4.1 
Informed Consent ................................................................................................. 74 
12.4.2 
Medical History ..................................................................................................... 74 
12.4.3 
Prior and Concomitant Medications ..................................................................... 74 
12.4.4 
Physical Examination ............................................................................................ 75 
12.4.5 
Vital Signs ............................................................................................................. 75 
12.4.6 
Assessment of Signs and Symptoms ................................................................... 75 
12.4.7 
12-Lead ECG ........................................................................................................ 76 
12.4.8 
Chest X-Ray/Radiology ........................................................................................ 77 
12.4.9 
Clinical Laboratory Assessments ......................................................................... 77 
12.4.10 Pharmacokinetic Sampling ................................................................................... 77 
12.4.11 Hospitalization Assessments ................................................................................ 78 
12.4.12 Mechanical Ventilator Assessments ..................................................................... 78 
12.4.13 Infection Source Control ....................................................................................... 78 
12.4.14 Microbiology Assessments ................................................................................... 78 
12.4.14.1 Urine Specimens ............................................................................................. 79 
12.4.14.2 Intra-abdominal Specimens ............................................................................ 80 
12.4.14.3 Respiratory Tract Specimens ......................................................................... 80 
12.4.14.4 Blood and Other Tissue Specimens ............................................................... 81 
13 
SUBJECT AND STUDY DISCONTINUATION ................................................................... 82 
13.1 
Screening Failures ...................................................................................................... 82 
13.2 
Withdrawal from Study Drug ....................................................................................... 82 
13.3 
Withdrawal from Study ................................................................................................ 83 
13.4 
Study Site Discontinuation .......................................................................................... 83 
14 
SAFETY ASSESSMENTS .................................................................................................. 84 
14.1 
Adverse Events ........................................................................................................... 84 
14.2 
Adverse Drug Reaction ............................................................................................... 85 
14.3 
Unexpected Adverse Drug Reaction .......................................................................... 85 
14.4 
Assessment and Reporting of Adverse Events by the Investigator ........................... 85 


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14.5 
Serious Adverse Events ............................................................................................. 87 
14.6 
Serious Adverse Event Reporting – Procedures for Investigators ............................ 87 
14.7 
Pregnancy Reporting .................................................................................................. 88 
14.8 
Expedited Reporting ................................................................................................... 89 
15 
EFFICACY EVALUATION .................................................................................................. 90 
15.1 
Efficacy Assessments ................................................................................................. 90 
15.1.1 
Exploratory Assessments ..................................................................................... 93 
15.1.2 
Clinical Outcome ................................................................................................... 93 
15.1.3 
Microbiologic Outcome ......................................................................................... 94 
15.1.4 
Overall Response ................................................................................................. 95 
16 
PHARMACOKINETIC ASSESSMENTS............................................................................. 97 
17 
DATA MANAGEMENT ........................................................................................................ 98 
18 
STATISTICAL METHODS AND DATA ANALYSIS ........................................................... 99 
18.1 
Analysis Populations ................................................................................................... 99 
18.2 
Disposition, Demographics, Baseline Characteristics, and Exposure ..................... 100 
18.3 
Efficacy Analysis ....................................................................................................... 100 
18.4 
Safety Analysis ......................................................................................................... 100 
18.5 
Sample Size Justification .......................................................................................... 101 
19 
REGULATORY AND ADMINISTRATIVE ASPECTS ...................................................... 102 
19.1 
Compliance with Regulatory Requirements ............................................................. 102 
19.2 
Institutional Review Board ........................................................................................ 102 
19.3 
Informed Consent ..................................................................................................... 102 
19.4 
Confidentiality............................................................................................................ 102 
19.5 
Compensation, Insurance and Indemnity ................................................................. 103 
19.6 
Protocol Amendment ................................................................................................ 103 
19.7 
Case Report Forms: Electronic ................................................................................ 103 
19.8 
Source Document Maintenance ............................................................................... 103 
19.9 
Study Monitoring Requirements ............................................................................... 103 
19.10 
Study File Management ............................................................................................ 104 
19.11 
Study Completion ...................................................................................................... 104 
19.12 
Audits ........................................................................................................................ 104 
19.13 
Retention of Records ................................................................................................ 104 
19.14 
Disclosure of Data ..................................................................................................... 105 
19.15 
Financial Disclosure .................................................................................................. 105 
19.16 
Publication Policy ...................................................................................................... 105 
20 
REFERENCES .................................................................................................................. 106 


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APPENDIX 1: 
 STATISTICAL ANALYSIS POPULATIONS ............................................... 108 
APPENDIX 2: 
 STUDY SCHEMA ........................................................................................ 109 
APPENDIX 3: 
 COMMON TOXICITY CRITERIA TABLE ................................................... 110 
APPENDIX 4: 
 A PHASE 1, OPEN-LABEL, SINGLE-DOSE STUDY TO DETERMINE 
THE SAFETY AND PHARMACOKINETICS OF CARBAVANCE IN SUBJECTS 
WITH RENAL INSUFFICIENCY (INCLUDING SUBJECTS ON STANDARD 
HEMODIALYSIS) .............................................................................................................. 111 
 


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List of In-Text Tables 
Table 1. 
Schedule of Procedures ....................................................................................... 28 
Table 2. 
Patient Demographics in Study 506NH ................................................................ 41 
Table 3. 
Outcomes of CRE Infections in Study 506NH by Infection Type and Overall ..... 42 
Table 4. 
Comparison 
Across 
Clinical 
Pharmacology 
Studies 
of 
RPX7009 
Pharmacokinetic Parameters (Mean ±Standard Deviation) Following Single- 
and Multiple-Dose Administration of RPX7009 2 g Alone and in Combination 
with Meropenem (Preliminary Data) ..................................................................... 45 
Table 5. 
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 Study Rempex-501 ......................................................................... 46 
Table 6. 
Reduced Renal Function Dose Adjustment Table ............................................... 47 
Table 7. 
Reduced Renal Function Dose Adjustment Table ............................................... 66 
Table 8. 
Signs and Symptoms for Presenting Indications ................................................. 76 
Table 9. 
Primary Endpoint Definitions By Regulatory Agency – cUTI and AP .................. 90 
Table 10. 
Criteria for Clinical Outcome ................................................................................. 94 
Table 11. 
Criteria for Microbiologic Outcome for cUTI or AP ............................................... 95 
Table 12. 
Criteria for Microbiologic Outcome for Bacteremia .............................................. 95 
Table 13. 
Overall Response at Test of Cure (TOC) Visit ..................................................... 96 
 
 


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6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ALT 
Alanine aminotransferase 
AM 
Alveolar macrophage 
AP 
Acute pyelonephritis 
APACHE  
Acute Physiology and Chronic Health Evaluation  
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
BAL 
Bronchial alveolar lavage 
BAT 
Best Available Therapy 
BI 
Blinded Investigator 
CE 
Clinical Evaluable 
CFR 
Code of Federal Regulations 
CFU 
Colony-forming unit 
CI 
Confidence interval 
cIAI 
Complicated intra-abdominal infection 
Cmax 
Maximum plasma concentration 
CRE 
Carbapenem-resistant Enterobacteriaceae 
CRE-ME 
Carbapenem-resistant Enterobacteriaceae Microbiological Evaluable  
CT 
Computed tomography 
cUTI 
Complicated urinary tract infection 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ELF 
Epithelial lining fluid 
EMA 
European Medicines Agency 
EOT 
End of Treatment 
ESRD 
End stage renal disease 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practices 
HABP 
Hospital-acquired bacterial pneumonia 


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Abbreviation 
Definition 
HD 
Hemodialysis 
hpf 
High-powered field 
ICH 
International Conference on Harmonization 
ICU 
Intensive care unit 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board  
ITT 
Intent-to-Treat 
IV 
Intravenous 
IWRS 
Interactive Web Response System  
KPC 
Klebsiella pneumoniae carbapenemase 
LCE 
Leukocyte esterase 
LFU 
Late Follow-up 
LTAC 
Long-term acute care 
mCRE-MITT 
Microbiological Carbapenem-resistant Enterobacteriaceae Modified Intent-to-Treat 
ME 
Microbiological Evaluable  
MIC 
Minimum inhibitory concentration 
MITT 
Modified Intent-to-Treat  
m-MITT 
Microbiological Modified Intent-to-Treat 
MRI 
Magnetic Resonance Imaging 
NBBAL 
Non-bronchoscopic bronchial alveolar lavage 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NDM 
New Delhi metallo 
OXA 
Oxacillinase 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PMN 
Polymorphonuclear leukocyte 
PSB 
Protected Specimen Brush 
q8h 
Every 8 hours 
QA 
Quality assurance 
SAE 
Serious adverse event 
SmPC 
Summary of Product Characteristics 
TEAE 
Treatment-emergent adverse event  
TOC 
Test of Cure 


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Abbreviation 
Definition 
ULN 
Upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
UTI 
Urinary tract infection 
VABP 
Ventilator-associated bacterial pneumonia 
VIM 
Verona integron-encoded metallo 
Vss 
Steady-state volume of distribution 
WBC 
White blood cell 


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7 
INTRODUCTION 
Beta-lactam antimicrobials are considered to be among the most useful classes of antimicrobial 
agents for treatment of bacterial infections. In particular, the development of broad-spectrum 
cephalosporin and carbapenem antimicrobials have represented a key advancement in replacing 
other classes of drugs with toxicities and limited spectra of activity against pathogens.  
In the current era of increased resistance to extended spectrum cephalosporins and penicillin/ 
beta-lactamase inhibitor combinations, carbapenem antimicrobial agents are frequently the 
antibiotics of “last defense” for the most resistant pathogens in serious infections. However, the 
recent dissemination of serine carbapenemases (e.g., Klebsiella pneumoniae carbapenemase 
[KPC]) in Enterobacteriaceae within many United States (US) and global hospitals now poses a 
considerable threat to carbapenem and other members of the beta-lactam class of antimicrobial 
agents.1,2,3 
Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) are associated with high 
mortality rates and have limited treatment options.1 The loss of the carbapenem class of 
antimicrobial agents for treatment of Enterobacteriaceae (the most frequently occurring pathogens 
in the hospital setting), Acinetobacter baumannii and Pseudomonas aeruginosa represents a 
critical setback in modern patient care. 
Meropenem is a broad-spectrum injectable carbapenem antibiotic used to treat a wide variety of 
infections. The spectrum of action includes many gram-positive bacteria, gram-negative bacteria, 
and anaerobic bacteria, and it is approved in many countries around the world at doses up to 2 g 
every 8 hours (q8h). Three-hour infusions of meropenem are commonly used to treat organisms 
with higher minimum inhibitory concentrations (MICs), such as Pseudomonas aeruginosa, to 
maximize the time above the MIC. 
RPX7009 is a novel beta-lactamase inhibitor that has inhibitory activity against many serine 
beta-lactamases and was optimized for inhibition of the KPC beta-lactamase and the potentiation 
of carbapenems against Enterobacteriaceae. RPX7009 is being developed for use with 
meropenem to address the challenges of treatment of serious infections caused by pathogens 
increasingly resistant to available treatments.  
Carbavance, the combination of meropenem and RPX7009 administered as a fixed combination 
by intravenous (IV) infusion, is being developed to treat serious gram-negative infections, such as 
complicated urinary tract infections (cUTI), acute pyelonephritis (AP), complicated 
intra-abdominal 
infections 
(cIAI), 
hospital-acquired 
bacterial 
pneumonia 
(HABP), 
ventilator-associated bacterial pneumonia (VABP), and bacteremia, including those infections 
caused by bacteria resistant to currently available carbapenems. 
7.1 
Overview of the Current Treatment of Infections due to CRE   
As a result of the current lack of an optimal treatment for patients who have infections due to a 
CRE, physicians manage these patients with the limited anti-infective options available, including 
aminoglycosides, polymyxin B, colistin, tigecycline, or various combinations of these. There are 
limited efficacy data available for many of these therapies when used to treat serious CRE 
infections, particularly in combination, but with limited or no alternative therapies currently 
available, such treatments have become the BAT despite the toxicities associated with many of 
them. 


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To inform on the efficacy of these regimens as well as the target patient population with CRE 
infections, Rempex recently performed an international, multi-center, retrospective study of 
infections due to known CRE (Study 506NH). This study was conducted in 22 major medical 
centers in 4 countries – the US, UK, Italy and Greece. The study population consisted of male and 
female patients, over 18 years of age with serious bacterial infections including cUTI/AP, HABP, 
VABP, and bacteremia due to known carbapenem-resistant Enterobacteriaceae occurring over a 
6 month period from September 1, 2013 to March 1, 2014. Data were collected from 257 patients 
with known CRE infections: 76 cases of cUTI/AP, 21 cases of HABP, 20 cases of VABP, and 140 
cases of bacteremia. Among study patients, there was a high prevalence of comorbid conditions: 
overall 33% of study patients had moderate-to-severe renal disease, with 20% requiring 
hemodialysis; 35% of patients had underlying malignancy; 16% of patients had undergone prior 
organ/tissue transplantation; and 16% of patients had deep-tissue infection (predominantly cIAI) 
(See Table 2). The average duration of hospitalization prior to identification of CRE in cultures 
was 22 days. The average duration of hospital stay for the index CRE infection was 14 days, with 
an average duration of intensive care unit stay of 8 days. The outcomes associated with these 
infections were poor. The average 28-day mortality was 28% with an in-house mortality of 33%. 
These mortality rates varied by indication, with cUTI showing the lowest 28-day mortality rate 
(18%) and VABP the highest at 35%. Rates of both clinical and microbiological cure were 
correspondingly poor. Only 41% of patients achieved a response of clinical cure and only 52% of 
patients had a microbiological response of eradication of the baseline pathogen. These data indicate 
the significant comorbidities, the underlying severity of illness and the poor outcomes associated 
with CRE infections and the need for new agents against CRE pathogens.  
Based on these data and in consultation with study investigators and key opinion leaders, the 
current amended protocol more accurately reflects the comorbidities and severity of illness 
associated with patients infected with CRE. The changes include expanded inclusion criteria, 
allowing patients with moderate-severe renal dysfunction, neutropenia, and patients on 
immunosuppressive medications to be included, and a modification of the exclusion criteria – 
eliminating exclusion of patients with neuromuscular disorders, elevated liver function tests, and 
history of seizure disorders. The goal of these changes is to make the study population more 
representative of the eventual target patient population of Carbavance – specifically patients with 
severe infections due to carbapenem-resistant Enterobacteriaceae. 
 
 
 
 
 
 
 
 
 


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Table 2. 
Patient Demographics in Study 506NH 
 
Number (%) of Patients 
 
Infection Type 
 
HABP 
(n= 21) 
VABP 
(n = 20) 
cUTI/AP 
(n= 76) 
Bacteremia 
(n=140) 
All 
(n= 257) 
Age 
60.3 (16.9) 
55.5 (17.2) 
63 (16.9) 
62.5 (15.6) 
61.8 (62.2) 
Gender (%) 
 
 
 
 
 
 
Male 
15 (71%) 
13 (65%) 
36 (47%) 
87 (62%) 
151 (59%) 
 
Female 
6 (29%) 
7 (35%) 
40 (53%) 
53 (38%) 
106 (41%) 
Mild liver disease (%) 
2 (9.5%) 
1 (5.0%) 
4 (5.3%) 
12 (8.6%) 
19 (7.4%) 
Moderate liver disease (%) 
2 (9.5%) 
2 (10%) 
5 (6.6%) 
14 (10%) 
23 (8.9%) 
Solid tumor, any (%)  
7 (33%) 
3 (15%) 
12 (16%) 
34 (24%) 
56 (22%) 
Hematologic malignancy 
(leukemia/lymphoma)  
3 (14.3%) 
1 (5%) 
9 (12%) 
22 (16%) 
35 (14%) 
Prior transplant (%) 
3 (14.3) 
4 (20%) 
10 (13.2%) 
24 (17.1%) 
41 (16.0%) 
Moderate-severe renal disease 
5 (23.8%) 
9 (45%) 
28 (36.8%) 
47 (33.6%) 
83 (33.1%) 
 
Need for dialysis 
2 (9.5%) 
9 (45%) 
8 (10.5) 
32 (22.9%) 
51 (19.8%) 
Deep tissue infection (endocarditis, cIAI, 
meningitis 
2 (9.5%) 
3 (15%) 
10 (13.2%) 
27 (19.3%) 
42 (16.3%) 
Other*  
8 (38%) 
9 (45%) 
30 (39.5%) 
75 (51%) 
119 (46.3%)  
AP = acute pyelonephritis; cIAI = complicated intra-abdominal infection; cUTI = complicated urinary tract infection; HABP = 
hospital-acquired bacterial pneumonia; VABP = ventilator-associated bacterial pneumonia. 
 
 
 
 
 
 
 


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Table 3. 
Outcomes of CRE Infections in Study 506NH by Infection Type and Overall 
 
Number (%) of Patients 
 
Infection Type 
 
Outcome 
HABP 
(n= 21) 
VABP 
(n = 20) 
cUTI/AP 
(n= 76) 
Bacteremia 
(n=140) 
All 
(n= 257) 
Duration of hospitalization for IV 
antibiotics (mean+SD) 
11.7 (7.2) 
12.4 (6.4) 
8.1 (12.6) 
17.9 (17.5) 
14 (15.4) 
Duration of ICU stay (mean+SD) 
7.7 (16.1) 
14.1 (12.0) 
3.6 (11.5) 
9.5 (15.8) 
8.0 (14.7) 
28 day mortality (%) 
7 (33%) 
7 (35%) 
14 (18%) 
45 (32%) 
73 (28%) 
In-house mortality (%)  
7 (33%) 
9 (45%) 
15 (20%) 
53 (38%) 
84 (33%) 
Number (%) with clinical cure 
(PI-ascertained) 
9 (43%) 
9 (45%) 
54 (71%) 
74 (53%) 
146 (57%) 
AP = acute pyelonephritis; CRE = carbapenem-resistant Enterobacteriaceae; cUTI = complicated urinary tract infection; 
HABP = hospital-acquired bacterial pneumonia; ICU = intensive care unit; IV = intravenous; PI = Principal Investigator; SD = 
standard deviation; VABP = ventilator-associated bacterial pneumonia. 
7.2 
Carbavance (Meropenem/RPX7009) 
Carbavance (meropenem/RPX7009) is a combination of the approved carbapenem antibiotic 
meropenem and the investigational beta-lactamase inhibitor RPX7009. This drug combination is 
being developed for IV administration for the treatment of patients with severe gram-negative 
infections, including those caused by bacteria resistant to currently available drugs. 
Meropenem is a broad-spectrum carbapenem antibiotic active against gram-positive and 
gram-negative bacteria, including the Enterobacteriaceae (the most frequently occurring 
pathogens in the hospital setting) and other key pathogens associated with hospital-acquired 
infections, such as Pseudomonas aeruginosa, Acinetobacter sp., and anaerobes. While meropenem 
has excellent stability to many bacterial beta-lactamases (the major pathway of resistance to 
penicillins and cephalosporins), resistance to meropenem (and other carbapenems) can be 
mediated by Class A serine carbapenemases, especially KPC. Meropenem is approved in most 
countries in the developed world. In many countries, meropenem is approved for treatment of both 
urinary tract infections (UTIs) and cUTIs. In the US, it is marketed under the proprietary name of 
Merrem IV or its generic version, Meropenem for Injection, United States Pharmacopeia (USP), 
and is indicated for the treatment of complicated skin and skin structure infections, complicated 
intra-abdominal infections, and bacterial meningitis.4 Approved dosing regimens for meropenem 
in adults include 500 mg, 1000 mg, and 2000 mg administered as 15- to 30-minute infusions q8h. 
While the approved infusion times for meropenem include bolus and 15- to 30-minute infusions, 
prolonged infusions for administration of meropenem are widely used, including the 3-hour 
infusions planned for evaluation in this study. There is no indication in the literature that the use 
of prolonged infusions affects the established safety profile of meropenem, and prolonged infusion 
of meropenem has been associated with increased probability of target attainment.5 The clinical 
study that evaluated the combination of meropenem and RPX7009, Rempex-501, confirmed that 
meropenem was safe when administered as 3-hour infusions q8h.  
RPX7009 is the first member of a new class of cyclic boronic acid beta-lactamase inhibitors. It has 
no antimicrobial activity alone, but has broad inhibitory activity against several clinically 
important bacterial beta-lactamases, particularly KPC. The pharmacological properties of 


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RPX7009 enable it to be administered in combination with meropenem. In vitro and in vivo studies 
show that the combination is highly active against gram-negative pathogens, including 
KPC-producing CRE. 
The Sponsor has developed an IV formulation of Carbavance (meropenem/RPX7009) for 
evaluation in clinical trials, and will administer Carbavance (meropenem/RPX7009) in a fixed 
combination by IV infusion. 
7.3 
Microbiology 
7.3.1 
Susceptibility Testing 
Carbavance (meropenem/RPX7009) has primary activity against gram-negative organisms. The 
potency and MICs of Carbavance (meropenem/RPX7009) have been evaluated against a variety 
of contemporary clinical strains. In the presence of RPX7009, the potency of meropenem was 
enhanced at least 32-fold against a panel of characterized gram-negative test strains. See the 
Investigator’s Brochure.6 
7.4 
Nonclinical Pharmacology and Toxicology 
A toxicology and safety assessment program to support clinical trials with RPX7009 was 
conducted. RPX7009 had no discernible effects in any of the safety pharmacology studies, 
demonstrated a similar pharmacokinetic (PK) profile to that of meropenem in preclinical species 
studies, and was devoid of mutagenic, clastogenic, and genotoxic effects for in vivo and in vitro 
Good Laboratory Practice (GLP) genotoxicity studies. See the Investigator’s Brochure.6 
7.4.1 
Mechanism of Action 
RPX7009 alone has no antimicrobial activity; however, when combined with meropenem in vitro 
and in vivo, it markedly enhanced the potency of meropenem against Enterobacteriaceae strains 
expressing KPC enzymes. See the Investigator’s Brochure.6 
7.4.2 
Metabolism and Excretion 
There is no evidence of accumulation with multiple RPX7009 doses and no differences in PK 
between males and females. RPX7009 has low plasma protein binding, is stable in human 
microsomes and hepatocytes, and shows no induction or inhibition of cytochrome P450 
isoenzymes. It shows no inhibition of key renal transporters, nor does it appear to be a substrate of 
them. See the Investigator’s Brochure.6 
7.5 
Overview of Clinical Pharmacology 
7.5.1 
Rempex 402 and Rempex 501 – Single and Multiple-Ascending Dose 
Studies in Healthy Volunteers 
Two ascending-dose studies in healthy volunteers have been conducted. Both studies evaluated 
RPX7009 when administered as a 3-hour infusion q8h for 7 days at a dose range of 250 mg to 2 g. 
The first-in-human study evaluated RPX7009 alone (Study 402), while the second study evaluated 
RPX7009 in combination with 1 g and 2 g doses of meropenem (Rempex-501). The RPX7009 PK 


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data from these two studies were very consistent and demonstrated the similarity of PK profiles 
between the two drugs, as well as a lack of drug-drug interaction. The PK parameters for RPX7009 
after single and multiple 2 g doses administered either alone or in combination with a 1 g or 2 g 
dose of meropenem are shown in Table 4. The PK parameters of meropenem after single and 
multiple 1 g or 2 g doses administered either alone or in combination with RPX7009 doses of 1 g 
and/or 2 g are shown in Table 5.  
In both clinical studies, RPX7009 exposure in subjects (maximum plasma concentration [Cmax] 
and area under the concentration-time curve [AUC]) increased with increasing dose. The mean 
Cmax and AUC values for RPX7009 following administration of a 2 g dose q8h for 7 days were 
41 mg/L and 145 mg·h/mL, respectively. The terminal half-life was less than 2 hours, resulting in 
no accumulation of drug between multiple doses of RPX7009 alone or in combination with 
meropenem. Volume of distribution and plasma clearance were independent of dose, and mean 
values ranged from 17.50 L to 24.95 L and 10.42 L/h to 17.61 L/h, respectively.  
There were no significant changes in RPX7009 PK when it was administered with 1 g or 2 g doses 
of meropenem. Likewise, the PK parameters for meropenem, and its metabolite, hydrolyzed 
meropenem, remain unchanged with co-administration of RPX7009. 
 


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Table 4. 
Comparison Across Clinical Pharmacology Studies of RPX7009 
Pharmacokinetic Parameters (Mean ±Standard Deviation) Following Single- 
and Multiple-Dose Administration of RPX7009 2 g Alone and in Combination 
with Meropenem (Preliminary Data) 
Parameter 
Study 402 
Rempex-501 
Alone 
Alone 
w/ Meropenem 1 g 
Alone 
w/ Meropenem 2 g 
Singlea 
(N=6) 
Lasta 
(N=6) 
Singleb 
(N=8) 
Firstc 
(N=8) 
Lastc 
(N=7) 
Singleb 
(N=8) 
Firstc 
(N=8) 
Lastc 
(N=8) 
Cmax (mg/L) 
41.6 
±4.75 
40.9 
±4.68 
39.20 
±4.29 
41.44 
±4.38 
34.93 
±3.96 
51.44 
±16.16 
51.66 
±7.26 
55.61 
±10.96 
AUCd 
(mg·h/L) 
144 
±13.9 
145 
±15.8 
133.26 
±20.89 
141.02 
±21.35 
112.31 
±8.56 
159.21 
±44.58 
170.44 
±31.99 
190.43 
±32.90 
Half-Life (h) 
1.51 
±0.08 
1.66 
±0.10 
1.31 
±0.32 
1.43 
±0.22 
1.19 
±0.21 
1.39 
±0.20 
1.98 
±0.81 
1.37 
±0.24 
Vss (L) 
 21.8 
±2.26 
33.4 
±4.52 
22.02 
±2.24 
22.43 
±2.00 
24.95 
±2.63 
21.37 
±3.33 
21.84 
±3.50 
17.50 
±1.99 
Plasma 
Clearance (L/h) 
14.0 
±1.40 
14.0 
±1.78 
15.32 
±2.33 
14.44 
±1.97 
17.61 
±1.44 
13.43 
±3.23 
12.08 
±2.09 
10.42 
±1.85 
a. The single dose of RPX7009 was administered on Day 1, and the last dose of RPX7009 following multiple-dose administration 
was on Day 8. 
b. The single dose of RPX7009 was administered on either Day 1 or Day 4, depending on whether the subject was randomized to 
receive RPX7009 first or meropenem first. 
c. The first dose of multiple-dose administration of meropenem/RPX7009 was on Day 8, and the last dose of every 8-hour dose 
administration was on Day 14. 
d.  AUC(0-∞) values are provided for single doses, and AUC(0-Tlast) values are provided for the last day of multiple dosing. 
AUC = area under the concentration-time curve; AUC(0-∞) = area under the concentration-time curve from time 0 to infinity; 
AUC(0-Tlast) = area under the concentration-time curve from time 0 to the last recorded measurement; Cmax = maximum plasma 
concentration; SD = standard deviation; Vss = steady-state volume of distribution; w/ = with. 


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Table 5. 
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 Study Rempex-501 
Parameter 
Meropenem 1 g 
Meropenem 2 g 
Alone 
w/ RPX7009  
1 g 
Alone 
w/ RPX7009  
2 g 
Alone 
w/ RPX7009  
2 g 
Singlea 
(N=9) 
Firstb 
(N=5) 
Lastb 
(N=5) 
Singlea 
(N=14) 
Firstb 
(N=7) 
Lastb 
(N=7) 
Singlea 
(N=14) 
Firstb 
(N=8) 
Lastb 
(N=8) 
Cmax (mg/L) 
18.93 
±3.65 
20.16 
±3.97 
17.04 
±1.65 
17.31 
±2.45 
18.21 
±2.06 
15.81 
±1.29 
42.54 
±15.24 
48.83 
±5.88 
43.35 
±8.82 
AUCc (mg·h/L) 
59.77 
±12.09 
65.88 
±15.33 
54.52 
±6.96 
53.78 
±8.81 
58.69 
±9.91 
48.06 
±2.01 
130.34
±34.95 
142.55
±28.72 
137.71 
±26.37 
Half-Life (h) 
0.96 
±0.11 
1.15 
±0.21 
0.94 
±0.03 
0.96 
±0.09 
1.01 
±0.31 
1.08 
±0.15 
1.14 
±0.36 
1.51 
±0.98 
1.07 
±0.16 
Vss (L) 
21.59 
±3.21 
21.06 
±4.50 
21.19 
±2.43 
23.46 
±2.53 
22.36 
±1.89 
24.97 
±2.41 
22.59 
±5.24 
21.74 
±3.05 
20.08 
±3.20 
Plasma 
Clearance (L/h) 
17.39 
±3.71 
15.84 
±3.57 
18.4 
±2.24 
19.11 
±3.44 
17.39 
±2.41 
20.65 
±0.84 
16.13 
±3.33 
14.49 
±2.67 
14.77 
±2.84 
a. The single dose of RPX7009 was administered on either Day 1 or Day 4, depending on whether the subject was randomized to 
receive RPX7009 first or meropenem first. 
b. The first dose of multiple-dose administration of meropenem/RPX7009 was on Day 8, and the last dose of every 8-hour dose 
administration was on Day 14. 
c.  AUC(0-∞) values are provided for single doses, and AUC(0-Tlast) values are provided for the last day of multiple dosing. 
AUC = area under the concentration-time curve; AUC(0-∞) = area under the concentration-time curve from time 0 to infinity; 
AUC(0-Tlast) = area under the concentration-time curve from time 0 to the last recorded measurement; Cmax = maximum plasma 
concentration; Vss = steady-state volume of distribution. 
 
7.5.2 
Rempex 503 – Randomized, Open-label Study of the Pulmonary 
Pharmacokinetics of Meropenem and RPX7009 (Carbavance) in Healthy 
Volunteers 
Study 503 was a randomized, open-label study in healthy adult subjects to evaluate the plasma, 
epithelial lining fluid (ELF), and alveolar macrophage (AM) penetration of a single dose level of 
2 g of meropenem/2 g of RPX7009 (Carbavance) after 3 doses, given 8 hours apart, administered 
as 3-hour infusions; safety and tolerability were also evaluated.  
Twenty-five subjects underwent bronchoscopy and BAL at 1 of 5 time points (1.5, 3.25, 4, 6, and 
8 hours) after the third dose of IV meropenem and RPX7009. Bronchial alveolar lavage samples 
provided ELF and AM concentrations for meropenem and RPX7009 for pulmonary PK analysis, 
and blood samples provided plasma concentrations for meropenem and RPX7009 plasma PK 
analysis. 
Preliminary data showed that IV dosing of 2 g meropenem/2 g RPX7009 (Carbavance) every 
8 hours, administered as 3-hour infusions, produced steady-state ELF concentrations of 
approximately 50% and 60% of simultaneous plasma concentrations for RPX700 and meropenem, 
respectively. See the Investigator’s Brochure for details.6 


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7.5.3 
Rempex 504- A Phase 1, Open-Label, Single-dose Study to Determine 
the Safety and Pharmacokinetics of Carbavance in Subjects With Renal 
Insufficiency (Including Subjects on Standard Hemodialysis)  
Study 504 was an open-label study in adult subjects with varying degrees of renal insufficiency, 
including those requiring hemodialysis (HD), or normal renal function. The safety and PK of a 
single IV dose of 1 g meropenem plus 1 g RPX7009 (Carbavance), infused over 3 hours, was 
evaluated. Forty-one subjects were enrolled in 5 groups based on their degree of renal 
insufficiency.  
Preliminary data demonstrate that meropenem and RPX7009 plasma clearance followed a linear 
PK model in subjects with decreasing renal function (see Appendix 4). This allows the ratio of 
meropenem and RPX7009 to be maintained for dose adjustment in subjects with reduced renal 
function (See the Investigator’s Brochure6). For subjects with an estimated creatinine clearance 
below 20 ml/min, including those on standard hemodialysis, data were recently obtained, and 
2 subgroups were noted. The first included subjects with an estimated creatinine clearance between 
10 ml/min and 19 ml/min (including those requiring hemodialysis). The second included all 
subjects with an estimated creatinine clearance below 10 ml/min (including those on 
hemodialysis).   
For subjects with an estimated creatinine clearance of 10-19 ml/min, the dosing strategy with the 
highest probability of target attainment was 500 mg of Carbavance (500 mg meropenem/500 mg 
RPX7009) every 12 hours. For subjects with estimated creatinine clearance below 10 ml/min, a 
dose of Carbavance (500 mg meropenem/500 mg RPX7009) every 24 hours best accounted for 
intersubject variability and had the greatest probability of target attainment across all subjects with 
exposure levels to both meropenem and RPX7009 that were well under the highest exposure 
achieved in this study, which was well tolerated in the setting of twice weekly hemodialysis. 
Subjects with an estimated creatinine clearance of less than 10 ml/min are required to receive 
dialysis at least twice per week. 
Based on this data, the following are recommended Carbavance dosing regimens for subjects with 
impaired renal function.   
Table 6. 
Reduced Renal Function Dose Adjustment Table 
Estimated Creatinine Clearance, 
ml/min (Cockcroft-Gault) 
Carbavance Dosage Regimen (All doses infused over 3 hours) 
 
50 
Meropenem 2 g / RPX7009 2 g q8h 
30 – 49 
Meropenem 1 g / RPX7009 1 g q8h 
20 – 29 
Meropenem 1 g / RPX7009 1 g q12h 
10-19
Meropenem 500 mg / RPX7009 500 mg q12h 
<10 
Meropenem 500 mg / RPX7009 500 mg q24ha 
a. Subjects with an estimated creatinine clearance of less than 10 ml/min are required to receive dialysis at least twice per week. 
Maintenance doses of Carbavance in these subjects should be administered as soon as possible after the dialysis session. For 
example, if a subject is scheduled to receive Carbavance at 18:00 but receives hemodialysis at 13:00, the planned 18:00 
Carbavance dose should be given after the dialysis session is completed (rather than waiting until 18:00). 
q8h = every 8 hours; q12h = every 12 hours; q24h = every 24 hours. 


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7.6 
Justification of Carbavance Dose Selection for Registration Clinical 
Program 
The Carbavance (meropenem/RPX7009) program was initiated with the goal of treating 
KPC-containing Enterobacteriaceae by combining meropenem with RPX7009 and improving the 
coverage against P. aeruginosa and Acinetobacter spp. by optimizing the dose and dose regimen 
of meropenem.  
The PK-pharmacodynamic parameter for efficacy of meropenem is free drug time above the MIC 
and the magnitude of this parameter necessary to achieve maximal efficacy is free drug above the 
MIC for 30% to 50% of the dosage interval. From the PK data obtained in Rempex-501, a 
meropenem dose of 2 g administered by 3 hour infusion every 8 hours will maintain concentrations 
above the 8 mg/L for 30% to 50% of the dosage interval.6 This meropenem dosage regimen has 
been chosen for this study to increase the likelihood of clinical success in difficult to treat 
infections. 
For RPX7009, studies both in vitro and in vivo were used to determine the minimum exposure 
required to potentiate meropenem against strains containing the KPC enzyme (or expressing KPC) 
as well as reduce the development of resistance during therapy. Based on in vitro resistance 
development studies, a minimum concentration of 8 mg/L of RPX7009 (in combination with 
8 mg/L of meropenem) was required to be present for 24 hours to prevent resistance. This became 
the basis for the minimum AUC (8 mg/L * 24 h = 192 mg*h/L) target in animal models and in 
vitro pharmacodynamic models. From the data obtained from Rempex-501, a dose of 2 g 
administered by 3 hour infusion every 8 hours was required to maintain an AUC above 192 
mg*h/L.6 This RPX7009 dosage regimen has been chosen for this study and for the Registration 
Clinical Development Program. 
The selected combination dosage regimen of 2 g meropenem /2 g RPX7009 was further studied 
using in vitro pharmacodynamic and animal models of infection against Enterobacteriaceae and 
P. aeruginosa strains with Carbavance MICs as high as 8 mg/L. In each of these models, the dosage 
regimen proved to not only be efficacious, but prevented the development of resistance in those 
studies. If this data is confirmed in the Registration Clinical Development Program, it may justify 
a Carbavance MIC breakpoint as high as 8 mg/L. 
Overall, based on the PK data from Rempex-501 and the in vitro and in vivo PK and 
pharmacodynamic data generated, the dose of 2 g meropenem in combination with 2 g RPX7009 
infused over 3 hours, every 8 hours, was chosen for development. 
7.7 
Overview of Clinical Safety 
7.7.1 
Rempex 402 and Rempex 501 – Single and Multiple-Ascending Dose 
Studies in Healthy Volunteers 
There have been no safety signals identified in the clinical pharmacology studies conducted with 
RPX7009 alone (Study 402) and in combination with meropenem (Rempex-501). Events related 
to the infusion site (dosing catheter) and/or PK catheter site (blood collections only) were the most 
prevalent events reported and were evenly distributed across subjects treated with placebo, 
RPX7009 alone, meropenem alone, and meropenem/RPX7009, indicating no evidence of local 
adverse events related to RPX7009 dosing, either alone or in combination with meropenem. 
Common adverse events in subjects treated with RPX7009 or meropenem/RPX7009, outside of 


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infusion site/PK catheter site events, were limited to headache, lethargy, dizziness, nausea, and 
diarrhea. Of these events, headache was the most frequently reported adverse event in both studies, 
being reported in 42% of subjects in RPX7009 multiple-dose groups in Study 402 and 30% in 
meropenem/RPX7009 dose groups in Rempex-501. In comparison, the incidence of headache was 
50% in subjects treated with meropenem alone in Rempex-501, and 25% in subjects treated with 
placebo in Studies 402 and Rempex-501. With the exception of 1 case of headache in a placebo 
subject in Rempex-501, the episodes of headache were mild in severity. 
Lethargy was reported in Study 402 in 1 of 6 subjects (17%) that received RPX7009 1 g q8h and 
4 of 6 subjects (67%) that received RPX7009 2 g q8h, for an overall incidence of 21% in subjects 
treated with RPX7009 in Study 402; however, lethargy was not reported in a single subject that 
received RPX7009 alone or in combination with meropenem q8h in Rempex-501. All episodes of 
lethargy in Study 402 were considered to be mild in severity. 
Dizziness, nausea, and diarrhea were all reported in a single RPX7009 subject (4%) each in 
Study 402 and 4 (9%) subjects that received either RPX7009 250 mg alone (1 of 8 subjects [13%] 
for each event) or a combination of meropenem/RPX7009 (3 of 37 subjects [8%] for each event) 
in Rempex-501. In addition, 1 (6%) and 2 (13%) subjects that received meropenem 1 g reported 
dizziness and diarrhea, respectively. All episodes of dizziness, nausea, and diarrhea were 
considered mild in severity. 
Two subjects in Remepx-501 had asymptomatic elevations in their alanine aminotransferase 
(ALT) levels to > 3 x ULN which were felt to be study drug-related by the Investigator. One 
subject was in the meropenem 1 g cohort and one was in the meropenem/RPX7009 1 g/ 2 g cohort. 
Neither were associated with alkaline phosphatase or bilirubin elevations and both resolved 
spontaneously after study drug treatment was completed. There were no other clinically significant 
trends in clinical laboratory parameters, or clinically significant changes in vital signs, physical 
examinations, or electrocardiogram (ECG) parameters in either study. 
7.7.2 
Rempex 503 – Randomized, Open-label Study of the Pulmonary 
Pharmacokinetics of Meropenem and RPX7009 (Carbavance) in Healthy 
Volunteers 
Study 503 was a randomized, open-label, PK study conducted in healthy adult male and female 
subjects to evaluate the lung penetration of 2 g meropenem/2 g RPX7009 (Carbavance) every 
8 hours administered as a 3-hour infusion. Twenty-five subjects underwent bronchoscopy and 
BAL at 1 of 5 time points (1.5, 3.25, 4, 6, and 8 hours) after the third dose of IV meropenem and 
RPX7009. Bronchial alveolar lavage samples provided ELF and AM concentrations for 
meropenem and RPX7009 for pulmonary PK analysis, and blood samples provided plasma 
concentrations for meropenem and RPX7009 plasma PK analysis.   
Twenty-six subjects were randomized and 25 subjects completed the study. One subject withdrew 
from the study during the second infusion of meropenem/RPX7009 because of chest pressure of 
unknown etiology that was moderate in intensity, lasted 90 minutes, resolved spontaneously when 
the infusion was stopped, and was considered by the investigator to be possibly related to study 
drug administration. 
Carbavance (meropenem/RPX7009) given as a 2 g/2 g dose was well tolerated in Study 503. 


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There were no serious adverse events or deaths reported. 
There were no clinically significant changes in laboratory values, vital signs, or ECG parameters 
during the study. 
For further details and a full list of all treatment-emergent adverse from Study 503 reference the 
Investigator’s Brochure.6 
7.7.3 
Rempex 504 – Open-label Study of the Safety and PK of a Single Dose of 
Meropenem and RPX7009 (Carbavance) in Volunteers with Varying 
Degrees of Renal Insufficiency or Normal Renal Function, and in 
Patients with Hemodialysis 
All subjects in the normal, mild, moderate, and severe renal function groups received a single 
3-hour IV infusion of Carbavance (1 g meropenem and 1 g RPX7009). Subjects in the end stage 
renal disease (ESRD) group received two infusions, one infusion immediately prior to HD, and 
the other infusion following HD on different days separated by a washout period to ensure that 
study drug administration was at least 6 days apart and no more than 14 days apart. 
Overall, 14 subjects (34.1%) reported a total of 20 treatment-emergent adverse events (TEAEs) 
during the conduct of the study. The most frequently reported TEAEs were diarrhoea, headache, 
abdominal pain, and dermatitis contact. All TEAEs were mild in severity except 1 moderate TEAE 
(abdominal pain) and 2 severe TEAEs (1 prostate cancer metastatic and 1 diarrhoea haemorrhagic). 
A similar proportion of subjects reported at least 1 TEAE in the mild (2 subjects [25.0%]), 
moderate (3 subjects [37.5%]), severe (1 subject [12.5%]), and normal (2 subjects [25.0%]) renal 
function groups. In the ESRD group, a larger proportion of subjects in Period 2 (i.e., when dialysis 
occurred prior to study drug administration) (5 subjects [62.5%]) reported TEAEs as compared to 
the Period 1 group (2 subjects [22.2%]; i.e., when dialysis occurred after study drug 
administration); however, the type and severity of these adverse events in the ESRD group were 
similar to those adverse events observed in the other renal function groups. The higher incidence 
of these mild TEAEs reported during Period 2, as opposed to Period 1, is consistent with the PK 
data indicating that both meropenem and RPX7009 are cleared by hemodialysis. 
Eight of the 20 TEAEs reported in the study were either “possibly” or “probably” related to study 
treatment and were reported by 7 subjects (17.1%). Only 1 TEAE (prostate cancer metastatic) was 
ongoing at study completion. Two (2) SAEs were reported (1 prostate cancer metastatic and 
1 diarrhoea haemorrhagic) in subjects with ESRD. The event of prostate cancer metastatic resulted 
in an interruption to study drug dose administration, and the subject did not receive the second 
dose. No adverse events resulted in death. 
There were no clinically significant trends in 12-lead ECG data, vital signs data, clinical laboratory 
results, or physical examination data. 
Overall Carbavance was well tolerated across all levels of renal insufficiency, including in subjects 
with severe renal insufficiency and those on hemodialysis. Guidelines on dosing of Carbavance in 
subjects with renal impairment is outlined in Section 11.1.2. 


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7.8 
Benefits and Risks Conclusions 
No safety signal was identified in any of the four clinical pharmacology studies, which is consistent 
with the preclinical toxicology and safety studies conducted with RPX7009 alone and in 
combination with meropenem. In those preclinical studies, no toxicity was attributed to RPX7009, 
minimal toxicity was attributed to meropenem, and the addition of RPX7009 to meropenem did 
not impact the known toxicity profile of meropenem. The PK data from animals and humans also 
support that the two drugs have similar PK profiles and do not affect the PK profiles of each other. 
Overall, the PK and safety results from the preclinical and clinical studies of the administration of 
RPX7009 alone and in combination with meropenem support the use of this drug combination in 
clinical studies up to the highest doses tested (2 g/2 g) infused over 3 hours, and support the 
inclusion of subjects with severe renal insufficiency in this study, including those on hemodialysis. 
 


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8 
STUDY OBJECTIVES 
The objectives of this study are: 
• To evaluate the safety, tolerability, and efficacy of Carbavance (meropenem/RPX7009) in 
treatment of subjects with selected serious infections, suspected or known to be due to CRE; 
and 
• To assess the PK of meropenem and RPX7009 in subjects with selected serious infections, 
suspected or known to be due to CRE. 


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9 
OVERALL STUDY DESIGN  
9.1 
Study Design 
This is a Phase 3, multi-center, randomized, open-label study of Carbavance (meropenem/ 
RPX7009) versus BAT in the treatment of subjects with selected serious infections, specifically 
cUTI or AP, cIAI, HABP, VABP, and bacteremia, suspected or known to be caused by CRE. See 
Appendix 2 for a flow diagram of the study. 
For this study, the specific serious infections selected for study will be defined as the following: 
• Complicated UTI (cUTI) is a urinary infection occurring in a subject with a structural or 
functional abnormality of the genitourinary tract associated with clinical signs and symptoms. 
• Acute pyelonephritis (AP) is an acute infection of the renal pelvis or parenchyma associated 
with clinical signs and symptoms. 
• Complicated Intra-abdominal Infection (cIAI) is an infection in the abdominal cavity which 
extends beyond the hollow viscus of origin (bowel, stomach, gallbladder, etc.) into the 
peritoneal space and is associated with either abscess formation or peritonitis associated with 
clinical signs and symptoms.   
• Hospital-acquired bacterial pneumonia (HABP) is an acute infection of the pulmonary 
parenchyma that is associated with clinical signs and symptoms in a subject hospitalized for 
more than 48 hours, or in a subject admitted from a long-term acute care or rehabilitation 
center, or admitted from home 7 days after discharge from a hospital or health care facility. 
• Ventilator-associated bacterial pneumonia (VABP) is an acute infection of the pulmonary 
parenchyma that is associated with clinical signs and symptoms beginning more than 48 hours 
after a subject receives ventilatory support via an endotracheal (or nasotracheal) tube. 
• Bacteremia is defined by the presence of a bacterial pathogen in a blood culture that is not 
thought to be a contaminant. Subjects enrolled with the indication of bacteremia will not have 
concurrent HABP, VABP, cIAI, or cUTI/AP infections. However, subjects enrolled with 
HABP, VABP, or cUTI/AP may also have concurrent secondary bacteremia.  
Approximately 150 subjects who are expected to need at least 7 days of treatment with IV 
antibiotics will be enrolled in a 2:1 ratio of Carbavance to BAT, respectively.  
The Treatment Arms in the study are as follows: 
• Treatment Arm A: Subjects (n = 100) will receive Carbavance (meropenem 2 g plus RPX7009 
2 g) IV q8h, with each dose infused for 3 hours for up to 14 days. 
NOTE: Dose adjustments will be required for subjects with renal insufficiency (see Section 
11.1.2). 
• Treatment Arm B: Subjects (n = 50) will receive BAT with IV antibiotics chosen from the 
following list, either in combination or alone, for up to 14 days: carbapenem (meropenem, 
ertapenem, or imipenem), tigecycline, colistin, aminoglycosides (amikacin, tobramycin or 
gentamicin), polymyxin B, and ceftazidime-avibactam. 


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Subjects (or subject’s legal representative) providing informed consent, meeting all study 
eligibility criteria including those criteria for their particular site of infection (e.g., cUTI or AP, 
cIAI, HABP, VABP, and bacteremia), and who have either a known CRE infection or a suspected 
CRE infection (based on colonization with a KPC-producing Enterobacteriaceae organism [which 
may be determined through rapid diagnostic tests, active surveillance cultures, or other 
documentation of CRE colonization] in the past 90 days or prior infection due to a CRE pathogen 
that was treated within the past 90 days) will be randomized to receive Carbavance 
(meropenem/RPX7009) or BAT.  
Any isolated bacterial pathogen will be identified by genus and species. The local laboratory will 
culture each subject sample for pathogen identification, quantification, and susceptibility testing. 
Isolated pathogens collected at the time points listed in Table 1 and cultured at the local laboratory 
will be sent to the central laboratory for confirmation of identification and testing results.  
Day 1 is defined as the first day of study drug administration (Carbavance [meropenem/ RPX7009] 
or BAT). Subsequent study days are defined by the number of calendar days thereafter. The 
planned total duration of IV study drug therapy is up to 14 days. A subject assessed as a clinical 
cure must receive 5 days of study drug therapy, and a subject assessed as a clinical failure must 
receive 3 days of study drug therapy. 
End of Treatment (EOT) will be the day on which the final dose of study drug is administered 
(+1 day). The Test of Cure (TOC) visit and Late Follow-up (LFU) visit will occur at time points 
as defined in the Schedule of Procedures (Table 1). 
9.1.1 
Blinding 
This is an open label study and the Principal Investigator (PI), study coordinators, and pharmacy 
staff will not be blinded. However, the measures outlined below will be implemented in order to 
optimize unbiased assessments of outcomes between treatment arms at the investigational site.  
9.1.1.1 
Subject Treatment Bias 
In order to ensure unbiased assessment of outcomes between treatment arms, subjects will not be 
informed what treatment arm they are assigned. Efforts should be made to keep subjects naïve to 
their treatment throughout the course of the study.  
9.1.1.2 
Blinded Investigator (BI) 
Each site will assign a Blinded Investigator(s) (BI) to evaluate criteria for Clinical Outcomes 
during designated study visits (See Table 1). A BI must be qualified to perform medical evaluations 
and determine medical diagnoses (e.g., physician, physician’s assistant, or nurse practitioner 
[within the US]). A BI should have no other role in the study other than making blinded 
assessments. For consistency, whenever possible the same BI should complete all blinded 
assessments for a study subject. All efforts should be made to keep a BI blinded during the course 
of the study. Data collection by the BI will be used for adjudication purposes only.  


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9.2 
Independent Monitoring Committees 
9.2.1 
Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) will review accumulated safety data for 
this study and Rempex-505 when the total combined enrollment in both trials is approximately 
25% (250 subjects) and 50% (500 subjects). They will also review serious adverse events on an 
ongoing basis. They will make recommendations to the Sponsor based on this safety data. Further 
details regarding the data safety monitoring guidelines will be included in the DSMB Charter, 
which is the governing document of the DSMB.  
9.2.2 
Blinded Adjudication Committee  
A blinded adjudication committee will also be formed to independently evaluate clinical outcome 
data in cases where the PI’s and BI’s assessment of outcome differ. In these instances the decision 
made by the blinded adjudication committee will factor into the final clinical outcome data as 
described in Section 15.1.2 of the protocol. Further details regarding the blinded adjudication 
committee will be included in a Blinded Adjudication Committee Charter, which is the governing 
document of the committee.  
9.3 
Rationale for Study Design 
There is a current lack of an optimal treatment for patients who have infections due to a CRE, 
making the use of a blinded comparator impractical due to the limited anti-infective options 
available. In addition, the different regimens, combinations, and toxicities associated with the 
various combinations and lack of a true comparator would make maintaining a blind nearly 
impossible. Therefore, an open-label study design is appropriate for this study. 
To minimize potential bias, efforts will be made to keep the subject unaware of their treatment 
assignment, a BI used to assess outcomes, and an adjudication committee used as described in 
Section 9.2.2.  
Eligible subjects will require at least 7 days of IV therapy, and mortality is generally high for this 
population of subjects with serious infections even with the best anti-microbial therapy available. 
Treatment with a placebo comparator would be unacceptable in this subject population. Therefore, 
using the BAT with any of the following IV antibiotics, alone or in combination, is the appropriate 
option for this study: carbapenems (meropenem, ertapenem, imipenem), tigecycline, colistin, 
aminoglycoside (amikacin, tobramycin, gentamicin), polymyxin B, and (where available) 
ceftazidime-avibactam. 
Randomization will be used to assure that study populations are similar between the test and 
control groups, and to avoid systemic differences between the 2 study groups with respect to 
known or unknown baseline variables that could affect outcome.  


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10 SELECTION OF STUDY POPULATION 
The following criteria for enrollment must be followed explicitly. The subject cannot be 
randomized until he/she satisfies the following inclusion and exclusion criteria. The Investigator 
or other study site personnel must document in the source documents (e.g., the hospital or clinic 
chart) that the subject’s informed consent was obtained. If a subject is unable to provide informed 
consent due to their medical condition, the subject’s legal representative will be provided with 
study information in order for consent to be obtained. The presence of inclusion criteria and the 
absence of exclusion criteria will be verified in the electronic case report form (eCRF). 
10.1 
Inclusion Criteria 
Subjects must meet all of the following criteria in order to be eligible for the study: 
1. Willingness to comply with all study activities and procedures and to provide signed, written 
informed consent prior to any study procedures. If a subject is unable to provide informed 
consent due to their medical condition, the subject’s legal representative will be provided with 
study information in order for consent to be obtained. 
2. Hospitalized male or female, 18 years of age. 
3. Weight 185 kg. 
4. Have a confirmed diagnosis of a serious infection, specifically cUTI or AP, cIAI, HABP, 
VABP, and bacteremia, requiring administration of IV antibacterial therapy (See inclusion 
number 7 for criteria for all indications). 
5. The following must be satisfied:  
For known CRE infection:  
• Have a known CRE infection based on evidence from CRE culture or other phenotypic or 
molecular testing within 72 hours prior to Day 1, alone or as a single isolate of a 
polymicrobial infection; 
• Have received no more than 24 hours of an antimicrobial agent to which the known CRE 
is susceptible prior to enrollment,  
OR 
• Have documented clinical evidence of failure (i.e., clinical deterioration or failure to 
improve) after at least 48 hours of treatment with an antimicrobial agent to which the 
known CRE is susceptible. 
For suspected CRE infection: 
• Have a suspected CRE infection based on evidence from CRE culture (KPC-producing, if 
known) or other phenotypic or molecular testing, alone or as a single isolate of a 
polymicrobial infection, from any source within 90 days prior to Day 1; 
• Have received no more than 24 hours of empiric antimicrobial therapy for gram negative 
organisms prior to enrollment. 
6. Expectation, in the opinion of the Investigator, that the subject’s infection will require 
treatment with IV antibiotics for a minimum of 7 days.  


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7. Expectation that subjects with an estimated creatinine clearance <10 ml/min (Cockcroft-Gault) 
will receive hemodialysis at least 2 times per week. 
8. Diagnosis with either cUTI or AP, cIAI, HABP, VABP, and bacteremia as defined below:  
Complicated Urinary Tract Infection 
Expectation, in the judgment of the Investigator, that any indwelling urinary catheter or 
instrumentation (including nephrostomy tubes and/or indwelling stents) will be removed or 
replaced (if removal is not clinically acceptable) before or as soon as possible, but not longer 
than 12 hours, after randomization, AND: 
Indication At least ONE of the following: 
AND at least TWO of the 
following signs or symptoms: 
AND at least ONE of the 
following: 
cUTI 
• Indwelling urinary catheter; 
• Neurogenic bladder with 
presence or history of urine 
residual volume of 100 mL; 
• Obstructive uropathy (e.g., 
nephrolithiasis, tumor, 
fibrosis) that is expected to be 
medically or surgically treated 
within 48 hours post-
randomization; 
• Azotemia due to intrinsic 
renal disease; 
• Urinary retention in men due 
to previously diagnosed 
benign prostatic hypertrophy 
• Chills, rigors, or fever* (oral 
or tympanic temperature 
38°C [100.4°F] or 
rectal/core temperature 
38.3°C [100.9°F]); 
• Elevated WBC count 
(>10,000/mm3) or left shift 
(>15% immature PMNs); 
• Nausea or vomiting; 
• Dysuria, increased urinary 
frequency, or urinary urgency; 
• Lower abdominal pain or 
pelvic pain 
 
• Positive LCE on urinalysis; 
• WBC count 10 cells/mm3 in 
unspun urine;  
• WBC count 10 cells/hpf in 
urine sediment 
cUTI = complicated urinary tract infection; hpf = high-power field; LCE = leukocyte esterase; PMN = polymorphonuclear 
leukocyte; WBC = white blood cell. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Acute Pyelonephritis 
Expectation, in the judgment of the Investigator, that any indwelling urinary catheter or 
instrumentation (including nephrostomy tubes and/or indwelling stents) will be removed or 
replaced (if removal is not clinically acceptable) before or as soon as possible, but not longer 
than 12 hours, after randomization, AND: 
Indication 
Presence of an ascending tract infection including at least 
TWO of the following signs or symptoms: 
AND at least ONE of the 
following: 
AP 
• Chills, rigors, or fever* (oral or tympanic temperature 
38°C [100.4°F] or rectal/core temperature 38.3°C 
[100.9°F]); 
• Elevated WBC count (>10,000/mm3), or left shift (>15% 
immature PMNs); 
• Nausea or vomiting; 
• Dysuria, increased urinary frequency, or urinary urgency; 
• Flank pain;  
• Costo-vertebral angle tenderness on physical examination 
• Positive LCE on urinalysis; 
• WBC count 10 cells/mm3 in 
unspun urine;  
• WBC count 10 cells/hpf in urine 
sediment 
AP = acute pyelonephritis; hpf = high-power field; LCE = leukocyte esterase; PMN = polymorphonuclear leukocyte; 
WBC = white blood cell. 
 
Complicated Intra-Abdominal Infection (cIAI)  
Patients may be enrolled approximately 24 hours before or 96 hours after the surgical 
procedure when the following conditions are met:  
• Expectation, 
in 
the 
judgment 
of 
the 
investigator, 
that 
operative 
drainage/debridement/removal (including open laparotomy, percutaneous drainage, or 
laparoscopic surgery) of any intra-abdominal collection or other potential source of 
intra-abdominal infection will be performed;                      
• Expectation that cultures from the aforementioned procedure (including open laparotomy, 
percutaneous drainage, or laparoscopic surgery) will be sent for microbiological 
evaluation, including gram stain, culture and susceptibility testing, and Carbavance 
susceptibility testing AND:    
 
Indication 
At least ONE of the following, either on intra-operative 
visualization of infection (e.g. pus within the abdominal 
cavity) OR supportive radiographic imaging) : 
AND at least ONE of the 
following: 
cIAI 
• Intra-abdominal abscess, including splenic or hepatic abscess; 
• Appendicitis or diverticulitis with peritonitis, perforation or 
abscess; 
• Perforation of stomach or intestine, associated with peritonitis, 
abscess or fecal contamination;  
• Cholecystitis or cholangitis with perforation, abscess or 
progression beyond the gallbladder wall or biliary tract.   
• Chills, rigors, or fever* (oral or 
tympanic temperature 38°C 
[100.4°F] or rectal/core temperature 
38.3°C; 
• Hypotension, systolic BP <90 mmHg;  
• Abdominal pain or tenderness; 
• Nausea or vomiting; 
• Abdominal mass on clinical 
examination; 
• Altered mental status. 
BP = blood pressure; cIAI = complicated intra-abdominal infection. 


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Hospital Acquired Bacterial Pneumonia  
Indication All of the following: 
AND signs or symptoms 
evidenced by at least TWO 
of the following: 
AND at least ONE of the following: 
HABP  
 
• The onset of symptoms 
>48 hours after 
admission or <7 days 
after discharge from an 
inpatient acute or chronic 
care facility (e.g., LTAC, 
rehabilitation center, 
hospital, or skilled 
nursing home); 
OR  
• Admission from LTAC 
or rehabilitation center, 
or admission from home 
<7 days after discharge 
from an LTAC or 
rehabilitation center; 
• New or evolving 
infiltrate on chest x-ray 
obtained within 48 hours 
prior to randomization 
and >48 hours after 
hospitalization 
• A new onset of cough (or 
worsening of baseline 
cough); 
• Auscultatory findings 
consistent with pneumonia/ 
pulmonary consolidation 
(e.g., rales, dullness on 
percussion, bronchial breath 
sounds, or egophony); 
• Dyspnea, tachypnea, or 
respiratory rate greater than 
25/min;  
• Hypoxemia (O2 saturation 
<90% or pO2 <60 mmHg 
while breathing room air, or 
worsening of the 
O2sat/FiO2); 
OR The following criterion 
ALONE: 
• New onset need for 
mechanical ventilation  
• Fever* (oral or tympanic 
temperature 38°C [100.4°F] or 
rectal/core temperature 38.3°C 
[100.9°F]) OR hypothermia 
(rectal/core temperature <35°C 
[<95°F]); 
• Elevated total peripheral WBC 
count (>10,000/mm3);  
• >15% immature neutrophils (bands) 
regardless of total peripheral WBC 
count;  
• Leukopenia (total WBC 
<4,500/mm3);  
• Procalcitonin >0.25 μg/mL 
HABP = hospital-acquired bacterial pneumonia; LTAC = long-term acute care; WBC = white blood cell. 
Ventilator Associated Bacterial Pneumonia  
Indication All of the following: 
AND signs or symptoms 
evidenced by at least TWO 
of the following: 
AND at least ONE of the following: 
VABP 
• The onset of symptoms 
>48 hours after receiving 
ventilatory support via an 
endotracheal (or 
nasotracheal) tube; 
• Require ventilatory 
support; 
• New or evolving 
infiltrate on chest x-ray 
obtained within 48 hours 
prior to randomization 
and >48 hours after 
intubation 
• Auscultatory findings 
consistent with pneumonia/ 
pulmonary consolidation 
(e.g., rales, dullness on 
percussion, bronchial breath 
sounds, or egophony); 
• An acute change in the 
ventilator support system to 
enhance oxygenation, as 
determined by a worsening 
oxygen saturation/FiO2 
ratio; 
• Increased suctioning; 
• Tracheal aspirate change to 
purulence 
• Fever* (oral or tympanic 
temperature 38°C [100.4°F] or 
rectal/core temperature 38.3°C 
[100.9°F]) OR hypothermia 
(rectal/core temperature <35°C 
[<95°F]); 
• Elevated total peripheral WBC 
count (>10,000/mm3);  
• >15% immature neutrophils (bands) 
regardless of total peripheral WBC 
count;  
• Leukopenia (total WBC 
<4,500/mm3);  
• Procalcitonin >0.25 μg/mL 
VABP = ventilator-associated bacterial pneumonia; WBC = white blood cell. 


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Bacteremia 
Indication 
All of the following: 
AND at least ONE of the following: 
Bacteremia 
• Isolation of a CRE from 
at least 1 blood culture 
• Fever* (oral or tympanic temperature 38°C [100.4°F] or 
rectal/core temperature 38.3°C [100.9°F]) OR hypothermia 
(rectal/core temperature <35°C [<95°F]); 
• Elevated total peripheral WBC count (>10,000/mm3); 
• >15% immature neutrophils (bands) regardless of total peripheral 
WBC count (>10,000/mm3); 
• Leukopenia (total WBC <4,500/mm3); 
• Tachycardia >100 bpm; 
• Tachypnea >20 breaths/min; 
• Hypotension, systolic <90 mmHg 
CRE = carbapenem-resistant Enterobacteriaceae; WBC = white blood cell. 
9. Female subjects of childbearing potential, including those who are less than 2 years 
post-menopausal, must agree to, and comply with, using 2 highly effective methods of birth 
control (i.e., condom plus spermicide, combined oral contraceptive, implant, injectable, 
indwelling intrauterine device, sexual abstinence, or a vasectomized partner) while 
participating in this study. In addition, all women of childbearing potential must agree to 
continue to use 2 forms of birth control throughout the study and for at least 30 days after 
administration of the last dose of study drug. 
* Evidence of fever within 24 hours of the screening visit is acceptable if observed and documented 
by a health care provider. 
10.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be enrolled in the study: 
1. History of any significant hypersensitivity or severe allergic reaction to any beta-lactam 
antibiotics (e.g., cephalosporins, penicillins, carbapenems, or monobactams). 
2. Known or suspected likely infection with New Delhi metallo- (NDM), Verona 
integron-encoded 
metallo- 
(VIM), 
or 
imipenemase-metallo-beta-lactamases 
or 
oxacillinase (OXA)-beta-lactamases (i.e., Class B or Class D beta-lactamases). 
3. For subjects to be enrolled with the primary indication of cUTI or AP, any of the following 
urologic conditions: 
a. Likely to receive ongoing antibacterial drug prophylaxis after treatment of cUTI 
(e.g., subjects with vesico-ureteral reflux); 
b. Suspected or confirmed prostatitis; 
c. Requirement for bladder irrigation with antibiotics or for antibiotics to be 
administered directly via urinary catheter; 
d. Previous or planned cystectomy or ileal loop surgery; 
e. Uncomplicated UTI (for example, female subjects with urinary frequency, urgency 
or pain or discomfort without systemic symptoms or signs of infection); 
f. Complete, permanent obstruction of the urinary tract; 


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g. Suspected or confirmed perinephric or renal corticomedullary abscess; 
h. Polycystic kidney disease; or 
i. Any recent history of trauma to the pelvis or urinary tract. 
4. For subjects to be enrolled with the primary indication of cIAI, any of the following 
conditions:  
a. Incomplete drainage of suspected or known intra-abdominal source; 
b. Likely to receive ongoing antibacterial drug prophylaxis or chronic suppressive 
therapy after intravenous treatment of cIAI; 
c. Source of infection thought to be related to or involving a non-removable prosthesis 
(e.g. intra-abdominal mesh) or implantable device, line (e.g. peritoneal catheter) or 
stent (e.g. biliary stent);  
d. Uncomplicated intra-abdominal infection, such as simple appendicitis, simple 
cholecystitis or gangrenous cholecystitis without rupture;  
e. Patients with infected necrotizing pancreatitis or pancreatic abscess;   
f. Patients whose surgery will include staged abdominal repair or “open abdomen” 
technique, or marsupialization (i.e. patients who undergo a surgical procedure 
where fascial closure is performed are eligible. The skin incision may be left open 
for purposes of wound management as long as fascial closure is accomplished);   
g. Patients in whom the intra-abdominal process is deemed not likely to be infectious 
in origin (e.g. bowel obstruction, ischemic bowel without perforation, traumatic 
bowel perforation within past 12 hours, perforated gastroduodenal ulcer within 
24 hours); or   
h. Non-intra-abdominal infection (e.g. infection or abscess of the abdominal wall 
without extension into the intra-abdominal cavity). 
5. For subjects to be enrolled with the primary indication of HABP or VABP, any of the 
following conditions:  
a. Diagnosis of ventilator-associated tracheobronchitis; or  
b. Inability to obtain proper respiratory specimens for culture. 
6. For subjects to be enrolled with the indication of bacteremia unrelated to cUTI or AP, cIAI, 
HABP, and VABP, any of the following: 
a. Unverified CRE infection; or  
b. Source of infection thought to be related to or involving a non-removable or 
implantable device or line. 


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7. Evidence of immediately life-threatening disease where in the opinion of the Investigator, 
the subject is unlikely to survive more than 72 hours from randomization.  
8. Acute Physiology and Chronic Health Evaluation (APACHE) II score >30. An APACHE 
II score is only required if calculated. 
9. Known or suspected endocarditis, meningitis, or osteomyelitis. 
10. Irremovable or implantable device or line thought to be the potential source of infection. 
11. Evidence of significant hepatic, hematological, or immunologic disease or dysfunction 
determined by any of the following: 
a. Known fulminant viral hepatitis 
b. Subjects meeting Hy’s criterion of ALT or AST >3  ULN AND total bilirubin >2 
 ULN AND no other explanation such as hepatitis or acute liver injury, etc.; 
c. Manifestations of end-stage liver disease, such as ascites or hepatic 
encephalopathy; or 
d. Human immunodeficiency virus with either a CD4 count <200 cells/mm3 at the last 
measurement, or current diagnosis of another Acquired Immune Deficiency 
Syndrome-defining illness. 
12. Women who are pregnant or breastfeeding. 
13. Require the use of inhaled antibiotics. 
14. Participation in any study involving administration of an investigational agent or device 
within 30 days prior to randomization into this study or previous participation in the current 
study. 
15. Previous participation in a study of RPX7009. 
16. Any condition that, in the opinion of the Investigator, would compromise the safety of the 
subject or the quality of the data. 
10.3 
Prior and Concomitant Treatment 
Reasonable efforts will be made to determine all relevant concomitant medications received during 
the study and within 14 days before administration of study drug. Relevant concomitant treatments 
(non-pharmacologic treatments) which include any surgical or diagnostic procedures will also be 
captured in the source documents. 
10.3.1 
Permitted Non-antibacterial Treatment 
Subjects may continue standard non-antibacterial therapy (unless excluded in Section 10.3.4).  
10.3.2 
Permitted Antibacterial Treatments  
Subjects in both treatment arms may receive coverage (e.g., vancomycin or linezolid) for 
gram-positive organisms, as deemed necessary by the Investigator.  
Subjects with cIAI randomized to the BAT treatment arm may receive metronidazole. 


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Subjects with cUTI or AP who are randomized to Carbavance (meropenem/RPX7009) or to BAT 
and are treated with ceftazidime-avibactam should receive Carbavance (meropenem/RPX7009) or 
ceftazidime-avibactam alone, respectively. 
Subjects with cIAI, HABP, VABP, or bacteremia who are randomized to Carbavance 
(meropenem/ RPX7009) or to BAT and are treated with ceftazidime-avibactam should receive 
Carbavance (meropenem/RPX7009) or ceftazidime-avibactam alone, respectively. However, if 
the Investigator believes it is medically necessary, subjects may receive supportive 
aminoglycoside therapy in conjunction with Carbavance (meropenem/RPX7009) 
or 
ceftazidime-avibactam until culture information is available or for the first 72 hours, whichever is 
the shorter. Aminoglycoside treatment should be discontinued once the subject’s organism is 
shown to be susceptible to Carbavance (meropenem/RPX7009) or ceftazidime-avibactam and the 
subject is clinically improving. The use of an aminoglycoside beyond 72 hours in subjects with a 
pathogen(s) susceptible to Carbavance (meropenem/RPX7009) or ceftazidime-avibactam will be 
considered a treatment failure. 
Inhaled antibiotics, including aminoglycosides, are not permitted.  
Bladder irrigation with antibiotics or antibiotics administered directly via a urinary catheter are 
not permitted. 
Intra-abdominal irrigation with antibiotics or antibiotics administered through a peritoneal 
dialysis catheter or other intra-abdominal catheter are not permitted.   
10.3.3 
Permitted Anti-infective Adjunctive Therapies and Procedures  
Local care for superficial wounds is permitted (i.e., topical antiseptic therapy, topical antibiotic 
ointment, wet-to-dry dressing change). The use of topical antibiotic therapy with activity against 
gram-negative organisms is discouraged, but will not constitute a failure of the primary antibiotic 
regimen if administered.  
10.3.4 
Concomitant Medication Precautions and Exclusions 
Caution should be used in subjects receiving concurrent valproic acid or probenecid as use of 
carbapenems may lower the serum concentration of these agents.  Physicians are therefore advised 
to consider checking serum levels of these agents frequently in patients receiving concurrent 
Carbavance or carbapenems. A one-time dose of vecuronium, rocuronium, or other paralytic agent 
during intubation is permitted. Due to drug-drug interactions between rocuronium, vecuronium, 
and similar paralytic agents and several BAT agents (including aminoglycosides and polymyxins) 
investigators are cautioned not to choose aminoglycosides or polymyxins as BAT in patients with 
ongoing receipt (i.e. continuous infusion) of rocuronium, vecuronium, or other paralytic agent.   
10.4 
Randomization and Treatment Group Assignment 
Subjects will be randomized to receive either Carbavance (meropenem/RPX7009) or BAT through 
a centralized Interactive Web Response System (IWRS). The time and date of randomization will 
be recorded on the IWRS confirmation, which will be the reference time point for screening 
procedures and diagnostic time windows. The subject will only be randomized after the inclusion 
and exclusion criteria are verified. A manual will be provided that describes the IWRS and includes 
complete user instructions. 


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To ensure balance among treatment arms, the randomization will be stratified by presenting 
indication (cUTI or AP, cIAI, HABP, VABP, and bacteremia) and by region (North America vs. 
Europe vs. Asia Pacific vs. Rest of World).  
Enrollment will continue until at least 45 subjects (30 Carbavance [meropenem/RPX7009], 
15 BAT) with cUTI or AP are documented to have a CRE organism at baseline and until at least 
30 subjects with cIAI with a documented CRE organism at baseline (20 Carbavance 
[meropenem/RPX7009], 10 BAT) are enrolled.  Once the specified number of subjects are enrolled 
in the cUTI and/or cIAI indications, data from these subjects may be submitted to regulatory 
agencies in support of a marketing application, and the enrollment of additional subjects into the 
specific indication(s) where enrollment was met may be stopped. 
Subjects will be randomized in a 2:1 ratio. A randomization notification will be sent to the 
appropriate site personnel; it will contain subject identification information and the treatment 
assignment for entry onto the eCRF. 
10.5 
Subject Numbering 
Subjects will be assigned a screening number during screening. Once enrolled in the study, subjects 
will be assigned a unique study subject number by IWRS.  
 
 


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11 STUDY DRUGS 
Intravenous study drug will be administered in an open-label design. The following drugs will be 
administered in this study: 
• Carbavance (meropenem/RPX7009) for IV infusion, administered as a 2 g/2 g dose diluted in 
normal saline to a volume of 250 mL and infused for 3 hours q8h; and 
• Subjects will receive BAT, with IV antibiotics, either alone or in combination, chosen from 
the following: carbapenem (meropenem, ertapenem, or imipenem), tigecycline, colistin, 
aminoglycoside 
(amikacin, 
tobramycin, 
or 
gentamicin), 
polymyxin 
B, 
and 
ceftazidime-avibactam. Details for dose and frequency of administration of BAT (as well as 
warnings, precautions, and contraindications) can be found in the referenced summaries of 
product characteristics for the specific antibacterials selected by the Investigator as 
BAT.4,7,8,9,10,11,12,13,14 Investigators will be instructed to select only country-approved therapies. 
Infusions of IV study drugs will occur for 7 to 14 days. Subjects whose cultured pathogen is shown 
not to be susceptible to Carbavance (meropenem/RPX7009) or the treatment chosen as BAT may 
continue that treatment as long as the subject is clinically improving. If, more than 72 hours 
post-randomization, the subject is not clinically improving, and the cultured pathogen is shown 
not to be susceptible to Carbavance (meropenem/RPX7009) or the treatment chosen as BAT and 
the Investigator elects to change antibacterial therapy, EOT procedures should be performed and 
the subject should complete further visits as planned. 
11.1 
Description of Carbavance (Meropenem/RPX7009) 
Meropenem is a white to pale yellow crystalline powder. The solution varies from colorless to 
yellow depending on the concentration. When reconstituted as instructed, each 1 g vial will deliver 
1 g of meropenem for injection. 
RPX7009 is a sterile, lyophilized white to off-white powder presented in 20 mL single-use vials. 
Each labeled vial contains enough RPX7009 to deliver either 500 mg or 1000 mg RPX7009 when 
reconstituted and prepared according to instructions. Once reconstituted, it is a clear, colorless to 
yellow solution. 
11.1.1 
Administration of Carbavance (Meropenem/RPX7009) 
A pharmacist will be responsible for providing Carbavance (meropenem/RPX7009) to the study 
personnel for administration. The study drug will be provided ready for IV infusion. Subjects will 
receive Carbavance (meropenem/RPX7009) 2 g/2 g diluted in normal saline to a volume of 
250 mL infused for 3 hours q8h.  
Each dose of IV study drug will be delivered over approximately 3 hours by programmable 
infusion pump. The time at which the infusion is started and stopped must be recorded. Instances 
where a dose is interrupted by more than 10 minutes should be noted in the source documents, 
including the reason for interruption. The reasons for missed doses should be noted in the source 
documents. Subjects will receive infusions every 8 hours (±2 hours). Infusions that fall outside of 
that q8h dosing (± 2 hours) will be captured as protocol deviations. 


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Dosing time is considered to be relative to the start of infusion. For additional information on drug 
product dilution, infusion volumes, and dispensing instructions, refer to the Rempex-506 
Pharmacy Manual. 
11.1.2 
Dosing in Subjects with Renal Insufficiency 
As summarized in Section 7.5.3 and Appendix 4, in subjects with impaired renal function, both 
meropenem and RPX7009 continue to follow a linear PK profile, allowing the ratio of meropenem 
and RPX7009 to be maintained in subjects with reduced renal function.  
Table 7 summarizes recommended Carbavance dosing regimens for subjects with renal 
impairment, including subjects receiving hemodialysis.   
Sites will be responsible for testing estimated creatinine clearance in the local laboratory per 
institutional standard operating procedures and are responsible for ensuring dose adjustments are 
made accordingly. Estimated creatinine clearance and dose adjustment data will be captured in 
source documents and in eCRF. 
Table 7. 
Reduced Renal Function Dose Adjustment Table 
Estimated Creatinine Clearance, 
ml/min (Cockcroft-Gault) 
Carbavance Dosage Regimen (All doses infused over 3 hours) 
 
50 
Meropenem 2 g / RPX7009 2 g q8h 
30 – 49 
Meropenem 1 g / RPX7009 1 g q8h 
20 – 29 
Meropenem 1 g / RPX7009 1 g q12h 
10-19
Meropenem 500 mg / RPX7009 500 mg q12h 
<10 
Meropenem 500 mg / RPX7009 500 mg q24ha 
a. Subjects with an estimated creatinine clearance of less than 10 ml/min are required to receive dialysis at least twice per week. 
Maintenance doses of Carbavance in these subjects should be administered as soon as possible after the dialysis session. For 
example, if a subject is scheduled to receive Carbavance at 18:00 but receives hemodialysis at 13:00, the planned 18:00 
Carbavance dose should be given after the dialysis session is completed (rather than waiting until 18:00). 
q8h = every 8 hours; q12h = every 12 hours; q24h = every 24 hours. 
 
11.2 
Description of Best Available Therapy 
Subjects randomized to BAT will be treated with IV antibiotics, either alone or in combination, 
chosen from the following: carbapenem (meropenem, ertapenem, or imipenem), tigecycline, 
colistin, aminoglycosides (amikacin, tobramycin or gentamicin), polymyxin B, and 
ceftazidime-avibactam. The doses and combinations for BAT will be determined by the 
Investigator.  
Ceftazidime-avibactam may also be used as BAT, but may not be given in combination with other 
BAT agents, with the exception of concurrent aminoglycoside therapy for either 72 hours/pending 
susceptibility testing in patients with cIAI, HABP, VABP and bacteremia, similar to Carbavance 
(See Section 10.3.2). Details for dose and frequency of administration of BAT (as well as 
warnings, precautions, and contraindications) can be found in the summaries of product 
characteristics for the specific antibacterials selected by the Investigator for BAT.4,7,8,9,10,11,12,13,14,16 
Investigators will be instructed to select only country-approved therapies.   


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Investigators will be asked to identify the choice of BAT in advance of randomization to minimize 
potential selection bias. Modification of BAT is permitted based on susceptibility information for 
up to 72 hours post-randomization. Changes in treatment (other than dose adjustment) more than 
72 hours post-randomization will constitute a clinical outcome of failure. End of Treatment 
procedures should be performed and treatment changed as determined by the Investigator. Subjects 
will complete all study visits and procedures according to Table 1. 
11.3 
Carbavance (Meropenem/RPX7009) Labeling and Packaging 
The Sponsor or their designee will package, label, and supply Carbavance (meropenem/RPX7009) 
according to applicable regulatory requirements. Other medications to be used in the BAT 
treatment arm will be obtained through usual processes as directed by the investigative sites. 
The investigational medicinal product will be labeled in appropriate local language according to 
Annex 13 Good Manufacturing Practices (GMP) and country specific requirements, packaged, 
stored released, and distributed according to current GMP. 
11.4 
Study Drug Storage Conditions 
The Investigator or an approved representative (e.g., pharmacist) will ensure that all Carbavance 
(meropenem/RPX7009) is stored in a locked secured area (with limited access available to 
appropriate study personnel) only under recommended storage conditions and in accordance with 
applicable regulatory requirements. Best Available Therapy medications will be stored in 
accordance with their label, as directed by the Investigator and/or associated care team members.  
All study drug should be stored, per labeling. Refer to the Pharmacy Manual and Temperature 
Excursion Process for temperatures and allowances. 
11.5 
Receipt of Supplies 
Upon receipt of Carbavance (meropenem/RPX7009), the pharmacist or designated study site 
personnel will visually inspect the shipment and verify the drug information, quantity, and 
condition of the kits received. An investigational drug transmittal and receipt form will be 
completed and signed by the pharmacist. Receipt of shipment will be verified through the IWRS. 
11.6 
Study Drug Accountability  
It is the responsibility of the Investigator to ensure that a current record of inventory/drug 
accountability is maintained. Inventory records must be readily available for inspection by the 
study monitor and available to regulatory agencies for inspection at any time. 
11.7 
Carbavance (Meropenem/RPX7009) Handling and Return  
Upon the completion or termination of the study, the Sponsor or the Sponsor’s representative will 
provide 
disposal 
instructions 
for 
all 
unused 
and/or 
partially 
used 
Carbavance 
(meropenem/RPX7009) at the investigational site. It is the Investigator’s responsibility to ensure 
that the instructions provided by the Sponsor or the Sponsor’s representative are followed and that 
appropriate records of the return or disposal of Carbavance (meropenem/RPX7009) are 
documented and maintained. No unused drug may be returned or destroyed until it has been fully 
accounted for by the Sponsor’s monitor (or designee). 


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12 STUDY ASSESSMENTS AND PROCEDURES 
12.1 
Screening (Day -1 or Day 1 Pre-randomization) 
The screening visit can occur up to 24 hours prior to first dose of study drug unless otherwise noted 
below. Screening procedures done only for study purposes may only be performed after informed 
consent has been obtained. If a subject is unable to provide informed consent due to their medical 
condition, the subject’s legal representative will be provided with study information in order for 
consent to be obtained. If the screening sample for culture is taken per standard of care before the 
subject signs informed consent (or consent is obtained from the subject’s legal representative), that 
isolate may be used for baseline and sent to the central laboratory as long as the sample was 
collected within 72 hours (96 hours for cIAI) of the first dose of study drug. Screening assessments 
will include the following: 
• Review of all inclusion and exclusion criteria (See Section 10.1 and Section 10.2, 
respectively); 
• Record medical/surgical history including all clinically significant past and present illnesses 
(See Section 12.4.2); 
• Record relevant prior and concomitant medications taken within the previous 14 days and all 
current drugs taken (See Section 12.4.3); 
• Record demographic information including name, sex, age, race, weight, and alcohol use 
(See Section 12.4.4); 
• Record height and weight (See Section 12.4.4); 
• Perform complete physical examination (See Section 12.4.4); 
• Perform a chest x-ray, magnetic resonance imaging (MRI), or computed tomography (CT) scan 
in subjects with HABP or VABP only; a chest x-ray, MRI, or CT scan performed for standard 
of care in order to support a diagnosis within 48 hours of randomization is acceptable (See 
Section 12.4.4); 
• Obtain vital sign measurements, including blood pressure, heart rate, respiratory rate, and 
temperature (See Section 12.4.5); 
• Assess clinical signs/symptoms (see Section 12.4.6); 
• Perform serum and urine pregnancy test (for women of childbearing potential only) 
(See Section 12.4.9); 
• Perform 12-lead ECG (See Section 12.4.7); 
• Urine sample for screening laboratory assessments; labs collected for standard of care in order 
to support a diagnosis within 48 hours of randomization are acceptable (See Section 12.4.9);  
• Blood samples for screening laboratory assessments: labs collected for standard of care in order 
to support a diagnosis within 48 hours of randomization are acceptable (See Section 12.4.9); 
and  
• Identify choice for BAT in the event the subject is randomized to BAT.   


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12.2 
Treatment Period (Day 1 up to Day 14) 
The date of the first dose of study drug will be considered Day 1, and subsequent study days are 
defined by calendar days thereafter. Starting on Day 1, subjects are expected to receive daily IV 
treatment for 7 to 14 days.  
The following procedures will be performed daily throughout the treatment period unless 
otherwise indicated: 
• Continue to administer routine care according to local standard; 
• Assess adverse events (See Section 14.1); 
• Record concomitant medications (See Section 12.4.3);  
• Perform a limited physical examination (If a subject does not display symptoms, no limited 
physical examination needs to be performed) (See Section 12.4.4); 
• Continue IV study drug therapy and record study drug dosing information (time of 
administration, dose) daily;  
• Assess clinical signs/symptoms and vital signs (See Section 12.4.6); and 
• When applicable (e.g., subjects with active bacteremia), collect blood cultures and send to the 
local lab for analysis (See Section 12.4.14). 
12.2.1 
Day 1 Pre-Dose 
Day 1 may be the same day as screening, or may occur up to 24 hours after screening. The calendar 
date of the first dose of study drug will be considered Day 1. The following procedures will be 
performed on Day 1 (in addition to any screening procedures also performed): 
• Review all inclusion and exclusion criteria, including microbiology data (if available) 
(See Section 10.1 and Section 10.2, respectively);  
• Assess adverse events (See Section 14.1);  
• Record relevant concomitant medications (See Section 12.4.3); 
• Obtain vital sign measurements, including blood pressure, heart rate, and respiratory rate. 
Screening vital signs may be used if collected within 4 hours of the first dose of IV study drug. 
(See Section 12.4.5); 
• Assess pre-dose clinical signs/symptoms. Screening clinical signs and symptoms may be used 
if collected within 4 hours of the first dose of IV study drug. (See Section 12.4.6); 
• Collect pre-dose urine sample for urinalysis and send to the central lab (See Section 12.4.9); 
• Collect pre-dose blood samples for serum chemistry and hematology analyses and send to the 
central lab (See Section 12.4.9);  
• Collect pre-dose infection site-specific sample for culture and send to local lab for analysis and 
susceptibility testing (See Section 12.4.14); 
• Collect blood cultures and send to local lab for analysis. (See Section 12.4.14); 


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• Blinded Investigator performs a baseline assessment of signs and symptoms (See 
Section 12.4.6); 
• Obtain randomized treatment assignment via the IWRS; and 
• For subjects with cIAI, operative drainage/debridement/removal (including open laparotomy, 
percutaneous drainage, or laparoscopic surgery) of any intra-abdominal collection or other 
potential source of intra-abdominal infection should be performed within 96 hours before or 
24 hours after the first dose of study drug.  
12.2.2 
Study Day 1 Post-Dose 
The following procedures will be performed on Day 1 after administration of first dose of study 
drug: 
• Administer IV study drug at appropriate times during the day and record start and stop time of 
study drug administration;  
• Assess adverse events (See Section 14.1); and 
• For subjects receiving Carbavance (meropenem/RPX7009) only: Collect PK blood samples 
within 30 minutes and 2 to 3 hours after end of first infusion (See Section 12.4.10).  
12.2.3 
Day 3 
All subjects will be assessed on Day 3 of treatment. The following procedures will be performed 
on Day 3: 
• Assess adverse events (See Section 14.1); 
• Record relevant concomitant medications (See Section 12.4.3); 
• Perform complete physical examination (See Section 12.4.4); 
• Assess clinical signs/symptoms and vital signs (See Section 12.4.6);  
• Record clinical outcome (See Section 12.4.6); 
• Collect urine sample for urinalysis (See Section 12.4.9);  
• Collect blood samples for serum chemistry and hematology analyses (See Section 12.4.9); 
• Administer IV study drug therapy at appropriate times and record study drug dosing 
information (time of administration, dose); 
• For subjects receiving Carbavance (meropenem/RPX7009) only: Collect PK blood sample 
within 30 minutes after end of one of that day’s infusions (See Section 12.4.10);  
• Collect infection site-specific sample for culture (See Section 12.4.14); and 
• When applicable (e.g., subjects with active bacteremia), collect blood cultures and send to local 
lab for analysis (See Section 12.4.14). 


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12.2.4 
Day 5 
All subjects will be assessed on Day 5 of treatment. The following procedures will be performed 
on Day 5: 
• Assess adverse events (See Section 14.1); 
• Record relevant concomitant medications (See Section 12.4.3);  
• Perform a complete physical examination (See Section 12.4.4); 
• Assess clinical signs/symptoms and vital signs (See Section 12.4.6);  
• When applicable (e.g., subjects with active bacteremia), collect blood cultures and send to local 
lab for analysis (See Section 12.4.14); 
• Administer IV study drug therapy and record study drug dosing information (time of 
administration, dose) daily; and 
• For subjects receiving Carbavance (meropenem/RPX7009) only: Collect PK blood sample 
within 30 minutes after end of one of that day’s infusions (See Section 12.4.10). 
12.2.5 
Day 7 
All subjects will be assessed on Day 7 of treatment. The following procedures will be performed 
on Day 7: 
• Assess adverse events (See Section 14.1); 
• Record relevant concomitant medications (See Section 12.4.3); 
• Perform complete physical examination (See Section 12.4.4); 
• Assess clinical signs/symptoms and vital signs (See Section 12.4.6);  
• Record clinical outcome (See Section 12.4.6); 
• Collect urine sample for urinalysis (See Section 12.4.9);  
• Collect blood samples for serum chemistry and hematology analyses (See Section 12.4.9); 
• Administer IV study drug therapy at appropriate times and record study drug dosing 
information (time of administration, dose); and 
• Collect infection site-specific sample for culture (see Section 12.4.14). 
12.2.6 
End of Treatment (EOT) 
All subjects will be assessed on their last day of treatment, +1 day (any time from Day 7 to Day 14). 
If EOT is on Day 7, visit activities will be combined. If a subject’s treatment is changed after 
72 hours post-randomization based on susceptibility data, EOT procedures will be performed and 
the subject will complete further visits as planned (See Section 11). The following procedures will 
be performed at the EOT visit: 
• Assess adverse events (See Section 14.1); 
• Record relevant concomitant medication (See Section 12.4.3); 


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• Perform complete physical examination (See Section 12.4.4); 
• Assess clinical signs/symptoms and vital signs (See Section 12.4.6);  
• Record clinical outcome (See Section 12.4.6); 
• Blinded Investigator completes assessment of signs and symptoms and records clinical 
outcome (See Section 12.4.6); 
• Perform 12-lead ECG (See Section 12.4.7); 
• Perform urine and serum pregnancy test (for women of childbearing potential only) (See 
Section 12.4.9); 
• Collect urine samples for urinalysis (See Section 12.4.9);  
• Collect blood samples for serum chemistry and hematology analyses (See Section 12.4.9);  
• When applicable (e.g., subjects with active bacteremia), collect blood cultures and send to local 
lab for analysis (See Section 12.4.14); 
• Administer IV study drug therapy at appropriate times and record study drug dosing 
information (time of administration, dose); and 
• Collect infection site-specific sample for culture (See Section 12.4.14). 
12.3 
Follow-up Period  
12.3.1 
Test of Cure (TOC) Visit (7 days [±2 days] post-EOT) 
Assessments for TOC will be performed 7 days (±2 days) post-EOT (Day 12 to Day 23). Any 
subjects receiving treatment for less than 7 days should have a TOC visit on Day 12 (+2 days). 
The following procedures will be performed at the TOC visit:  
• Assess adverse events (See Section 14.1); 
• Record relevant concomitant medications (See Section 12.4.3); 
• Perform limited physical examination (If a subject does not display symptoms, no limited 
physical examination needs to be performed) (See Section 12.4.4); 
• Perform a chest x-ray, MRI, or CT scan in subjects with HABP or VABP only (See 
Section 12.4.4); 
• Assess clinical signs/symptoms and vital signs (See Section 12.4.6);  
• Record clinical outcome (See Section 12.4.6); 
• Blinded Investigator assesses signs and symptoms and records clinical outcome (See 
Section 12.4.6); 
• Collect urine samples for urinalysis (See Section 12.4.9); 
• Collect blood samples for serum chemistry and hematology analyses (See Section 12.4.9);  
• Collect infection site-specific sample for culture (See Section 12.4.14); and 


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• When applicable (e.g., subjects with active bacteremia), collect blood cultures and send to local 
lab for analysis (See Section 12.4.14). 
12.3.2 
Late Follow-Up (LFU) Visit (14 days [±2 days] post-EOT) 
Assessments for LFU will be performed 14 days (±2 days) post-EOT (Day 19 to Day 30). Any 
subjects receiving treatment for less than 7 days should have an LFU visit on Day 19 (+2 days). 
The LFU visit should be performed in-house (with limited physical examination) if at all possible. 
If not possible, a phone call to assess the subject’s wellbeing may be substituted. For any outpatient 
subjects with an LFU visit occurring before Day 28, a phone call to assess survival will be made 
on Day 28. The following procedures will be performed at the LFU visit: 
• Assess adverse events (See Section 14.1); 
• Record relevant concomitant medications (See Section 12.4.3); 
• Perform limited physical examination (If a subject does not display symptoms, no limited 
physical examination needs to be performed) (See Section 12.4.4); 
• Assess clinical signs/symptoms and vital signs (See Section 12.4.6); 
• Record clinical outcome (See Section 12.4.6); 
• Collect urine samples for urinalysis (See Section 12.4.9); 
• Collect blood samples for serum chemistry and hematology analyses (See Section 12.4.9);  
• Collect infection site-specific sample for culture (See Section 12.4.14); and 
• When applicable (e.g., subjects with active bacteremia), collect blood cultures and send to local 
lab for analysis (See Section 12.4.14). 
12.3.3 
Early Termination 
Subjects who withdraw from the study for any reason prior to the completion of the trial will 
complete an early termination visit. The following procedures will be performed at the early 
termination visit: 
• Assess adverse events (See Section 14.1); 
• Record relevant concomitant medication (See Section 12.4.3); 
• Perform complete physical examination (See Section 12.4.4); 
• Obtain vital sign measurements, including blood pressure, heart rate, respiratory rate and 
temperature (See Section 12.4.5); 
• Assess clinical signs/symptoms (See Section 12.4.6);  
• Record clinical outcome (See Section 12.4.6); 
• Blinded Investigator performs a review of blinded vital signs and laboratory data, an 
assessment of signs and symptoms, and an assessment of clinical outcome (See 
Section 12.4.6); 
• Perform 12-lead ECG (See Section 12.4.7); 


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• Perform urine and serum pregnancy test (for women of childbearing potential only) 
(See Section 12.4.9); 
• Collect urine samples for urinalysis (See Section 12.4.9);  
• Collect blood samples for serum chemistry and hematology analyses (See Section 12.4.9);  
• Collect infection site-specific sample for culture (See Section 12.4.14); and 
• When applicable (e.g., subjects with active bacteremia), collect blood cultures and send to local 
lab for analysis (See Section 12.4.14). 
12.4 
Study Interventions/Procedures 
12.4.1 
Informed Consent 
Informed consent should be obtained by the Investigator from the subject prior to study 
participation in accordance with Good Clinical Practice (GCP) and applicable regulatory 
requirements. When a subject is not capable of giving informed consent, the permission of a legally 
authorized representative should be obtained in accordance with applicable law.  
All subjects will be informed of the nature and purpose of this study. An informed consent 
document approved by a regional Independent Ethics Committee (IEC)/Institutional Review 
Board (IRB) must be signed and dated prior to any study-related procedures being performed at 
screening. The original signed informed consent form for each participating subject will be filed 
with records kept by the Investigator(s) and will be documented in the clinical or research record. 
A copy of the signed/dated informed consent document must be provided to the subject and/or the 
subject’s legal representative. The rights and welfare of the subjects will be protected by 
emphasizing to them (or their legal representative) that the quality of their care will not be 
adversely affected if they decline to participate in or withdraw from the study. Subjects may 
withdraw from the study at any time.  
For non-English speaking subjects, a translated version of the informed consent document will be 
available and the consent process will take place in that subject’s primary language.  
12.4.2 
Medical History 
Relevant medical history, surgical history, and allergies will be collected at screening. 
12.4.3 
Prior and Concomitant Medications 
All relevant medications used in the 14 days prior to first dose of study drug and any medications 
used for standard subject care during the study are to be recorded. Concomitant treatments 
(non-pharmacological treatments) which include any surgical or diagnostic procedures will be 
captured in the source documents. See Section 10.3.4 for precautions and exclusions of 
concomitant medications during the study. 


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12.4.4 
Physical Examination 
A complete physical examination must include source documentation of skin, head and neck, 
heart, lung, abdomen, extremities, back/flank/costo-vertebral angle tenderness, and neuromuscular 
assessments. Height and weight will be included at screening. Demographic data including name, 
sex, age, race, weight, and alcohol use will be recorded at screening. A limited, symptom-based, 
physical examination will be performed at other indicated visits. If a subject does not display 
symptoms, no limited physical examination needs to be performed.  
Clinically significant physical examination findings noted during a preceding physical 
examination (complete or limited) should be followed until resolution. 
Physical examinations may be performed at various unscheduled time points if deemed necessary 
by the Investigator. 
All physical examinations will be performed by site personnel who are experienced and routinely 
conduct physical examinations (e.g., physician, physician’s assistant, or nurse practitioner [within 
the US]). 
12.4.5 
Vital Signs 
Vital signs, including blood pressure, heart rate, respiratory rate, and temperature, will be measured 
at the indicated visits. Vital signs at approximately the same time as the assessment of signs and 
symptoms and recorded in the source and eCRF.  
12.4.6 
Assessment of Signs and Symptoms 
Each sign/symptom for each respective presenting indication (Table 8) will be assigned a 
classification of new onset, continuing (increased, decreased, no change), or resolved (returned to 
pre-infection state). Responses should be collected by the PI or qualified Sub-investigator and 
recorded in the source documents on each study day. When possible the same investigator should 
collect the information at approximately the same time each day. Indication specific Signs and 
Symptoms are only collected for a subject’s primary site of infection (i.e., if a subject has a cUTI 
and bacteremia, only cUTI information is collected). 


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Table 8. 
Signs and Symptoms for Presenting Indications 
Presenting Indication 
Signs and Symptoms 
cUTI or AP  
• 
Urinary frequency,  
• 
Urinary urgency,  
• 
Dysuria,  
• 
Nausea,  
• 
Vomiting,  
• 
Abdominal pain, 
• Supra-pubic pain or discomfort,  
• Flank pain,  
• Costo-vertebral angle tenderness on 
examination, and 
• Fever* (oral or tympanic temperature 
38°C [100.4°F] or rectal/core 
temperature 38.3°C [100.9°F]) 
cIAI 
• 
Chills, rigors, or fevers  
(oral or tympanic temperature 
38°C [100.4°F] or rectal/core 
temperature38.3°C [100.9°F]) 
Hypotension, systolic BP < 
90mmHg 
• Abdominal pain, 
• Nausea or vomiting, 
• Abdominal mass on clinical 
examination, 
• Altered mental status, and 
• Elevated total peripheral WBC count 
(> 10,000/mm) 
HABP/VABP 
mechanically ventilated 
subjects 
• 
Rales,  
• 
Dullness on percussion, 
• 
Bronchial breath sounds,  
• 
Egophony, 
• Purulent secretion, and 
• Fever* (oral or tympanic temperature 
38°C [100.4°F] or rectal/core 
temperature 38.3°C [100.9°F]) 
HABP/VABP 
non-mechanically 
ventilated subjects 
• 
Cough, 
• 
Rales,  
• 
Dullness on percussion, 
• 
Bronchial breath sounds,  
• 
Egophony, 
• Dyspnea, 
• Respiratory rate >25 per minute, and 
• Fever (oral or tympanic temperature 
38°C [100.4°F] or rectal/core 
temperature 38.3°C [100.9°F]) 
Bacteremia 
• 
Heart rate >100 bpm,  
• 
Respiratory rate >25 per minute,  
• 
Systolic blood pressure <90 mmHg, and  
• 
Fever* (oral or tympanic temperature 38°C [100.4°F] or rectal/core 
temperature 38.3°C [100.9°F]) 
*Maximum daily temperature over the previous 24 hours will be recorded when fever is reported.  
 
Findings from the Assessment of Signs and Symptoms will be captured on a Signs and Symptoms 
CRF and should not be documented as adverse events.  
12.4.7 
12-Lead ECG 
Twelve-lead ECGs will be performed per the Schedule of Procedures (Table 1) in triplicate, at 
least 1 minute apart, after the subject has been in the supine position for at least 10 minutes. The 
ECG will include all 12 standard leads and should be recorded at a paper speed of 25 mm/sec. The 
following ECG parameters will be recorded:  
• PR interval,  
• QRS interval,  
• Heart rate,  


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• RR interval,  
• QT interval, and  
• QTc interval. 
All ECGs must be evaluated by a qualified physician for the presence of abnormalities. If clinically 
indicated per the Investigator for a safety event, a 12-lead ECG will be performed according to site 
standards and recorded in the electronic data capture (EDC) database according to the EDC 
guidelines.  
12.4.8 
Chest X-Ray/Radiology 
Chest x-rays, CT scans or MRIs will be performed in subjects with HABP or VABP at designated 
time points as specified by the Schedule of Procedures (Table 1) to evaluate for the presence of 
infiltrates. Imaging should be conducted per institutional guidelines and results recorded in the 
source documents and the eCRF. 
12.4.9 
Clinical Laboratory Assessments 
Blood samples for serum chemistry and hematology analyses will be collected as specified by the 
Schedule of Procedures (Table 1).  
Eligibility criteria related to laboratory assessments (i.e., screening laboratory assessments) will 
be processed/analyzed by a local laboratory within 48 hours of randomization and must include, 
at a minimum, AST, ALT, total bilirubin, creatinine, white blood cell (WBC) count with 
differentials, platelet count, and leukocyte esterase (LCE) in urine. 
All other study-related analyses will be performed by the central laboratory. 
The chemistry, hematology, and urinalysis parameters assessed in this study include the following: 
• Chemistry: creatinine, estimated creatinine clearance, blood urea nitrogen, AST, ALT, 
alkaline phosphatase, total bilirubin, uric acid, lipase, amylase, albumin, total protein, 
glucose, sodium, potassium, chloride, carbon dioxide, calcium, and phosphorus. 
• Hematology: complete blood count (red blood cell count and white blood cell (WBC) count 
with differentials (manual differential at baseline), platelet count, hemoglobin, and 
hematocrit). 
• Urinalysis: dipstick analysis of protein, glucose, ketones, bilirubin, blood, nitrites, LCE, and 
urobilinogen; microscopic evaluation for red blood cells, WBCs, bacteria, and casts; specific 
gravity; and pH. 
For women of childbearing potential, a serum and urine pregnancy test will be performed before 
the first dose of study drug, however, only urine results are required to initiate treatment. A urine 
and serum pregnancy test will be performed at EOT or early termination. 
12.4.10 
Pharmacokinetic Sampling 
Pharmacokinetic sampling will be completed in subjects randomized to Carbavance 
(meropenem/RPX7009) only. Samples will be collected for PK analysis on Day 1 within 


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30 minutes and 2 to 3 hours after the end of the first infusion. On Day 3 and Day 5, PK samples 
will be collected within 30 minutes after the end of one of that day’s infusions. Samples will be 
taken as close to the 30-minute mark as possible and within the 1-hour window 2 to 3 hours after 
the end of the selected infusion. 
If subject is on a ventilator at the time of PK sampling, ventilator settings should be noted at the 
time of the blood draw. 
For specific collection and storage procedures, please refer to the Study Reference Manual. 
12.4.11 
Hospitalization Assessments 
Hospital admissions, transfers, and discharges will be captured in the source documents for each 
enrolled subject over the course of the study. Date and time will be captured for the original 
admission as well as each time a subject is transferred from an ICU to a non-ICU. The date and 
time of hospital discharge will be captured as well as where each subject was discharged to (e.g., 
home, another hospital, long term adult care facility, etc.).  
12.4.12 
Mechanical Ventilator Assessments 
Subjects whose primary indication for enrollment into the study is HABP or VABP, and require 
mechanical ventilation support, will be managed by the study investigators per institutional 
guidelines. Data regarding mechanical ventilation will be captured in the source documents and 
the eCRFs. 
12.4.13 
Infection Source Control  
It is expected that prior to enrollment adequate source control (in the opinion of the PI) should be 
achieved for each subject’s index infection (for example, for a subject enrolled due to cIAI, the 
intra-abdominal source should be properly drained/debrided/removed; for a subject with cUTI, any 
indwelling catheter should be removed or replaced). Any secondary drainage that occurs within 4 
days of the initial procedure will be counted as a second part of the initial planned procedure. It is 
further expected that such control should be maintained throughout the subject’s participation in 
the study to the extent possible (i.e. if the subject has a recurrent intra-abdominal abscess, this 
should be drained in accordance with site-specific practices).  A qualified independent reviewer 
will access the adequacy of source control in subjects whose outcome is clinical failure, death or 
indeterminate. Additional medical records will be collected and submitted to the reviewer as 
appropriate. 
12.4.14 
Microbiology Assessments 
Accurate microbiologic results are critical to successfully meet the study objectives. All specimens 
will be sent to the local laboratory for culture and susceptibility testing per institutional standards. 
For all carbapenem-resistant gram-negative organisms, the MIC to carbapenems will be captured 
in the eCRF. Susceptibility to Carbavance as determined by Kirby-Bauer disk methodology will 
be captured at baseline. If the resistance mechanism for each carbapenem-resistant organism 
cultured during the study is known, it should be captured in source documents.  


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Any isolated bacteria deemed to be contributory to the infectious process will be designated a 
pathogen by the PI and identified by genus and species. The local laboratory will culture each 
sample for organism identification, quantification (when applicable), and susceptibility testing per 
institutional standards. CRE cultures at baseline and all post-baseline isolates cultured at the local 
laboratory and designated as pathogens by the PI will be sent to the central laboratory (Medpace 
Reference Laboratory [MRL]) for confirmation of identification and susceptibility testing results. 
All subjects must have a specimen sample from the site of infection (i.e., blood, urine, 
intra-abdominal fluid/tissue, or respiratory secretion) and two sets of blood samples from two 
separate venipuncture sites collected immediately prior to the first dose of study drug (or, for cIAI, 
96 hours before or 24 hours after the first dose of study drug), and submitted to the local 
microbiology laboratory for culture and susceptibility testing. When it is not possible to collect 
specimens for culture immediately prior to the first dose of study drug, cultures that have been 
obtained no more than 72 hours prior to (or for cIAI, 96 hours before or 24 hours after) the first 
dose of study drug are acceptable. The results of this culture will determine whether the subject 
meets the criteria for the Microbiological CRE Modified Intent-to-Treat (mCRE-MITT) 
Population or the Microbiological Modified Intent-to-Treat (m-MITT) Population. 
Kirby-Bauer disks for Carbavance (meropenem\RPX7009) susceptibility testing will be provided 
by the Sponsor for baseline testing. Susceptibility testing for BAT and other antimicrobials will be 
done per each institution’s standard procedures. In instances where susceptibility testing indicates 
resistance to the study drug but the subject is clinically improving, the subject should remain on 
study drug at the Investigator’s discretion. 
If the screening sample for culture is taken per standard of care before the subject (or a subject’s 
legal representative) signs informed consent, that isolate may be used for baseline and sent to the 
central laboratory once consent is obtained as long as the sample was collected within 72 hours of 
(or for cIAI, 96 hours before or 24 hours after) the first dose of study drug. 
12.4.14.1 
Urine Specimens 
For subjects with cUTI or AP, urine samples will be collected by clean catch midstream, from a 
newly-inserted Foley catheter (no bag specimens allowed), bladder needle aspiration, or ureter 
aspiration. 
CRE isolates at baseline, and all post-baseline isolates cultured at the local laboratory and 
designated as pathogens by the PI will be sent to the central laboratory for confirmation of 
identification and susceptibility testing results.  
The baseline urine cultures must grow at least one defined bacterial pathogen at concentration of 
105 CFU/mL. Up to 2 isolated pathogens will be allowed per baseline urine culture provided they 
are at concentrations of 105 CFU/mL of urine. 
The baseline urine samples submitted for culture must have a microscopic evaluation (e.g., gram 
stain) and a dipstick analysis performed by the local microbiology laboratory.  
For all post-baseline urine cultures, only pathogens at concentrations of 103 CFU/mL of urine 
will be sent to the central laboratory.  Up to 2 isolated pathogens will be allowed per post-baseline 
urine culture provided they are at concentrations of 103 CFU/mL. 


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For both baseline and post-baseline cultures - if a subject grows 3 or more bacterial organisms in 
the urine, the urine culture will be considered contaminated. An organism will not be considered 
a contaminant if the organism also grows in a concurrently obtained blood culture.  Isolates from 
contaminated samples should not be sent to the central lab. 
12.4.14.2 
 Intra-abdominal Specimens 
For subjects with cIAI, acceptable specimens should include at least one intra-abdominal culture 
obtained during the time of surgical (or percutaneous) intervention. The specimen must be 
collected within approximately 96 hours before or 24 hours after of the first dose of study drug 
(preferably prior to study drug administration). Baseline specimens should be sent for gram stain, 
pathogen identification, and susceptibility testing at the local laboratory. Isolates from the baseline 
specimen will also be sent to the central laboratory for confirmatory testing. 
Post-baseline specimens should be collected as clinically indicated and sent to the local laboratory 
for testing. Isolates from all post-baseline specimens should be sent to the central laboratory for 
confirmatory testing.  
To be considered adequate, a specimen should consist of at least 1mL of fluid or tissue 
representative of the material associated with the clinical infection.  
Gram stains will be conducted per institutional standards and gram stain data should be captured 
in source documents. If any intra-abdominal culture is performed (including cultures taken on 
swab), pathogens exhibiting significant growth on cultures identified by the site laboratory’s 
routine procedures should be sent to the central lab, even if from a specimen that does not meet 
the aforementioned adequacy criteria.   
12.4.14.3 
Respiratory Tract Specimens 
For subjects with HABP or VABP, acceptable specimens should include at least one positive 
pretreatment sample obtained by Protected Specimen Brush (PSB) with bronchial alveolar lavage 
(BAL) or mini-BAL, by non-bronchoscopic-BAL (NBBAL), or by Protected Endotracheal 
Catheter obtained prior to randomization and treatment. Non-ventilated subjects may have 
specimens obtained via deep expectoration or expectorated/induced sputum.  
All specimens should be sent for gram stain, quantitative culture, pathogen identification and 
susceptibility testing.  
To be adequate, respiratory samples from expectorated or induced sputum should show 
<10 squamous epithelial cells and >25 polymorphonuclear neutrophils per 100x field. Colony 
counts ≥103 CFU/mL are considered the threshold for identifying pathologic bacteria from PSB 
and the CombiCath® NBBAL, ≥104 CFU/mL for bronchoscopic BAL or the BALCath NBBAL, 
and ≥106 CFU/mL for endotracheal aspirate specimens.  
Gram stains will be conducted per institutional standards and gram stain data should be captured 
in source documents. Colony counts are not expected to be performed on expectorated or induced 
sputum. If the sputum is cultured all pathogens exhibiting significant growth identified by the site 


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laboratory’s routine procedures should be sent to the central lab, even if from a specimen that does 
not meet the specimen adequacy criteria described above.  
12.4.14.4 
Blood and Other Tissue Specimens 
Two sets of samples from 2 separate venipuncture sites are required for blood cultures in all study 
participants. If a blood culture is positive at baseline, daily blood cultures will be collected until 
the first negative blood culture (culture reading at 24 hours or more).  
Additional blood cultures, including blood cultures taken during fever spikes (oral or tympanic 
temperature 38°C [100.4°F] or rectal/core temperature 38.3°C [100.9°F]) may also will be 
collected at the Investigator’s discretion.  
Isolated pathogens (e.g., considered not to be a contaminant by the PI) from each individual 
positive blood culture will be sent to the central lab. 
If a tissue sample (e.g., kidney biopsy) is collected to determine target pathogen, it should be 
obtained 72 hours prior to first dose of study drug. The isolated pathogen should be shipped to the 
central laboratory for confirmation and susceptibility testing. In the event that pre-randomization 
urine and blood cultures are negative and the subject has a positive tissue culture, the isolated 
pathogen may qualify as a defined baseline CRE pathogen.  


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13 SUBJECT AND STUDY DISCONTINUATION  
A clear distinction will be made between subjects who withdraw from study drug dosing and those 
who withdraw from the study. All subjects who withdraw from study drug dosing should be 
encouraged to follow all study procedures to the LFU visit for safety assessment, even if they 
withdraw from dosing in absence of a clinical outcome of failure.  
The clinical report will include the reason(s) for subject withdrawal from either study drug or the 
study, as well as details relevant to the withdrawal. If a subject is withdrawn from the study prior 
to study completion, the subject will undergo early termination procedures (See Section 12.3.3). 
Any subject withdrawn due to an adverse event (whether serious or non-serious) or clinically 
significant abnormal laboratory test value will be evaluated by the Investigator or a monitoring 
physician and will be treated and/or followed up until the symptoms or values return to normal or 
acceptable levels, as judged by the Investigator.  
Subjects withdrawn for reasons other than drug-related adverse events may be replaced per 
Investigator and Sponsor discretion.  
13.1 
Screening Failures 
Subjects who sign and date the informed consent form but who fail to meet the inclusion and 
exclusion criteria will be defined as screen failures. A screening log, which documents the 
subject’s initials, screening number, and reason(s) for screen failure, is to be maintained by the 
Investigator for all screen failures. A copy of the log should be retained in the Investigator’s study 
files. Screen Failures will be captured in IWRS. 
13.2 
Withdrawal from Study Drug  
Study drug administration may be discontinued for any of the following reasons at the discretion 
of the Investigator or the Sponsor’s Medical Monitor: 
• Occurrence of any medical condition or circumstance that exposes the subject to substantial 
risk and/or does not allow the subject to adhere to the requirements of the protocol; 
• Any serious adverse event (SAE), clinically significant adverse event, severe laboratory 
abnormality, intercurrent illness, or other medical condition that indicates to the Investigator 
that continued participation is not in the best interest of the subject; 
• Subject's decision to withdraw; 
• Requirement of prohibited concomitant medication; or 
• Lack of clinical improvement.  
Any subject who prematurely discontinues study drug should complete the study through the LFU 
visit. The EOT procedures will be performed on the day study drug is discontinued (+1 day).  


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13.3 
Withdrawal from Study 
A subject may be withdrawn from the study for any of the following reasons: 
• Lost to follow-up; 
• Subject’s decision to withdraw; 
• Withdrawal of consent for reasons other than an adverse event; 
• Non-compliance or unwillingness to comply with the procedures required by the protocol; or 
• Termination of the study by the Sponsor or designee, contract research organization, US Food 
and Drug Administration (FDA), or other regulatory authorities. 
13.4 
Study Site Discontinuation 
Reasons for discontinuation of the study at an investigational site may include, but are not limited 
to, the following: 
• The incidence or severity of adverse events in this or other studies indicates a potential health 
hazard to subjects; 
• Subject enrollment is unsatisfactory; 
• Investigator request to withdraw from participation; 
• Sponsor decision; 
• Serious and/or persistent non-compliance by the Investigator with the protocol, the clinical 
research agreement, and/or applicable regulatory guidelines in conducting the study; 
• Decision by the IRB or IEC to terminate or suspend approval for the investigation or the 
Investigator; or 
• Investigator fraud (i.e., altered data, omitted data, or manufactured data). 


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14 SAFETY ASSESSMENTS 
Safety assessments will include adverse events, clinical laboratory evaluations, vital signs, 
physical examinations, and ECGs. Relevant changes in physical examinations, vital signs, and 
safety laboratory tests that are identified as occurring after receiving the first dose of study drug, 
regardless of whether the change is in an examination finding, test result, or sign or symptom 
reported by a subject, and regardless of relationship to study drug, will be reported.  
14.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence deemed clinically relevant by the 
Investigator in a clinical investigation subject administered a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment. An adverse event can therefore 
be any unfavorable and/or unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of an investigational medicinal product, whether or 
not related to the investigational medicinal product. All adverse events, including observed or 
volunteered problems, complaints, or symptoms, are to be recorded and entered on the appropriate 
eCRF. Adverse events will be coded using the most updated version of the Medical Dictionary for 
Regulatory Activities available (version 15.0 or higher). 
Adverse events, which include clinically significant laboratory test variables, will be monitored 
and documented from the time of informed consent until study participation is complete. 
Treatment-emergent adverse events, which include clinically significant laboratory test variables, 
will be monitored and documented from the first dose of study drug until study participation is 
complete. Subjects should be instructed to report any adverse event that they experience to the 
Investigator. Investigators should make assessments for adverse events and record the event on the 
appropriate adverse event eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate adverse event on the eCRF. 
Additionally, the condition that led to a medical or surgical procedure (e.g., surgery, endoscopy, 
tooth extraction, transfusion) should be recorded as an adverse event, not the procedure. The 
protocol specific Assessment of Signs and Symptoms (see Section 12.4.6) associated with the 
index infection (cUTI, AP, cIAI, HABP, VABP or bacteremia) and protocol defined Treatment 
Failure should not be documented as adverse events.  
Any medical condition already present at screening or baseline should not be reported as an 
adverse event, unless the medical condition or signs or symptoms present at baseline worsen in 
severity or seriousness at any time during the study. In this case, it may be reported as an adverse 
event at the discretion of the Investigator. 
Clinically significant abnormal laboratory or other examination (e.g., ECG) findings detected 
during the study or that are present at baseline and significantly worsen during the study should be 
reported as adverse events. At the discretion of the Investigator, all National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade 3 laboratory values 


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should be reported as adverse events. If a clinically significant abnormal laboratory value or 
assessment is clearly related to a medically defined diagnosis or syndrome, the diagnosis or 
syndrome will be recorded on the Adverse Event eCRF, not the individual laboratory values. The 
Investigator will exercise his or her medical judgment in deciding whether an abnormal laboratory 
finding or other abnormal assessment is clinically significant. Significant abnormal laboratory 
values occurring during the clinical study will be followed until repeat tests return to normal, 
stabilize, or are no longer clinically significant. Any abnormal test that is determined to be an error 
does not require being reported as an adverse event. 
14.2 
Adverse Drug Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product means that a causal 
relationship between a medicinal product and an adverse event is at least a reasonable possibility.  
14.3 
Unexpected Adverse Drug Reaction 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information. For Carbavance 
(meropenem/RPX7009), the reference safety information is included in the Investigator’s 
Brochure.  
Product information for BAT includes referenced summaries of product characteristics (SmPCs) 
for meropenem, ertapenem, imipenem, tigecycline, colistin, amikacin, tobramycin, gentamicin, 
polymyxin B, and ceftazidime-avibactam. 4,7,8,9,10,11,12,13,14,16  
The reference safety information will be reviewed yearly and the periodicity of the review will be 
harmonized with the reporting period of the Development Safety Update Report.  
14.4 
Assessment and Reporting of Adverse Events by the Investigator 
The Investigator will review each event and assess its relationship to study drug treatment (not 
related, unlikely, possible, or probable). Each sign or symptom reported will be graded on the 
NCI-CTCAE V4.0 toxicity grading 5-point severity scale (Grade 1, 2, 3, 4, and 5), details of which 
can be found in Appendix 3. The date and time of onset, duration, and outcome 
(Recovered/Resolved, Recovering/Resolving, Resolved with Sequelae, Not recovered/Resolved, 
Fatal, or Unknown/Lost to follow-up) of each event will be noted.  
Adverse events, including those not listed on the NCI-CTCAE grading system, will be graded on 
the 5-point scale (mild, moderate, severe, life-threatening, death) and reported in detail as indicated 
on the eCRF according to the following definitions for rating severity: 
• Grade 1 - Mild: asymptomatic or mild symptoms OR clinical or diagnostic observations only 
OR intervention not indicated. 
• Grade 2 - Moderate: minimal, local or noninvasive intervention indicated OR limiting 
age-appropriate instrumental activities of daily living (e.g., preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc.). 


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• Grade 3 - Severe or medically significant but not immediately life-threatening: hospitalization 
or prolongation of hospitalization indicated OR disabling OR limiting self-care 
activities of daily living (e.g., bathing, dressing and undressing, feeding self, using 
the toilet, taking medications, not being bedridden). 
Note: An experience may be severe but may not be serious (e.g., severe headache). 
• Grade 4 - Life-threatening consequences: urgent intervention indicated. 
• Grade 5 - Death related to adverse event. 
Causality Assessment 
The relationship of each adverse event will be assessed using the following definitions: 
Not related 
• Event occurring before dosing. 
• Event or intercurrent illness due wholly to factors other than drug 
treatment. 
Unlikely 
• Poor temporal relationship with drug treatment. 
• Event easily explained by subject’s clinical state or other factors. 
Possible 
• Reasonable temporal relationship with drug treatment. 
• Event could be explained by subject’s clinical state or other 
factors.  
Probable 
• Reasonable temporal relationship with drug treatment. 
• Likely to be known reaction to agent or chemical group, or 
predicted by known pharmacology. 
• Event cannot easily be explained by subject’s clinical state or 
other factors. 
The following factors should also be considered: 
• The temporal sequence from study drug administration– 
The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event. 
• Underlying, concomitant, intercurrent diseases– 
Each report should be evaluated in the context of the natural history and course of the disease 
being treated and any other disease the subject may have. 
• Concomitant drug– 
The other drugs the subject is taking or the treatment the subject receives should be examined 
to determine whether any of them might be recognized to cause the event in question. 
• Known response pattern for this class of study drug– 
Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 
• Exposure to physical and/or mental stresses– 
The exposure to stress might induce adverse changes in the recipient and provide a logical and 
better explanation for the event. 


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• The pharmacology and PK of the study drug– 
The known pharmacologic properties (absorption, distribution, metabolism, and excretion) of 
the study drug should be considered. 
14.5 
Serious Adverse Events 
An adverse event or adverse reaction is considered serious if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes: 
• Death; 
• A life-threatening adverse event; 
• NOTE: An adverse event or adverse reaction is considered “life-threatening” if, in view of 
either the Investigator or Sponsor, its occurrence places the subject at immediate risk of 
death. It does not include an event that, had it occurred in a more severe form, might have 
caused death. 
• Requires hospitalization or prolongation of existing hospitalizations; 
NOTE: Any hospital admission with at least 1 overnight stay will be considered an inpatient 
hospitalization. An emergency room visit without hospital admission will not be recorded as 
an SAE under this criterion, nor will hospitalization for a procedure scheduled or planned 
before signing of informed consent. However, unexpected complications and/or prolongation 
of hospitalization that occur during elective surgery should be recorded as adverse events and 
assessed for seriousness. As the subjects in this study will already be hospitalized, it is likely 
that unexpected complications and/or prolongation of hospitalization will be the only 
applicable aspect of this criterion. 
• Admission to the hospital for social or situational reasons (i.e., no place to stay, live too far 
away to come for hospital visits) will NOT be considered inpatient hospitalizations;  
• A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions; 
• A congenital anomaly/birth defect; or 
• An important medical event. 
NOTE: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalizations, or the development of drug dependency. 
14.6 
Serious Adverse Event Reporting – Procedures for Investigators 
Initial Reports 
All SAEs occurring from the time of informed consent until 30 days following the last 
administration of study drug must be reported to Medpace Clinical Safety within 24 hours of the 
knowledge of the occurrence (this refers to any adverse event that meets any of the aforementioned 
serious criteria). All SAEs that the Investigator considers related to study drug occurring after the 
30-day follow-up period must be reported to the Sponsor. 


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To report the SAE, the SAE form should be completed electronically in the EDC system for the 
study. When the form is completed, Medpace Clinical Safety personnel will be notified 
electronically and will retrieve the form. If the event meets serious criteria and it is not possible to 
access the EDC system, send an email to the Medpace Clinical Safety Department (email listed 
below) or call the Medpace SAE hotline (phone number listed below), and fax the completed paper 
SAE form to Medpace (fax number listed below) within 24 hours of awareness. When the EDC 
system becomes available, the SAE information must be entered within 24 hours of the system 
becoming available. 
Safety Contact Information: 
Medpace Clinical Safety 
Medpace SAE hotline – USA: 
Telephone: +1-800-730-5779, ext. 2999 or +1-513-579-9911, ext. 2999 
Fax: +1-866-336-5320 or +1-513-579-0444 
e-mail: medpace-safetynotification@medpace.com 
Medpace SAE hotline – Europe: 
Telephone: +49-89-89-55-718-44 
Fax: +49-89-89-55-718-104 
e-mail: EUsafetynotification@medpace.com   
Follow-up Reports 
The Investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the subject 
dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(e.g., subject discharge summary or autopsy reports) to Medpace Clinical Safety via fax or e-mail. 
If it is not possible to access the EDC system, refer to the procedures outlined above for initial 
reporting of SAEs.  
14.7 
Pregnancy Reporting 
If the subject or partner of a subject participating in the study becomes pregnant during the study 
or within 30 days of discontinuing study drug, the Investigator should report the pregnancy to 
Medpace Clinical Safety within 24 hours of becoming aware of the pregnancy. Medpace Clinical 
Safety will then provide the Exposure In Utero form to the Investigator for completion.  
A subject becoming pregnant while on study drug will immediately be withdrawn from the study 
and early termination study procedures will be performed. 
The subject or partner should be followed by the Investigator until completion of the pregnancy. 
If the pregnancy ends for any reason before the anticipated date, the Investigator should notify 
Medpace Clinical Safety. At the completion of the pregnancy, the Investigator will document the 
outcome of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 


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14.8 
Expedited Reporting  
The Sponsor will report all relevant information about suspected unexpected serious adverse 
reactions that are fatal or life-threatening as soon as possible to the applicable competent 
authorities concerned, and to the Ethics Committee, and in any case no later than 7 days after 
knowledge by the Sponsor of such a case, and that relevant follow-up information will 
subsequently be communicated within an additional 8 days.  
Please refer to the Investigator’s Brochure for a list of expected adverse reactions associated with 
Carbavance (meropenem/RPX7009). 
For a list of expected adverse reactions associated with BAT, please refer to the referenced SmPCs 
for the following antibacterials: meropenem4, ertapenem7, imipenem8, tigecycline9, colistin10, 
amikacin11, tobramycin12, gentamicin13, polymyxin B14, and ceftazidime-avibactam16. 
All other suspected unexpected serious adverse reactions for Carbavance (meropenem/RPX7009) 
and BAT will be reported to the applicable competent authorities concerned and to the Ethics 
Committee concerned as soon as possible, but within a maximum of 15 days of first knowledge 
by the Sponsor.  
The Sponsor will also inform all Investigators as required.  


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15 EFFICACY EVALUATION 
15.1 
Efficacy Assessments 
Efficacy Assessments for cUTI or AP 
Primary Endpoint 
The primary endpoint for cUTI or AP is defined differently by the EMA and FDA. The primary 
endpoint for the EMA is proportion of subjects in the mCRE-MITT Population that 
demonstrate microbiological eradication (See Table 9). The primary endpoint for the FDA is 
the proportion of subjects in the mCRE-MITT Population who demonstrate a response of 
overall success at the TOC visit (See Table 9).  
To meet the primary endpoint for EMA and FDA, a subject’s gram-negative antimicrobial 
therapy to treat the baseline infection cannot be altered (other than dose adjustment or 
modification of BAT based on susceptibility of baseline pathogen within the first 72 hours 
after first dose of study drug) after randomization due to concerns of microbiological failure, 
clinical failure, or tolerability AND must meet the criteria in Table 9. 
Table 9. Primary Endpoint Definitions By Regulatory Agency – cUTI and AP 
Parameter 
Analysis for EMA 
Analysis for FDA 
Outcome measure 
Microbiological eradicationa) 
Overall Success (Clinical cureb) and 
microbiological eradicationa)) 
Efficacy time 
point(s) 
TOCc) 
TOCc) 
a. 
Microbiological eradication is defined as the demonstration that the bacterial pathogen(s) found at baseline 
is reduced to <103 CFU/mL of urine for EMA and <104 CFU/mL of urine for FDA. 
b. Clinical cure is defined as complete resolution or significant improvement of the baseline signs and 
symptoms of cUTI or AP such that no further surgical intervention or antimicrobial therapy is warranted. 
c. 
The TOC visit occurs 7 days (±2 days) post-EOT (Day 12 to Day 23). 
CFU = colony-forming unit; EMA = European Medicines Agency; EOT = End of Treatment; FDA = Food and 
Drug Administration; TOC = Test of Cure. 
Secondary Endpoints 
• The all-cause mortality rate in the mCRE-MITT and m-MITT Populations at Day 28; 
• Proportion of subjects in the m-MITT and ME Populations who demonstrate a response of 
overall success at the TOC visit; 
• Proportion of subjects in the mCRE-MITT, m-MITT, CE, CRE-ME, and ME Populations 
with a clinical outcome of cure at Day 3, EOT, TOC, and LFU;  
• Proportion of subjects in the mCRE-MITT, m-MITT, CRE-ME, and ME Populations with 
a microbiological outcome of eradication at Day 3, EOT, TOC, and LFU; 
• Relapse/recurrence rates of baseline cUTI or AP at the LFU visit; and 
• Per-pathogen outcome in the mCRE-MITT, m-MITT, CRE-ME, and ME Populations at 
Day 3, EOT, TOC, and LFU. 
 
 
 


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Efficacy Assessments for cIAI  
Primary Endpoint  
The primary endpoint for cIAI for both the EMA and the FDA is the proportion of patients 
with a clinical outcome of cure in the mCRE-MITT population at TOC visit, approximately 
Day 28.   
To meet the primary endpoint, a subjects’ gram-negative antimicrobial therapy to treat the 
baseline infection cannot be altered (other than dose adjustment or modification of BAT based 
on susceptibility of baseline pathogen within the first 72 hours after first dose of study drug) 
after randomization due to concerns of microbiologic failure, clinical failure, or tolerability. In 
addition, subjects cannot require any further unplanned surgical or radiologic intervention after 
randomization until TOC due to concerns of microbiologic failure or clinical failure.   
Secondary Endpoints  
• The all-cause mortality rate in the mCRE-MITT and m-MITT Populations at Day 28; 
• Proportion of subjects in the m-MITT and ME Populations who demonstrate a response of 
overall success at the TOC visit; 
• Proportion of subjects in the mCRE-MITT, m-MITT, CE, CRE-ME, and ME Populations 
with a clinical outcome of cure at Day 3, EOT, TOC, and LFU;  
• Proportion of subjects in the mCRE-MITT, m-MITT, CE, CRE-ME, and ME Populations 
with a clinical outcome of cure at TOC, where the use of an aminoglycoside beyond 
72 hours in subjects with a pathogen susceptible to Carbavance (meropenem/RPX7009) is 
assigned to failure;  
• Relapse/recurrence rates of baseline cIAI at the LFU visit; and  
• Per-pathogen outcome in the mCRE-MITT, m-MITT, CRE-ME, and ME Populations at 
Day 3, EOT, TOC, and LFU. 
Efficacy Assessments for HABP and VABP 
Primary Endpoint 
The primary endpoint for HABP and VABP is the all-cause mortality rate in the mCRE-MITT 
Population at Day 28 for all subjects with HABP and VABP, combined with all subjects with 
bacteremia (not related to cUTI/AP or HABP/VABP). 
Secondary Endpoints 
• The all-cause mortality rate in the mCRE-MITT and m-MITT Populations at Day 28; 
• The proportion of subjects in the mCRE-MITT Population who demonstrate a clinical 
outcome of cure at the TOC visit. 
A clinical outcome of cure is defined as: 
o A subject whose gram-negative antimicrobial therapy to treat the baseline infection is 
not altered (other than dose adjustment or modification of BAT based on susceptibility 
of baseline pathogen within the first 72 hours after first dose of study drug) after 


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randomization due to concerns of microbiological failure, clinical failure, or tolerability 
AND  
o Complete resolution or significant improvement of the baseline signs and symptoms of 
HABP or VABP such that no further surgical intervention or antimicrobial therapy is 
warranted; 
• Proportion of subjects in the mCRE-MITT, m-MITT, CE, CRE-ME, and ME Populations 
with a clinical outcome of cure at Day 3, EOT, TOC, and LFU; 
• Proportion of subjects in the mCRE-MITT, m-MITT, CE, CRE-ME, and ME Populations 
with a clinical outcome of cure at TOC, where the use of an aminoglycoside beyond 
72 hours in subjects with a pathogen susceptible to Carbavance (meropenem/RPX7009) is 
assigned to failure; 
• Per-pathogen outcome in the mCRE-MITT, m-MITT, CRE-ME, and ME Populations at 
Day 3, EOT, TOC, and LFU; 
• Relapse/recurrence rates of baseline bacterial pneumonia at the LFU visit; 
• Total ventilator days measured from time of randomization; 
• Change in the partial pressure arterial oxygen to fraction of inspired oxygen (PaO2:FiO2) 
ratio from baseline to Day 3, Day 7, and EOT; and 
• Time (days) to extubation in subjects who are on the ventilator at baseline (i.e., Day 1). 
Efficacy Assessments for Bacteremia 
Primary Endpoint 
The primary endpoint for bacteremia is the all-cause mortality rate in the mCRE-MITT 
Population at Day 28 for all subjects with HABP and VABP, combined with all subjects with 
bacteremia (not related to cUTI/AP or HABP/VABP). 
Secondary Endpoints 
• The all-cause mortality rate in the mCRE-MITT and m-MITT Populations at Day 28;  
• The proportion of subjects in the mCRE-MITT Population who demonstrate a response of 
overall success at the TOC visit. 
For subjects whose gram-negative antimicrobial therapy to treat the baseline infection is 
not altered (other than dose adjustment or modification of BAT based on susceptibility of 
baseline pathogen within the first 72 hours after first dose of study drug) after 
randomization due to concerns of microbiological failure, clinical failure, or tolerability, a 
response of success is defined by clearance of bacteremia (microbiological eradication) 
and a clinical assessment of cure.  
Clearance of bacteremia (microbiological eradication) is defined as the demonstration that 
bacterial pathogen(s) found at baseline is absent with repeat culture. 
Clinical cure is defined as complete resolution or significant improvement of the baseline 
signs and symptoms of bacteremia, such that no further surgical intervention or 
antimicrobial therapy is warranted; 


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• Proportion of subjects in the m-MITT, CRE-ME, and ME Populations who demonstrate a 
response of overall success at the TOC visit;  
• Proportion of subjects in the mCRE-MITT, m-MITT, CE, CRE-ME, and ME Populations 
with a clinical outcome of cure at Day 3, EOT, TOC, and LFU; 
• Proportion of subjects in the mCRE-MITT, m-MITT, CE, CRE-ME, and ME Populations 
with a clinical outcome of cure at TOC, where the use of an aminoglycoside beyond 
72 hours in subjects with a pathogen susceptible to Carbavance (meropenem/RPX7009) is 
assigned to failure; 
• Proportion of subjects in the mCRE-MITT, m-MITT, CRE-ME, and ME Populations with 
a microbiological outcome of eradication at Day 3, EOT, TOC, and LFU;  
• Relapse/recurrence rates of baseline bacteremia at the LFU visit;  
• Per-pathogen outcome in the mCRE-MITT, m-MITT, CRE-ME, and ME Populations at 
Day 3, EOT, TOC, and LFU; and 
• Time to bacterial clearance in mCRE-MITT, m-MITT, CRE-ME, and ME Populations. 
Exploratory analyses will be conducted based on subject evaluability and may include clinical and 
microbiological responses in various analysis populations at EOT, TOC, and LFU. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
15.1.2 
Clinical Outcome 
Clinical outcome will be used to determine a response of success for subjects with cIAI, HABP, 
or VABP. Clinical outcome, as a component of an assessment of overall response, will also be 
used to determine a response of success for subjects with cUTI or AP (FDA only), or bacteremia. 
The Investigator will be provided with a choice of clinical outcomes based on definitions to make 
a clinical assessment of the subject at the Day 3, Day 7, EOT, TOC, and LFU visits. The 
Investigator will assign a clinical outcome as defined in Table 10. 
If all symptoms present at baseline are classified as mostly resolved or continuing (decreased), 
with no new onset symptoms, such that no further surgical intervention or antimicrobial therapy is 
warranted, the subject will have a clinical outcome of cure at Day 7, EOT, TOC, and LFU visits. 
Subjects with lessening, incomplete resolution, or no worsening of these symptoms (i.e., 
continuing [decreased or no change] and resolved), who still warrant antimicrobial therapy, will 


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have a clinical outcome of improvement at Day 3 and Day 7. Subjects with worsening of symptoms 
or the development of new onset symptoms sufficient to require unplanned surgical 
procedures/percutaneous drainage or initiation of non-study antimicrobials, in addition to the 
criteria in Table 10 will have a clinical outcome of failure. In addition to the above components of 
clinical outcome, subjects with HABP or VABP will be monitored for oxygen requirements and 
ventilator settings per site standard of care to evaluate clinical outcome.  
Table 10. 
Criteria for Clinical Outcome 
Category 
Criteria 
Cure 
Complete resolution or significant improvement of the baseline signs and symptoms, 
such that no further surgical intervention or antimicrobial therapy is warranted. This 
outcome category will only be used at Day 7, EOT, TOC, and LFU visits. 
Improvement 
Lessening, incomplete resolution, or no worsening of baseline clinical signs and 
symptoms, but continued therapy is warranted. This outcome category will only be 
used at Day 3 and Day 7 visits. 
Failure 
Subjects who experience any one of the following:  
• 
At any study visit, worsening of baseline clinical signs and symptoms or the 
development of new clinical signs and symptoms of infection, sufficient to stop 
study medication and initiate non-study antimicrobial or require unplanned 
surgical procedures or percutaneous drainage; 
• 
Surgical site wound infection; 
• 
At TOC and LFU visits, persistence, incomplete resolution of baseline clinical 
signs and symptoms of infection;  
• 
Withdrawal from the study due to an adverse event or due to lack of clinical 
improvement; or 
• 
Death of the subject during the study. 
Indeterminate 
Clinical outcome cannot be determined. 
EOT = End of Treatment; LFU = Late Follow-up; TOC = Test of Cure. 
15.1.3 
Microbiologic Outcome 
The microbiologic outcome will be used, as a component of an assessment of overall response, to 
determine a response of success for subjects with cUTI or AP (FDA only), or bacteremia. The 
microbiologic outcome will be used to determine a response of success for subjects with cUTI or 
AP for the EMA. The criteria for microbiological outcome for subjects with cUTI or AP are 
defined in Table 11. 


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Table 11. 
Criteria for Microbiologic Outcome for cUTI or AP 
Category 
Criteria 
Eradication 
• 
Eradication is the demonstration that the bacterial pathogen(s) found at baseline 
is reduced to <104 CFU/mL on urine culture for FDA or <103 CFU/mL for EMA 
• 
AND a negative blood culture (after positive blood culture at baseline). 
Persistence 
• 
Persistence is the demonstration at EOT that 1 or more of the bacterial 
pathogen(s) found at baseline remains 104 CFU/mL of urine culture for FDA or 
103 CFU/mL for EMA, 
• 
OR a positive blood culture. 
Recurrence 
• 
Recurrence is the isolation of the same baseline bacterial pathogen(s) from 
culture after a response of eradication,  
• 
OR a positive blood culture with the same baseline organism that was identified 
as a uropathogen after a response of eradication. 
Indeterminate 
• 
An indeterminate outcome will occur if there is no culture or the culture cannot 
be interpreted for any reason. 
AP = acute pyelonephritis; CFU = colony-forming unit; cUTI = complicated urinary tract infection; 
EMA = European Medicines Agency; EOT = End of Treatment; FDA = Food and Drug Administration. 
 
The criteria for microbiological outcome for subjects with bacteremia are presented in Table 12. 
Table 12. 
Criteria for Microbiologic Outcome for Bacteremia 
Category 
Criteria 
Eradication 
• 
Eradication is the demonstration that the bacterial pathogen(s) found at baseline 
is absent with repeat blood culture. 
Persistence 
• 
Persistence is the demonstration at EOT that the bacterial pathogen(s) found at 
baseline is present with repeat blood culture. 
Recurrence 
• 
Recurrence is the isolation of the same baseline bacterial pathogen(s) from blood 
culture after a response of eradication.  
Indeterminate 
• 
An indeterminate outcome will occur if there is no blood culture or the blood 
culture cannot be interpreted for any reason. 
EOT = End of Treatment. 
15.1.4 
Overall Response 
Overall response will be used to determine a response of success for subjects with cUTI or AP 
(FDA only), or bacteremia. This efficacy measure is derived from a composite of the clinical 
outcome and the microbiological outcome.  
The algorithm for overall response at the TOC visit is summarized in Table 13. 


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Table 13. 
Overall Response at Test of Cure (TOC) Visit 
Clinical 
Outcome 
Microbiologic Outcome 
Eradication 
Persistence 
Recurrencea 
Indeterminate 
Cured 
Success 
Failure 
Failure 
Success based on 
presumed eradicationb 
Failure 
Failure 
Failure 
Failure 
Failure based on 
presumed persistencec 
Indeterminate 
Failed if clinical 
outcome for any 
previous visit = failed; 
otherwise = 
indeterminate 
Failure 
Failure 
Failed if clinical 
outcome for any 
previous visit = failed; 
otherwise = 
indeterminate 
a. 
For an outcome of recurrence, subjects must have documented prior eradication at any prior time point.  
b. Presumed eradication occurs when there is no material available for culture, and the subject has an investigator 
assessment of clinical outcome of cure. 
c. 
Presumed persistence occurs when there is no material available for culture, or no culture was obtained, and the 
subject has an investigator assessment of clinical outcome of failure. 


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16 PHARMACOKINETIC ASSESSMENTS 
Pharmacokinetic characterization, evaluation of plasma PK, and exposures of meropenem and 
RPX7009 in treated subjects will be performed. Analysis of the PK data will be described in a 
separate Statistical Analysis Plan. 
A pharmacodynamic analysis will be conducted to link meropenem and RPX7009 exposures in 
each subject with clinical and microbiological outcomes.  


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17 DATA MANAGEMENT 
Study data will be entered into eCRFs at the study sites. Prior to database lock, programmed 
computer edit checks will be run against the database to check for discrepancies and 
reasonableness of the data. All issues resulting from the computer-generated checks will be 
resolved. 
Standard eCRFs from the clinical research organization will be used for the study. The data 
contained in the eCRFs will be obtained directly from the clinical data at the site and will be 
source-document verified. Each eCRF will be reviewed and signed off by the Investigator.  
The data management system to be used will be a fully-integrated study management and clinical 
database. 
Visual and computerized methods of data validation will be applied in order to ensure accurate, 
consistent, and reliable data for the subsequent statistical analysis. 
All raw data generated in connection with this study will be retained in the scientific archives of 
the site and/or stored by the site in a designated storage facility until at least 2 years after the last 
approval of a marketing application in an International Conference of Harmonization (ICH) region 
and until there are no pending or contemplated marketing applications in an ICH region or at least 
2 years have elapsed since the formal discontinuation of clinical development of the investigational 
product. These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirements or by an agreement with the Sponsor. It is the responsibility of 
the Sponsor to inform the Investigator/Institution as to when these documents no longer need to 
be retained. 
 


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18 STATISTICAL METHODS AND DATA ANALYSIS  
18.1 
Analysis Populations 
A schematic summary of the analysis populations for this study is provided in Appendix 1. 
The Intent-to-Treat (ITT) Population will include all subjects screened and randomized to study 
drug (Carbavance [meropenem/RPX7009] or BAT). 
The Modified Intent-to-Treat (MITT) Population will include subjects who meet the ITT criteria 
and receive at least 1 dose of study drug as randomized. 
The Safety Population will include subjects who meet the ITT criteria and receive at least one dose 
of study drug, based on the actual treatment received. 
The PK Population will include subjects who meet the MITT criteria and have at least one plasma 
PK sample drawn.  
The m-MITT Population will include subjects who meet the MITT criteria and have a baseline 
gram negative bacterial pathogen(s). 
The mCRE-MITT Population (i.e., Primary Efficacy Population) will include subjects who meet 
the m-MITT criteria and who have a baseline Enterobacteriaceae that is confirmed to be 
meropenem-resistant. 
The CE Population will include subjects who meet the MITT criteria, as well as the following 
criteria:  
• Have no key inclusion or exclusion violations;  
• Obtain a clinical outcome (cure, improvement, or failure) at EOT and a clinical outcome of 
cure or failure at TOC, unless criteria for failure were met at an earlier time point; 
• Receive 80% of expected IV doses for the completed treatment duration, miss no more than 
1 IV dose in the first 48 hours of treatment, and miss no more than 2 consecutive IV doses 
overall; and  
• Receive 3 days of study drug if classified as a failure on clinical outcome, or receive 5 days 
of study drug if classified as a cure on clinical outcome. 
The ME Population will include subjects who meet the m-MITT criteria, as well as the following 
criteria: 
• Have no key inclusion or exclusion violations;  
• Obtain a clinical outcome (cure, improvement, or failure) and a microbiological outcome 
(eradication or persistence) at EOT and an overall outcome of cure or failure at TOC, unless 
criteria for failure were met at an earlier time point; 


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• Receive 80% of expected IV doses for the completed treatment duration, miss no more than 
1 IV dose in the first 48 hours of treatment, and miss no more than 2 consecutive IV doses 
overall; and  
• Receive 3 days of study drug if classified as a failure on overall outcome, or receive 5 days 
of study drug if classified as a cure on overall outcome. 
The CRE Microbiological Evaluable (CRE-ME) Population will include subjects who meet the 
ME criteria and who have a baseline Enterobacteriaceae that is confirmed to be 
meropenem-resistant. 
18.2 
Disposition, Demographics, Baseline Characteristics, and Exposure 
The number of subjects randomized, treated, completed, and discontinued early from treatment 
and from study, and the reasons for discontinuation, will be summarized descriptively. 
Demographic and baseline characteristics will be summarized descriptively. The number of doses 
of study drug taken by subjects will be summarized descriptively for each treatment group. 
18.3 
Efficacy Analysis 
The efficacy analyses will be descriptive summaries of the proportion of subjects in the 
mCRE-MITT Population at the TOC visit with a response of success defined according to primary 
indication. A descriptive summary of all-cause mortality for subjects with HABP, VABP, and 
bacteremia will be provided. Two-sided, exact binomial 95% confidence intervals (CIs) for the 
true proportion of responses of success for the primary efficacy endpoint will be reported.  
Exploratory analyses will be conducted based on subject evaluability and may include clinical and 
microbiological responses in various analysis populations at EOT, TOC, and LFU. 
Analyses of the other secondary and exploratory endpoints will be conducted in a similar manner 
as the analyses above.  
18.4 
Safety Analysis 
All subjects who receive at least 1 dose of study drug (i.e., the MITT Population) will be included 
in the safety analyses and analyzed based on the actual treatment received. Adverse events will be 
collected throughout the study duration. A TEAE is defined as an adverse event with a start date 
and time on or after the first dose of study drug. Treatment-emergent adverse events will be 
tabulated by NCI-CTCAE Grade. The number and percentage of subjects in each treatment group 
reporting at least 1 occurrence of a TEAE for each unique System Organ Class and Preferred Term 
will be tabulated. Treatment-emergent adverse events will also be tabulated by severity and by the 
relationship to study drug in treatment groups as assessed by the Investigator. The number and 
percentage of subjects in each treatment group reporting at least one occurrence of an SAE will be 
tabulated. The number and percentage of subjects (in each treatment group) prematurely 
discontinuing study drug treatment due to a TEAE will be tabulated by System Organ Class and 
Preferred Term.  
Safety laboratory data will be presented by change from baseline. The number and percentage of 
subjects with laboratory, vital sign, ECG, or physical examination abnormalities at baseline, 
subsequent visits, or early termination from the study will be tabulated by treatment group. The 


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results of all laboratory tests, physical examination findings, ECG, and vital signs will be presented 
in data listings. 
18.5 
Sample Size Justification 
Due to the infeasibility of recruiting a large number of subjects infected with CRE pathogens, no 
formal power calculations have been performed for this study. The sample size is based on 
practical considerations. 
The study will enroll approximately 150 subjects with serious infections, of whom a proportion 
will have CRE infections across the following indications: cUTI or AP, cIAI, HABP, VABP, 
and/or bacteremia.  
Subjects will be stratified at randomization based on their presenting indication and by region 
(North America vs. Europe vs. Asia Pacific vs. Rest of World). 
Enrollment will continue until at least 45 subjects (30 Carbavance [meropenem/RPX7009, 
15 BAT) with cUTI or AP are documented to have a CRE organism at baseline and until at least 
30 subjects with cIAI (20 Carbavance [meropenem/RPX7009], 10 BAT) are enrolled.  Once the 
specified number of subjects are enrolled in the cUTI and/or cIAI indications, data from these 
subjects may be submitted to regulatory agencies in support of a marketing application, and the 
enrollment of additional subjects into the specific indication(s) where enrollment was met may be 
stopped. 


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19 REGULATORY AND ADMINISTRATIVE ASPECTS 
19.1 
Compliance with Regulatory Requirements 
This study will be conducted in compliance with the protocol and all regulatory requirements, in 
accordance with GCP, including ICH guidelines, and in general conformity with the most recent 
version of the Declaration of Helsinki. 
19.2 
Institutional Review Board 
This protocol, the informed consent document, and all relevant supporting data must be submitted 
to an IRB/IEC for approval. The IRB/IEC approval of the protocol and informed consent form 
must be obtained before the study may be initiated. 
The Investigator is responsible for keeping the IRB/IEC advised of the progress of the study and 
of any changes made to the protocol as deemed appropriate, but in any case, at least once a year. 
The Investigator is also responsible for notifying the IRB/IEC of all unanticipated risks involving 
human subjects that occur during the study. 
The Office for Human Research Protections considers unanticipated risks to subjects or others to 
include, in general, any incident, experience, or outcome that meets all of the following criteria: 
• Unexpected in terms of nature, severity, or frequency given the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and the characteristics of the subject population being studied; 
• Related or possibly related to participation in the research (“possibly related” means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research); and 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
19.3 
Informed Consent 
The informed consent document must be signed and dated prior to any study-related procedures 
being performed at screening. The original signed informed consent form for each participating 
subject will be filed with records kept by the Investigators. A copy of the informed consent 
document must be provided to the subject and/or the subject’s legal representative. Where 
applicable, the informed consent form will be provided in a certified translation of the local 
language.  
19.4 
Confidentiality 
Personal study subject data collected and processed for the purposes of this study should be 
managed by the Investigator and his/her staff with adequate precautions to ensure the 
confidentiality of those data, in accordance with applicable national and/or local laws and 
regulations on personal data protection. 
Monitors, auditors, and other authorized agents of the Sponsor and the clinical research 
organization (if applicable); the IRB/IEC approving this research; and the FDA and EMA as well 


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as any other applicable regulatory authorities, will be granted direct access to study subject original 
medical records for verification of clinical study procedures and/or data, without violating the 
confidentiality of the subjects, to the extent permitted by the law and regulations. In any 
presentation of the results of this study at meetings or in publications, subject identity will remain 
confidential.  
19.5 
Compensation, Insurance and Indemnity 
Information regarding compensation, insurance, and indemnity is addressed in the Clinical Trial 
Research Agreement. 
19.6 
Protocol Amendment 
If a protocol has been filed with regulatory agencies or submitted to an IRB/IEC and requires 
significant changes, a protocol amendment must be written. Any changes to the protocol will be 
made by the Sponsor. All amendments will be sent to the study sites that are then responsible for 
submitting the amendment to their IRB/IEC for approval. 
19.7 
Case Report Forms: Electronic 
An eCRF will be used to record all subject data specified by this protocol. The eCRF must be 
completed by designated and trained study personnel. The eCRF will be electronically signed by 
the PI or a sub-investigator. It is the responsibility of the PI to ensure the eCRFs are completed in 
an accurate and timely manner. The processing of eCRFs will include an audit trail (to include 
changes made, reason for change, date of change and person making change). At the completion 
of the study, a disk will be provided to the Sponsor that will include the per subject eCRF in an 
individual subject profile.  
19.8 
Source Document Maintenance 
Source documents are defined as the results of original observations and activities of a clinical 
investigation. Source documents may include, but are not limited to, study progress notes, e-mail 
correspondence, computer printouts, laboratory data, and drug accountability records. All source 
documents produced in this study will be maintained by the Investigator(s) and made available for 
inspection by the Sponsor’s representatives, the FDA and EMA, or other regulatory authorities. 
19.9 
Study Monitoring Requirements 
Site visits will be conducted by an authorized Sponsor representative (the monitor) to inspect study 
data, subject’s medical records, and eCRFs in accordance with ICH guidelines, GCP, and the 
respective US or national regulations and guidelines, as applicable. It will be the monitor’s 
responsibility to inspect the eCRF at regular intervals throughout the study, to verify the adherence 
to the protocol and the completeness, consistency and accuracy of the data being entered. The 
monitor should have access to laboratory test reports and other subject records needed to verify 
the entries on the eCRFs. 
The Investigator will permit representatives of the Sponsor, the FDA and EMA, and/or respective 
health authorities to inspect facilities and records relevant to this study. 


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19.10 Study File Management 
It will be the responsibility of the Investigator to assure that the study file at the site is maintained. 
The Investigator must retain all study records required by the Sponsor and by the applicable 
regulatory agencies in a secure and safe facility. The Investigator must consult the Sponsor (or 
designee) before disposal of any study records, and must notify the Sponsor of any change in the 
location, disposition, or custody of the study files.  
19.11 Study Completion 
The Sponsor requires the following data and materials before a study can be considered complete 
or terminated: 
• 
Laboratory findings, clinical data, and all special test results from screening through the end 
of the study follow-up period; 
• 
All eCRFs properly completed by appropriate study personnel and electronically signed and 
dated by the Investigator; 
• 
Complete Drug Accountability records (drug inventory log and an inventory of returned or 
destroyed clinical material); 
• 
Copies of protocol amendments and IRB/IEC approval/notification if appropriate; and 
• 
A summary of the study prepared by the PI (an IRB/IEC summary letter is acceptable). 
19.12 Audits 
During the course of the study, or after completion of the study, study sites will be selected for an 
audit by a Quality Assurance (QA) Auditor from the Sponsor (or an auditor appointed by the 
Sponsor or the Sponsor’s authorized representative) and/or an inspector from the FDA, EMA, 
and/or other regulatory authority.  
19.13 Retention of Records 
The Sponsor follows US and other national regulations and ICH guidelines in its retention policy. 
In the US, the Code of Federal Regulations (CFR) requires for Investigational New Drugs 
(21 CFR 312.62) that records and documents pertaining to the conduct of this study and the 
distribution of investigational drugs including eCRFs, consent forms, laboratory test results, and 
medication inventory records be kept on file by the PI for 2 years after a marketing application is 
approved for the drug for the indication for which it is being studied. If no application is filed or 
approved, these records must be kept for 2 years after the investigation has been discontinued and 
the FDA has been notified. International Conference on Harmonization guidelines indicate that 
documents should be retained until at least 2 years after the last approval of a marketing application 
in an ICH region and until there are no pending or contemplated marketing applications in an ICH 
region, or at least 2 years have elapsed since the formal discontinuation of clinical development of 
the investigational product. If there is a country or institutional policy that specific records and 
documents be retained for a longer period than described above, the applicable sites must comply 
with those policies in addition to US and ICH policies. No study records should be destroyed 
without prior authorization from the Sponsor. 


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19.14 Disclosure of Data 
The Investigator agrees by his/her participation that the results of this study may be used for 
submission to national and/or international registration and supervising authorities. If required, 
these authorities will be provided with the names of Investigators, their addresses, qualifications 
and extent of involvement. It is understood that the Investigator is required to provide the Sponsor 
with all study data, complete reports, and access to all study records.  
Data generated by this study must be available for inspection by the FDA and other regulatory 
authorities, by the Sponsor, and the IRB/IEC as appropriate. At a subject’s request, medical 
information may be given to his or her personal physician or other appropriate medical personnel 
responsible for his or her welfare. Subject medical information obtained during the course of this 
study is confidential and disclosure to third parties other than those noted above is prohibited. 
19.15 Financial Disclosure 
Investigators must provide financial disclosure statements to the Sponsor prior to the start of the 
study and on a yearly basis and also when any change occurs up to 1 year after the completion of 
the study. 
19.16 Publication Policy 
The publication policy is outlined in the Clinical Trial Agreement. 


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20 REFERENCES 
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2. Gupta N, Limbago BM, Patel JB, Kallen AJ. Carbapenem-resistant Enterobacteriaceae: 
epidemiology and prevention. Clin Infect Dis. 2011;53(1):60-67.  
3. Grundmann 
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Livermore DM, Giske CG, et al. Carbapenem-non-susceptible 
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6. Investigator’s Brochure: Carbavance™ (Meropenem/RPX7009). San Diego, CA; Rempex 
Pharmaceuticals, Inc.:2014.  
7. Summary of Product Characteristics. Invanz 1 g powder for concentrate for solution for 
infusion. Hertfordshire, UK; Merck Sharp & Dohme Limited:2011.  
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9. Summary of Product Characteristics. Tygacil 50 mg powder for solution for infusion. Kent, 
UK; Pfizer Limited:2011.  
10. Summary of Product Characteristics. Colomycin injection 1 million or 2 million international 
units. Kent, UK; Forest Laboratories Limited:2012. 
11. Summary of Product Characteristics. Amikacin 250 mg/mL injection. Warwickshire, UK; 
Hospira UK Limited:2012. 
12. Summary of Product Characteristics. Tobramycin 40 mg/mL injection. Warwickshire, UK; 
Hospira UK Limited:2009. 
13. Summary of Product Characteristics. Gentamicin 40 mg/mL injection. Warwickshire, UK; 
Hospira UK Limited:2011.  
14. US Package Insert. Polymyxin B for injection USP 500 000 units. Bedford, OH; Bedford 
Laboratories:2011.  


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Carbavance™ (Meropenem/RPX7009) 
CONFIDENTIAL 
Clinical Study Protocol: REMPEX-506 
24 APR 2015, Version 3.0 
Page 107 of 116 
15. Kuti JL, Nicolau DP. Optimal cefepime and meropenem dosing for ventilator-associated 
pneumonia patients with reduced renal function: an update to our clinical pathway. J Crit Care 
2010;25(1):155-156.  
16. US Package Insert. AVYCAZ (ceftazidime-avibactam) for injection, for intravenous use; 
Cincinnati, OH; Forest Pharmaceuticals, Inc: 2015.  
 


REMPEX PHARMACEUTICALS, INC. 
 
Carbavance™ (Meropenem/RPX7009) 
CONFIDENTIAL 
Clinical Study Protocol: REMPEX-506 
24 APR 2015, Version 3.0 
Page 108 of 116 
APPENDIX 1: 
STATISTICAL ANALYSIS POPULATIONS 
CRE Microbiologic 
Evaluable (CRE-ME) 
Population 
• Meets all ME evaluability 
criteria  
• Has a confirmed Meropenem 
resistant Enterobacteriaceae 
infection 
Microbiological CRE 
Modified Intent-to-Treat 
(mCRE-MITT) Population 
• Meets all m-MITT 
evaluability criteria  
• Has a confirmed Meropenem 
resistant Enterobacteriaceae 
infection 
Microbiological Modified 
Intent-to-Treat (m-MITT) 
Population 
• baseline bacterial 
pathogen(s) 
Screen failure 
Drop no-med 
subjects 
Clinical Evaluable (CE) 
Population 
Meets all MITT 
Evaluability Criteria: 
• Have no key 
inclusion/exclusion 
violations 
• Clinical Outcome of (C/I/F) 
at EOT 
• Clinical Outcome of (C/F) at 
TOC (unless F at earlier time 
point) 
• Receive >80% of expected 
IV doses 
• Miss no more than 1 dose in 
1st 48 hours of treatment 
• Miss no more than 
2 consecutive IV doses 
• >3 days for failure, ≥5 days 
for cure 
Screened Population 
Intent-to-Treat (ITT) 
Population 
Modified Intent-to-Treat 
(MITT) Population 
• Receive ≥1 dose of Study Drug 
Microbiological Evaluable 
(ME) Population 
Meets all m-MITT 
evaluability criteria and: 
• Have no key 
inclusion/exclusion violations 
• Clinical Outcome of (C/I/F) and 
Microbiological Outcome of 
(E/P) at EOT 
• Overall Outcome of (C/F) at 
TOC (unless F at earlier time 
point) 
• Receive >80% of expected IV 
doses 
• Miss no more than 1 dose in 1st 
48 hours of treatment 
• Miss no more than 
2 consecutive IV doses 
• >3 days for failure, ≥5 days for 
cure 
C = Cure; E = Eradication; EOT = End of Treatment; F = Failure; I = Improvement; IV = intravenous; P = Persistence; 
PK = pharmacokinetic; TOC = Test of Cure 
Pharmacokinetic (PK) 
Population 
• Have at least one plasma 
PK sample drawn 


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CONFIDENTIAL 
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Page 109 of 116 
APPENDIX 2: 
STUDY SCHEMA 
 
 
 
 
Subjects with: 
• cUTI or AP 
• cIAI 
• HABP 
• VABP 
• Bacteremia 
Known or 
suspected to 
be caused by 
CRE 
Randomization 
Best Available Therapy* 
Carbavance 
(meropenem/RPX7009) 
2 g/2 g q8h via IV infusion 
over 3 hours 
Screening 
Day -1 to Day 1 
Treatment  
Day 1 through Day 7 (up to 
Day 14) 
TOC 
7 days (±2 days) 
post-EOT 
 
LFU 
14 days 
(±2 days) 
post-EOT 
  
Follow-up 
Day 12 up to Day 30 
EOT 
Day 7 up to Day 14  
* Best Available Therapy is treatment with any of the following antibiotics, alone or in combination: carbapenem (meropenem, ertapenem, or imipenem), tigecycline, 
colistin, aminoglycoside (amikacin, tobramycin, or gentamicin), polymyxin B, and ceftazidime-avibactam. 
AP = acute pyelonephritis; cIAI = complicated intra-abdominal infection; CRE = carbapenem-resistant Enterobacteriaceae; cUTI = complicated urinary tract infection; EOT = 
End of Treatment; HABP = Hospital-acquired bacterial pneumonia; IV = intravenous; LFU = Late Follow-up; PK = pharmacokinetics; q8h = Every 8 hours; TOC = Test of Cure; 
VABP = Ventilator-associated bacterial pneumonia. 
The objectives of this study are: 
To evaluate the safety, tolerability and efficacy of Carbavance (meropenem/RPX7009) in treatment of 
subjects with selected serious infections, suspected or known to be due to carbapenem-resistant 
Enterobacteriaceae; and 
To assess the PK of meropenem and RPX7009 in subjects with selected serious infections, suspected or known 
to be due to carbapenem-resistant Enterobacteriaceae. 
REMPEX 506 Carbavance (Meropenem/RPX7009)  
A Phase 3, Multi-center, Randomized, Open-Label Study of Carbavance (Meropenem/RPX7009) Versus Best Available Therapy in 
Subjects with Selected Serious Infections Due to Carbapenem-Resistant Enterobacteriaceae  
For cIAI Subjects – Surgical/Percutaneous Intervention 


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Carbavance™ (Meropenem/RPX7009) 
CONFIDENTIAL 
Clinical Study Protocol: REMPEX-506 
24 APR 2015, Version 3.0 
Page 110 of 116 
APPENDIX 3: 
COMMON TOXICITY CRITERIA TABLE 
For details on Common Terminology Criteria for Adverse Events (CTCAE) and Common Toxicity 
Criteria (CTC), see the online references at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 


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Clinical Study Protocol: REMPEX-506 
24 APR 2015, Version 3.0 
Page 111 of 116 
APPENDIX 4: 
 A PHASE 1, OPEN-LABEL, SINGLE-DOSE STUDY TO 
DETERMINE THE SAFETY AND PHARMACOKINETICS OF 
CARBAVANCE IN SUBJECTS WITH RENAL INSUFFICIENCY 
(INCLUDING SUBJECTS ON STANDARD HEMODIALYSIS) 
Study 504 was an open-label study in adult subjects with varying degrees of renal insufficiency, 
including those requiring hemodialysis (HD). The safety and PK of a single IV dose of 1 g 
meropenem plus 1 g RPX7009, infused over 3 hours, was evaluated. Forty-one subjects were 
enrolled in 5 groups based on their degree of renal insufficiency. The five cohorts included: 
subjects with normal renal function (CrCl >90 ml/min), mild renal impairment (CrCl 
60-89 ml/min), moderate renal impairment (CrCl 30-<60 ml/min), severe renal impairment (CrCl 
<30 ml/min, and subjects with end stage renal disease requiring hemodialysis. Patients on renal 
replacement therapy other than standard hemodialysis (including continuous veno-venous 
hemofiltration, continuous veno-venous hemodialysis and continuous renal replacement therapy) 
were not studied.   
Figure 1 shows the relation between estimated GFR (eGFR) and meropenem or RPX7009 plasma 
clearance. The plasma clearance of both drugs remained similar throughout the range of renal 
function as evidenced by the clustering of values and the linear decline in clearance with 
decreasing renal function.  
The removal of meropenem and RPX7009 during hemodialysis was studied in 9 patients with 
severe renal insufficiency on chronic hemodialysis. Patients received a single meropenem 1 g/ 
RPX7009 1 g dose, followed by a hemodialysis session. Both meropenem and RPX7009 were 
removed from plasma by hemodialysis. These data indicate that maintenance doses of each drug 
(adjusted for degree of underlying endogenous renal function) should be administered after a 
dialysis session.  
Figure 1: Meropenem and RPX7009 clearance according to creatinine clearance in subjects 
with varying degrees of renal impairment 
 


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24 APR 2015, Version 3.0 
Page 112 of 116 
Determination of Carbavance (meropenem/RX7009) Dosage in Renal Impairment 
Dosage adjustment according to degree of renal impairment was determined by analysis of 
estimates of each subject’s pharmacokinetics and exposures determined by analysis of various 
potential dosage regimens of meropenem or RPX7009. The objective was to maintain exposures 
(as AUC) across the range of renal function to be as consistent as possible across the spectrum of 
renal function. In view of PK-PD analyses in nonclinical models that show AUC is linked to 
efficacy for RPX7009, AUC was the appropriate controller of efficacy for this agent. Since T>MIC 
is the PK-PD index important for meropenem, different dosing intervals were evaluated to insure 
T>MICbreakpoint was above threshold values (T>MIC >40%) for efficacy. For purposes of this 
analysis, the forecasted susceptibility breakpoint for meropenem based on the 2 gram dose and 
3 hr infusion was 8 ug/ml.  For purposes of this analysis, the forecasted susceptibility breakpoint 
for meropenem based on the 2 gram dose and 3 hr infusion was 8 ug/ml.  This breakpoint was 
determined by results of in vitro resistance development experiments which showed that a a 
minimum concentration of 8 mg/L of RPX7009 (in combination with 8 mg/L of meropenem) was 
required to be present for 24 hours to prevent resistance. Free drug was considered for both 
meropenem and RPX7009 (plasma protein binding of 6% and 33%, respectively). Free drug was 
considered for both meropenem and RPX7009 (plasma protein binding of 6% and 33%, 
respectively).  
Meropenem 
Table 1 shows meropenem Time > MIC (T> MIC) measured in each patient and PK-PD indices 
for three potential dosage regimens in each subject according to measured meropenem PK in each 
subject. Meropenem dosage regimens were identified for each of the strata of renal function that 
would meet or achieve target exposures (T>MIC of at least 40% of the dosing interval) in all 
subjects (see shaded cells).   
 
 
 
 
 
 
 
 
 
 
 
 
 


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CONFIDENTIAL 
Clinical Study Protocol: REMPEX-506 
24 APR 2015, Version 3.0 
Page 113 of 116 
Table 1.  Analysis of different meropenem dosing regimens by individual subjects enrolled in Study 
504. The pharmacokinetic target for meropenem is a Time>MIC of at least 40% of the dosing 
interval where the MIC is 8 µg/mL. The green shading denotes the recommended meropenem 
dosing regimen.  
Expected Meropenem Time, in hours per day, (% of dosing interval) Above MIC of 
8 µg/mL According to Dosage Regimen  
Estimated 
Creatinine 
Clearance 
(ml/min) 
2g q8h 
1g q8h 
1g q12h 
1g q24h 
500 mg 
q12h 
500 mg 
q24h 
Normal  
Mean  
13.8 (58)  
Range  
10.5 - 16.5 
(44 - 69) 
  
  
  
  
  
> 50 mL/min group 
83 
16.5 (69) 
13.5 (56) 
9 (38) 
4.5 (19) 
7 (29) 
3.5 (15) 
79 
15.0 (63) 
12 (50) 
8 (33) 
4 (17) 
6 (25) 
3 (13) 
77 
16.5 (69) 
13.5 (56) 
9 (38) 
4.5 (19) 
7 (29) 
3.5 (15) 
77 
16.5 (69) 
13.5 (56) 
9 (38) 
4.5 (19) 
7.6 (32) 
3.8 (16) 
71 
20 (83) 
16.5 (69) 
11 (46) 
5.5 (23) 
8 (33) 
4 (17) 
67 
16.5 (69) 
13.5 (56) 
9 (38) 
4.5 (19) 
7 (29) 
3.5 (15) 
56 
20 (83) 
16.5 (69) 
11 (46) 
5.5 (23) 
9 (38) 
4.5 (19) 
55 
20 (83) 
16.5 (69) 
11 (46) 
5.5 (23) 
7.6 (32) 
3.8 (16) 
30 - 49 ml/min group 
46 
24 (100) 
18 (75) 
12 (50) 
6 (25) 
10 (42) 
5 (21) 
44 
24 (100) 
18 (75) 
12 (50) 
6 (25) 
9 (38) 
4.5 (19) 
42 
24 (100) 
16.5 (69) 
11 (46) 
5.5 (23) 
8 (33) 
4 (17) 
40 
24 (100) 
24 (100) 
16 (67) 
8 (33) 
12 (50) 
6 (25) 
38 
24 (100) 
24 (100) 
20 (83) 
10 (42) 
12 (50) 
6 (25) 
32 
24 (100) 
24 (100) 
20 (83) 
10 (42) 
14 (58) 
7 (29) 
10 - 19 ml/min group 
15 
24 (100) 
24 (100) 
24 (100) 
12 (50) 
20 (83) 
10 (42) 
14 
24 (100) 
24 (100) 
24 (100) 
12 (50) 
16 (67) 
8 (33) 
14 
24 (100) 
24 (100) 
20 (83) 
10 (42) 
16 (67) 
8 (33) 
12 
24 (100) 
24 (100) 
24 (100) 
12 (50) 
20 (83) 
10 (42) 
11 
24 (100) 
24 (100) 
24 (100) 
12 (50) 
16 (67) 
8 (33) 
10 
24 (100) 
24 (100) 
24 (100) 
14 (58) 
24 (100) 
12 (50) 
5 - 9 ml/min group 
8 
24 (100) 
24 (100) 
24 (100) 
24 (100) 
24 (100) 
12 (50) 
7 
24 (100) 
24 (100) 
24 (100) 
24 (100) 
24 (100) 
12 (50) 
7 
24 (100) 
24 (100) 
24 (100) 
14 (58) 
20 (83) 
10 (42) 
6 
24 (100) 
24 (100) 
24 (100) 
24 (100) 
24 (100) 
12 (50) 
6 
24 (100) 
24 (100) 
24 (100) 
24 (100) 
24 (100) 
12 (50) 
5 
24 (100) 
24 (100) 
24 (100) 
24 (100) 
24 (100) 
24 (100) 
5 
24 (100) 
24 (100) 
24 (100) 
24 (100) 
24 (100) 
12 (50) 


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24 APR 2015, Version 3.0 
Page 114 of 116 
 
RPX7009 
Table 2 shows RPX7009 AUC measured in each subject and 24h AUC for three potential dosage 
regimens according to measured RPX7009 clearance in each subject. Since AUC is the target PK 
metric and RPX7009 clearance remained close to meropenem clearance, unit and 24 hr doses 
remained at a 1:1 ratio throughout the range of renal function.  
Considerations for subjects with creatinine clearance < 10 ml/min 
As noted in the Figure 1, as creatinine clearance falls below 10 ml/min, meropenem non-renal 
clearance assumes a greater proportion of total clearance. In contrast, RPX7009 has no 
measureable non-renal clearance. Thus, to maintain a 1:1 dose ratio and, more importantly 
provide therapeutic exposures of each component and to avoid accumulation of RPX7009, 
patients with a creatinine clearance <10 ml/min should receive hemodialysis at least every 3 days 
(i.e., at least twice weekly).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


REMPEX PHARMACEUTICALS, INC. 
 
Carbavance™ (Meropenem/RPX7009) 
CONFIDENTIAL 
Clinical Study Protocol: REMPEX-506 
24 APR 2015, Version 3.0 
Page 115 of 116 
Table 2.  Analysis of different RPX7009 dosing regimens by individual subjects enrolled in 
Study 504. The green shading denotes the recommended RPX7009 dosing regimen. 
 
Expected RPX7009 Free Drug 24h AUC (mg*hr/L) 
Estimated 
Creatinine 
Clearance 
(ml/min) 
Observed 
AUC0-inf 
following a 1 g 
dose 
2g q8h 
1g q8h 
1g q12h 
1g q24h 
500 mg 
q12h 
500 mg 
q24h 
Normal  
 
Mean 
357.9 
Range 
283 - 470 
 
 
 
 
 
> 50 mL/min group 
83 
70.0 
420.0 
210.0 
140.0 
70.0 
70.0 
35.0 
79 
62.7 
376.3 
188.2 
125.4 
62.7 
62.7 
31.4 
77 
69.2 
415.0 
207.5 
138.3 
69.2 
69.2 
34.6 
77 
88.4 
530.5 
265.2 
176.8 
88.4 
88.4 
44.2 
71 
70.7 
424.2 
212.1 
141.4 
70.7 
70.7 
35.4 
67 
68.1 
408.7 
204.3 
136.2 
68.1 
68.1 
34.1 
56 
108.4 
650.6 
325.3 
216.9 
108.4 
108.4 
54.2 
55 
108.0 
648.1 
324.0 
216.0 
108.0 
108.0 
54.0 
30 - 49 ml/min group 
46 
119.3 
715.7 
357.8 
238.6 
119.3 
119.3 
59.6 
44 
129.1 
774.5 
387.2 
258.2 
129.1 
129.1 
64.5 
42 
115.2 
690.9 
345.5 
230.3 
115.2 
115.2 
57.6 
40 
228.1 
1368.4 
684.2 
456.1 
228.1 
228.1 
114.0 
38 
251.1 
1506.5 
753.3 
502.2 
251.1 
251.1 
125.5 
32 
310.6 
1863.5 
931.8 
621.2 
310.6 
310.6 
155.3 
10 - 19 ml/min group 
15 
505.1 
3030.3 
1515.2 
1010.1 
505.1 
505.1 
252.5 
14 
427.3 
2563.8 
1281.9 
854.6 
427.3 
427.3 
213.7 
14 
493.6 
2961.8 
1480.9 
987.3 
493.6 
493.6 
246.8 
12 
790.7 
4744.3 
2372.2 
1581.4 
790.7 
790.7 
395.4 
11 
830.3 
4981.6 
2490.8 
1660.5 
830.3 
830.3 
415.1 
10 
719.6 
4317.6 
2158.8 
1439.2 
719.6 
719.6 
359.8 
5 - 9 ml/min group 
8 
8617.7 
51706.2 
25853.1 
17235.4 
8617.7 
8617.7 
4308.9 
7 
4189.5 
25137.0 
12568.5 
8379.0 
4189.5 
4189.5 
2094.8 
7 
794.5 
4767.0 
2383.5 
1589.0 
794.5 
794.5 
397.3 
6 
923.3 
5539.8 
2769.9 
1846.6 
923.3 
923.3 
461.7 
6 
840.0 
5040.0 
2520.0 
1680.0 
840.0 
840.0 
420.0 
5 
7581.7 
45490.2 
22745.1 
15163.4 
7581.7 
7581.7 
3790.9 
5 
2289.0 
13734.0 
3270.0 
4578.0 
2289.0 
2289.0 
1144.5 
 


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CONFIDENTIAL 
Clinical Study Protocol: REMPEX-506 
24 APR 2015, Version 3.0 
Page 116 of 116 
Based on the above analysis, the Carbavance dosage regimens in Table 3 are recommended for 
subjects with impaired renal function. 
   
Table 3: Carbavance Dosage according to renal function  
Estimated Creatinine 
Clearance, ml/min  
(Cockcroft-Gault) 
Carbavance Dosage Regimen (All doses infused over 3 hrs) 
 
50 
Meropenem 2 g / RPX7009 2 g q8h 
30 - 49 
Meropenem 1 g / RPX7009 1 g q8h 
20 - 29 
Meropenem 1 g / RPX7009 1 g q12h 
10-19
Meropenem 500 mg / RPX7009 500 mg q12h 
<10 
Meropenem 500 mg / RPX7009 500 mg q24h1 
1 Dosage regimen assumes subjects receive hemodialysis at least twice per week. Maintenance doses of Carbavance 
in these subjects should be administered as soon as possible after the dialysis session.  
q8h = every 8 hours; q12h = every 12 hours; q24h = every 24 hours. 
 
 

SAP_001.pdf: 
 
 
Statistical Analysis Plan 
(SAP) 
Interim Analysis 
 
A Phase 3, Multi-Center, Randomized, Open-Label 
Study of Carbavance (Meropenem/RPX7009) Versus 
Best Available Therapy in Subjects with Selected 
Serious Infections Due to Carbapenem-Resistant 
Enterobacteriaceae 
 
 
 
 
Protocol Number: REMPEX-506 
 
 
 
Version: 2.0, 10 June 2016 
 
Sponsor: Rempex Pharmaceuticals, Inc. 
A wholly-owned subsidiary of 
The Medicines Company San Diego, CA 92121 
 
 
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. 


Meropenem-Vaborbactam 
 Statistical Analysis Plan: REMPEX 506 
Rempex Pharmaceuticals 
      
 
Confidential 
 
2 
SAP APPROVAL FORM 
 
Document Title: 
Statistical Analysis Plan 
 
Protocol Number: 
REMPEX 506 
 
Study Title: 
A Phase 3, Multi-Center, Randomized, Open-Label Study of 
Carbavance (Meropenem/RPX7009) Versus Best Available 
Therapy in Subjects with Selected Serious Infections Due to 
Carbapenem-Resistant Enterobacteriaceae 
 
Document Date: 
10 June 2016 
 
Document Version: 
Version 2.0 
 
This Statistical Analysis Plan has been reviewed and approved by:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                   
  
                              
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                    
 
  
                              
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                       
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
                                                           
 
   
 
   
 
  
 


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 Statistical Analysis Plan: REMPEX 506 
Rempex Pharmaceuticals 
      
 
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3 
TABLE OF CONTENTS 
 
SAP APPROVAL FORM..................................................................................................2 
TABLE OF CONTENTS ..................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................6 
1. 
INTRODUCTION ..........................................................................................8 
2. 
STUDY OBJECTIVES ..................................................................................8 
3. 
STUDY DESIGN ............................................................................................8 
3.1. 
General Study Design and Plan ........................................................................8 
3.2. 
Treatment Bias ................................................................................................11 
3.3. 
Data Safety Monitoring Board ........................................................................11 
3.4. 
Blinded Adjudication Committee ...................................................................11 
3.5. 
Source Control Assessment ............................................................................11 
3.6. 
Study Population .............................................................................................11 
3.7. 
Randomization ................................................................................................11 
3.8. 
Unblinding ......................................................................................................12 
3.9. 
Study Assessments..........................................................................................12 
4. 
SAMPLE SIZE JUSTIFICATION .............................................................15 
5. 
STUDY ASSESSMENT ...............................................................................15 
5.1. 
Efficacy Assessments .....................................................................................15 
5.1.1. 
Efficacy Assessments for cUTI or AP ............................................................15 
5.1.2. 
Efficacy Assessments for cIAI ........................................................................16 
5.1.3. 
Efficacy Assessments for HABP and VABP ..................................................17 
5.1.4. 
Efficacy Assessments for Bacteremia ............................................................17 
5.1.5. 
Exploratory Efficacy Assessments .................................................................18 
5.1.6. 
Clinical Outcome ............................................................................................19 
5.1.7. 
Microbiologic Outcome ..................................................................................20 
5.1.8. 
Overall Response ............................................................................................21 
5.1.9. 
Overall Mortality Rate ....................................................................................22 
5.2. 
Safety Assessments .........................................................................................22 
5.2.1. 
Adverse Events ...............................................................................................22 
5.2.2. 
Clinical Laboratory Evaluations .....................................................................22 


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4 
5.2.3. 
Vital Signs ......................................................................................................23 
5.2.4. 
Electrocardiograms (ECGs) ............................................................................23 
5.2.5. 
Acute Kidney Injury Evaluations ...................................................................23 
5.2.6. 
Physical Examination .....................................................................................24 
5.3. 
Medical History ..............................................................................................24 
5.4. 
Prior and Concomitant Medications ...............................................................24 
5.5. 
Pharmacokinetic Assessments ........................................................................24 
6. 
ANALYSIS POPULATIONS ......................................................................25 
6.1. 
Intent-to-Treat Population ..............................................................................25 
6.2. 
Modified Intent-to-Treat Population ...............................................................25 
6.3. 
Safety Population ............................................................................................25 
6.4. 
Microbiological Modified Intent-to-Treat Population ....................................25 
6.5. 
Microbiological Carbapenem-resistant Enterobacteriaceae Modified 
Intent-to-Treat Population ..............................................................................25 
6.6. 
Clinical Evaluable Population ........................................................................25 
6.7. 
Microbiological Evaluable Population ...........................................................26 
6.8. 
Carbapenem-resistant Enterobacteriaceae Microbiological Evaluable 
Population .......................................................................................................26 
6.9. 
Pharmacokinetics Population..........................................................................26 
7. 
STATISTICAL ANALYSIS ........................................................................28 
7.1. 
General Statistical Considerations ..................................................................28 
7.2. 
Handling of Dropouts/Missing Data ...............................................................28 
7.3. 
Baseline Definition .........................................................................................28 
7.4. 
Subject Disposition .........................................................................................29 
7.5. 
Demographic and Baseline Characteristics ....................................................30 
7.6. 
Baseline Infection Characteristics ..................................................................30 
7.7. 
Medical History ..............................................................................................30 
7.8. 
Prior and Concomitant Medications ...............................................................30 
7.9. 
Dosing and Extent of Exposure ......................................................................31 
7.10. 
Efficacy Analyses ...........................................................................................31 
7.10.1. 
Analyses of Overall Response ........................................................................32 
7.10.2. 
Analyses of Clinical Response .......................................................................32 
7.10.3. 
Analyses of Microbiological Outcome ...........................................................33 


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5 
7.10.4. 
All-Cause Mortality Rate ................................................................................34 
7.10.5. 
Analyses of Other Efficacy Endpoints ...........................................................35 
 
 
 
 
 
 
 
7.14. 
Safety Analyses ..............................................................................................37 
7.14.1. 
Adverse Events ...............................................................................................37 
7.14.2. 
Clinical Laboratory Evaluations .....................................................................38 
7.14.3. 
Vital Signs ......................................................................................................40 
7.14.4. 
12-Lead ECG ..................................................................................................40 
7.14.5. 
Acute Kidney Injury .......................................................................................40 
7.14.6. 
Physical Examination .....................................................................................40 
7.15. 
Pharmacokinetic Concentration Analyses ......................................................40 
7.16. 
Protocol Deviations ........................................................................................40 
7.17. 
Interim Analyses .............................................................................................41 
8. 
APPENDICES ...............................................................................................42 
 
 
8.2. 
Appendix 2  Algorithm to Determine Immunocompromised Patients ...........45 
8.3. 
Appendix 3  SMQ for AESI Search Terms Hypersensitivity .........................46 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AESI 
Adverse Events of Special Interest 
ALT 
Alanine Aminotransferase 
AP 
Acute Pyelonephritis 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BAT 
Best Available Therapy 
BMI 
Body Mass Index  
CDAD 
Clostridium difficile–Associated Diarrhea 
CE 
Clinical Evaluable 
CFU 
Colony-forming Unit 
cIAI 
Complicated Intra-abdominal Infection 
CRE 
Carbapenem-resistant Enterobacteriaceae 
CRE-ME 
Carbapenem-resistant Enterobacteriaceae Microbiological Evaluable  
CT 
Computed Tomography 
cUTI 
Complicated Urinary Tract Infection 
ECG 
Electrocardiogram 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
HABP 
Hospital-acquired Bacterial Pneumonia 
ICU 
Intensive Care Unit 
ITT 
Intent-to-Treat 
IV 
Intravenous 
IWRS 
Interactive Web Response System  
KPC 
Klebsiella pneumoniae Carbapenemase 
LCE 
Leukocyte Esterase 
LFU 
Late Follow-up 
LLN 
Lower Limit of Normal 
LTAC 
Long-term Acute Care 


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mCRE-MITT 
Microbiological Carbapenem-resistant Enterobacteriaceae Modified Intent-to-Treat 
ME 
Microbiological Evaluable  
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
Minimum Inhibitory Concentration 
MITT 
Modified Intent-to-Treat  
m-MITT 
Microbiological Modified Intent-to-Treat 
MRI 
Magnetic Resonance Imaging 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NDM 
New Delhi Metallo Beta-lactamase 
OXA 
Oxacillinase 
PCS 
Potentially Clinically Significant 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment-emergent Adverse Event  
TOC 
Test of Cure 
ULN 
Upper Limit of Normal 
VABP 
Ventilator-associated Bacterial Pneumonia 
VIM 
Verona Integron-encoded Metallo Beta-lactamase 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 
 
 


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1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) is created based on the Study Protocol for REMPEX 
Study 506 (Version 3.0, April 24, 2015) and describes in detail the statistical methodology 
and the statistical analyses to be conducted for the above mentioned protocol.   
2. 
STUDY OBJECTIVES 
The objectives of this study are: 
• To evaluate the safety, tolerability, and efficacy of Carbavance (henceforth referred to 
as meropenem-vaborbactam) in treatment of subjects with selected serious infections, 
suspected or known to be due to carbapenem-resistant Enterobacteriaceae (CRE); 
and 
• To assess the pharmacokinetics (PK) of meropenem and vaborbactam in subjects with 
selected serious infections, suspected or known to be due to CRE. 
3. 
STUDY DESIGN 
3.1. 
General Study Design and Plan 
This is a Phase 3, multi-center, randomized, open-label study of meropenem-vaborbactam 
versus Best Available Therapy (BAT) in the treatment of subjects with selected serious 
infections, specifically cUTI or AP, HABP, VABP, and bacteremia, suspected or known 
to be caused by CRE.  
For this study, the specific serious infections selected for study will be defined as the 
following: 
• Complicated UTI (cUTI) is a urinary infection occurring in a subject with a structural 
or functional abnormality of the genitourinary tract associated with clinical signs and 
symptoms. 
• 
Acute pyelonephritis (AP) is an acute infection of the renal pelvis or parenchyma 
associated with clinical signs and symptoms. 
• Complicated Intra-abdominal Infection (cIAI) is an infection in the abdominal cavity 
which extends beyond the hollow viscus of origin (bowel, stomach, gallbladder, etc.) 
into the peritoneal space and is associated with either abscess formation or peritonitis 
associated with clinical signs and symptoms.  
• Hospital-acquired bacterial pneumonia (HABP) is an acute infection of the 
pulmonary parenchyma that is associated with clinical signs and symptoms in a 
subject hospitalized for more than 48 hours, or in a subject admitted from a long-term 
acute care or rehabilitation center, or admitted from home <7 days after discharge 
from a hospital or health care facility. 
• Ventilator-associated bacterial pneumonia (VABP) is an acute infection of the 
pulmonary parenchyma that is associated with clinical signs and symptoms beginning 


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more than 48 hours after a subject receives ventilatory support via an endotracheal (or 
nasotracheal) tube. 
• Bacteremia is defined by the presence of a bacterial pathogen in a blood culture that 
is not thought to be a contaminant. Subjects enrolled with the indication of bacteremia 
will not have concurrent HABP, VABP, cIAI, or cUTI/AP infections. However, 
subjects enrolled with HABP, VABP, cIAI, or cUTI/AP may also have concurrent 
secondary bacteremia. 
Approximately 150 subjects who are expected to need at least 7 days of treatment with IV 
antibiotics will be enrolled in a 2:1 ratio of meropenem-vaborbactam to BAT, respectively.  
The Treatment Arms in the study are as follows: 
• Treatment Arm A:  Subjects (n = 100) will receive meropenem 2 g plus vaborbactam 
2 g IV q8h, with each dose infused for 3 hours for up to 14 days.         
 
NOTE: Dose adjustments will be required for subjects with renal insufficiency. 
• Treatment Arm B: Subjects (n = 50) will receive BAT with IV antibiotics chosen from 
the following list, either in combination or alone, for up to 14 days: carbapenem 
(meropenem, ertapenem, or imipenem), tigecycline, colistin, aminoglycosides 
(amikacin, tobramycin or gentamicin), polymyxin B, and ceftazidime-avibactam. 
Subjects (or subject’s legal representative) providing informed consent, meeting all study 
eligibility criteria including those criteria for their particular site of infection (e.g., cUTI or 
AP, cIAI, HABP, VABP, and bacteremia), and who have either a known CRE infection or 
a suspected CRE infection (based on colonization with a KPC-producing 
Enterobacteriaceae organism [which may be determined through rapid diagnostic tests, 
active surveillance cultures, or other documentation of CRE colonization] in the past 90 
days or prior infection due to a CRE pathogen that was treated within the past 90 days) will 
be randomized to receive meropenem-vaborbactam or BAT.   
Any isolated bacterial pathogen will be identified by genus and species. The local 
laboratory will culture each subject’s sample for pathogen identification, quantification, 
and susceptibility testing. Isolated pathogens collected at the time points listed in Table 1 
and cultured at the local laboratory will be sent to the central laboratory for confirmation 
of identification and testing results.  
Day 1 is defined as the first day of study drug administration (meropenem-vaborbactam or 
BAT).  Subsequent study days are defined by the number of calendar days thereafter. The 
planned total duration of IV study drug therapy is up to 14 days.  A subject assessed as a 
clinical cure must receive ≥5 days of study drug therapy, and a subject assessed as a clinical 
failure must receive ≥3 days of study drug therapy. 
End of Treatment (EOT) will be the day on which the final dose of study drug is 
administered (+1 day). The Test of Cure (TOC) visit and Late Follow-up (LFU) visit will 
occur at time points as defined in the Schedule of Procedures (Table 1). 
Figure 1 presents the flow diagram of the study. 
 


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Figure 1: Study Schema 
 
Subjects with: 
• cUTI or AP 
• cIAI 
• HABP 
• VABP 
• Bacteremia 
Known or 
suspected to 
be caused by 
CRE 
Randomization 
Best Available Therapy* 
Carbavance 
(meropenem/RPX7009) 
2 g/2 g q8h via IV infusion 
over 3 hours 
Screening 
Day -1 to Day 1 
Treatment  
Day 1 through Day 7 (up to 
Day 14) 
TOC 
7 days (±2 days) 
post-EOT 
 
LFU 
14 days 
(±2 days) 
post-EOT 
  
Follow-up 
Day 12 up to Day 30 
EOT 
Day 7 up to Day 14  
* Best Available Therapy is treatment with any of the following antibiotics, alone or in combination: carbapenem (meropenem, ertapenem, or imipenem), tigecycline, 
colistin, aminoglycoside (amikacin, tobramycin, or gentamicin), polymyxin B, and ceftazidime-avibactam. 
AP = acute pyelonephritis; cIAI = complicated intra-abdominal infection; CRE = carbapenem-resistant Enterobacteriaceae; cUTI = complicated urinary tract infection; EOT = 
End of Treatment; HABP = Hospital-acquired bacterial pneumonia; IV = intravenous; LFU = Late Follow-up; PK = pharmacokinetics; q8h = Every 8 hours; TOC = Test of Cure; 
VABP = Ventilator-associated bacterial pneumonia. 
 
REMPEX 506 Carbavance (Meropenem-Vaborbactam)  
A Phase 3, Multi-center, Randomized, Open-Label Study of Carbavance (Meropenem/RPX7009) Versus Best Available 
Therapy in Subjects with Selected Serious Infections Due to Carbapenem-Resistant Enterobacteriaceae  


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3.2. 
Treatment Bias 
This is an open label study and the Principal Investigator, study coordinators, and pharmacy 
staff will not be blinded. However, measures were implemented to optimize unbiased 
assessments of outcomes between treatment arms at the investigational sites.  For example, 
subjects will not be informed which treatment arm they are assigned to and each site will 
designate a Blinded Investigator who will be blinded to study drug treatment and will 
evaluate criteria for Clinical Outcomes during designated study visits.  Details regarding 
minimizing subject treatment bias can be referenced in the Rempex-506 Protocol. 
In an effort to ensure unbiased assessment of outcomes between treatment arms, subjects 
will not be informed what treatment arm they are assigned. Efforts should be made to keep 
subjects naïve to their treatment throughout the course of the study.  
3.3. 
Data Safety Monitoring Board  
An independent Data Safety Monitoring Board (DSMB) will review accumulated safety 
data for this study and Rempex-505 when the total combined enrollment in both trials is 
approximately 25% and 50%. They will also review serious adverse events on an ongoing 
basis. They will make recommendations to the Sponsor based on this safety data. Further 
details regarding the data safety monitoring guidelines will be included in the DSMB 
Charter, which is the governing document of the DSMB.  
3.4. 
Blinded Adjudication Committee  
A blinded adjudication committee will also be formed to independently evaluate clinical 
outcome data in cases where the Investigator’s and Blinded Investigator’s assessment of 
outcome differ. In these instances the decision made by the blinded adjudication committee 
will factor into the final clinical outcome data as described in Section 15.1.2 of the protocol.  
Further details regarding the blinded adjudication committee, will be included in a Blinded 
Adjudication Committee Charter, which is the governing document of the committee.  
3.5. 
Source Control Assessment 
An independent assessor will review adequacy of source control in all cIAI patients.  
3.6. 
Study Population 
The study will enroll approximately 150 subjects with serious infections, of whom a 
proportion will have CRE infections across the following indications: cUTI or AP, cIAI, 
HABP, VABP, and bacteremia.  
3.7. 
Randomization  
Subjects will be randomized to receive either meropenem-vaborbactam or BAT through a 
centralized Interactive Web Response System (IWRS). The time and date of randomization 
will be recorded on the IWRS confirmation, which will be the reference time point for 
screening procedures and diagnostic time windows. The subject will only be randomized 
after the inclusion and exclusion criteria are verified. The detailed randomization algorithm 
is documented in the IWRS specification Appendix C. 


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To ensure balance among treatment arms, the randomization will be stratified by presenting 
indication (cUTI or AP, cIAI, HABP, VABP, and bacteremia) and by region (North 
America vs. Europe vs. Rest of World).  
Enrollment will continue until at least 45 subjects (30 meropenem-vaborbactam, 15 BAT) 
with cUTI or AP are documented to have a CRE organism at baseline and until at least 30 
subjects with cIAI with a documented CRE organism at baseline (20 meropenem-
vaborbactam, 10 BAT) are enrolled.  Once the specified number of subjects are enrolled in 
the cUTI and/or cIAI indications, data from these subjects may be submitted to regulatory 
agencies in support of a marketing application, and the enrollment of additional subjects 
into the specific indication(s) where enrollment was met may be stopped. 
Subjects will be randomized in a 2:1 ratio. A randomization notification will be sent to the 
appropriate site personnel; it will contain subject identification information and the 
treatment assignment for entry onto the electronic Case Report Form (eCRF). 
3.8. 
Unblinding  
This is an open label study and the Principal Investigator (PI), study coordinators, and 
pharmacy staff will not be blinded. However, the measures outlined in the protocol will be 
implemented in order to optimize unbiased assessments of outcomes between treatment 
arms at the investigational site (See Section 3.2 Treatment Bias).   
3.9. 
Study Assessments 
Table 1 presents the visit schedule and procedures of the study to be conducted at each 
visit. 


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Table 1. 
Schedule of Procedures 
 
Screening 
Treatment 
Follow-Up 
 
Early 
Terminationc 
Day 
 
Assessment/Procedure 
-1 or 1a 
1a 
2 
3 
4 
5 
6  
7 
8-14 
 
EOTb 
(+1 day) 
 TOCc  
EOT + 7 
(±2) days 
LFUd  
EOT + 14 
(±2) days 
Pre 
Dose 
Post 
Dose 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographicsf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and weightg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical examinationg 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Limited physical examinationg 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Chest x-ray, MRI, or CT scanp 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Assessment of signs & symptoms (Unblinded)h 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of signs & symptoms (Blinded)q 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
Assessment of clinical outcome (Unblinded) 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
Assessment of clinical outcome (Blinded)q 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Vital signsi 
X 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
Randomization to treatment arm 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testj 
X 
X 
 
 
 
 
 
 
 
 
Xj 
 
 
Xj 
Screening laboratoriesk (Local laboratory) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyl (Central laboratory) 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
Serum chemistryl (Central laboratory) 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
Urinalysisl (Central laboratory) 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
Pharmacokinetic samplingm 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
12-lead electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Blood culturen 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Infection-site specific sample for cultureo 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
Study drug administration  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Assessment of adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Footnotes appear on the following page.


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a. Screening/baseline procedures may be performed up to 24 hours prior to the first dose of study drug. All screening procedures must be completed PRIOR to randomization and 
the first dose of study drug (Day 1). The date of the first dose of study drug will be considered Day 1, and subsequent study days are defined by calendar days thereafter. 
b. All subjects will be assessed on their last day of treatment (any time from Day 7 to Day 14). The EOT visit activities should occur within 24 hours of last dose of study drug. If 
EOT is on Day 7, visit activities will be combined. If a subject’s treatment is changed after 72-hours post-randomization, EOT procedures will be performed and the subject will 
complete further visits as planned. 
c. The TOC visit will occur 7 days (±2 days) after EOT, between Day 12 and Day 23. Any subject receiving treatment for less than 7 days should have a TOC visit on Day 12 
(+2 days). 
d. The LFU visit will occur 14 days (±2 days) after EOT, between Day 19 to Day 30. The LFU visit should be performed in-house (with limited physical examination) if at all 
possible. If not possible, a phone call to assess the subject’s wellbeing may be substituted. Any subject receiving treatment for less than 7 days should receive an LFU visit on 
Day 19 (+2 days). For outpatient subjects with an LFU visit occurring before Day 28, a phone call to assess survival will be made on Day 28.  
e. Subjects are expected to complete all study visits. In circumstances where a subject discontinues the study early, early termination visit procedures are required. 
f. Demographic data will be collected, including name, sex, age, race, weight, and alcohol use. 
g. Height will be taken at screening only. A limited, symptom-based, physical examination will be performed at indicated visits. If a subject does not display symptoms, no limited 
physical examination needs to be performed. 
h. Assessment of signs and symptoms will include assessments to classify as new onset, continuing (increased, decreased, no change), or resolved (returned to pre-infection state) 
indication-based symptoms as outlined in the protocol.  
i. Vital signs include blood pressure, heart rate, respiratory rate, and temperature. Vital signs should be captured at approximately the same time as the Signs and Symptoms 
assessment.  
j. A urine and serum pregnancy test will be performed before the first dose of study drug in women of childbearing potential, however, only urine results are required to initiate 
treatment. A urine and serum pregnancy test will be performed as part of EOT/early termination procedures. 
k. Screening laboratories will be processed/analyzed by the local laboratory within 48 hours of randomization and include AST, ALT, total bilirubin, creatinine, WBC count with 
differentials, platelet count, and LCE in urine. 
l. Laboratory samples will be collected, processed, and sent to the central laboratory for analysis. Hematology includes complete blood count (with red blood cell count, total 
WBC count with differential counts, platelet count, hemoglobin, and hematocrit). Serum chemistry includes creatinine, estimated creatinine clearance, blood urea nitrogen, AST, 
ALT, alkaline phosphatase, total bilirubin, uric acid, lipase, amylase, albumin, total protein, glucose, sodium, potassium, chloride, carbon dioxide, calcium, and phosphorus. 
Urinalysis includes dipstick analysis of protein, glucose, ketones, bilirubin, blood, nitrites, LCE, and urobilinogen; microscopic evaluation for red blood cells, WBCs, bacteria, 
and casts; specific gravity; and pH. 
m. For subjects randomized to Carbavance (meropenem/RPX7009vaborbactam only: Day 1 plasma PK samples will be collected within 30 minutes and 2 to 3 hours after the end of 
the first infusion. Day 3 and Day 5 plasma PK samples will be collected within 30 minutes after the end of one of that day’s infusions. 
n. Blood cultures are required from all study participants at baseline. All subjects with bacteremia will have daily blood cultures collected until the first negative blood culture 
(culture reading at 24 hours or more). Subsequent blood cultures may be collected at the Investigator’s discretion, but are not required. Isolates from each positive culture will be 
sent to the central laboratory.  
o. An adequate and appropriate infection site-specific specimen based upon diagnosis (e.g., cUTI or AP, cIAI, HABP, or VABP) should be obtained immediately prior to the first 
dose of study drug (or for cIAI, 96 hours before or 24 hours after the first dose of study drug) and submitted to the local microbiology laboratory for culture and susceptibility 
testing. If the screening sample for culture is taken per standard of care before the subject or the subject’s legal representative signs informed consent, that isolate may be used 
for baseline and sent to the central laboratory once consent is obtained as long as the sample was collected within72 hours (96 hours for cIAI) of the first dose of study drug. 
Additional samples for culture should also be collected at the specified time points. If at any point in the study a subject fails while on therapy, an adequate and appropriate 
specimen should be obtained prior to the initiation of a new treatment.  When bacteremia is a subject’s primary index infection, daily blood cultures will be collected until the 
first negative blood culture (culture reading at 24 hours or more). When cIAI is the subject’s baseline infection, post-baseline samples should be collected as clinically indicated. 
p. A chest x-ray, MRI, or CT scan done within 48 hours of enrollment is acceptable. 
q.  The Blinded Investigator will be responsible for establishing a baseline level of health and performing outcome assessments independent of the unblinded staff per the Blinded 
Adjudication Charter. 
ALT = alanine aminotransferase; AP = acute pyelonephritis; AST = aspartate aminotransferase; CT = computed tomography; cUTI = complicated urinary tract infection; cIAI = 
complicated intra-abdominal infection; EOT = End of Treatment; HABP = hospital-acquired bacterial pneumonia; LCE = leukocyte esterase; LFU = Late Follow-up; MRI = 
magnetic resonance imaging; PK = pharmacokinetic; TOC = Test of Cure; VABP = ventilator-associated bacterial pneumonia; WBC = white blood cell. 


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4. 
SAMPLE SIZE JUSTIFICATION 
Due to the infeasibility of recruiting a large number of subjects infected with CRE pathogens, 
no formal power calculations have been performed for this study. The sample size is based on 
practical considerations. 
The study will enroll approximately 150 subjects with serious infections, of whom a proportion 
will have CRE infections across the following indications: cUTI or AP, cIAI, HABP, VABP, 
and bacteremia. Subjects will be stratified at randomization based on their presenting 
indication and by region (North America vs. Europe vs. Rest of World). 
Enrollment will continue until at least 45 subjects (30 meropenem-vaborbactam, 15 BAT)  
with cUTI or AP are documented to have a CRE organism at baseline and until at least 30 
subjects with cIAI (20 meropenem-vaborbactam, 10 BAT) are enrolled.  Once the specified 
number of subjects are enrolled in the cUTI and/or cIAI indications, data from these subjects 
may be submitted to regulatory agencies in support of a marketing application, and the 
enrollment of additional subjects into the specific indication(s) where enrollment was met may 
be stopped. 
5. 
STUDY ASSESSMENT 
5.1. 
Efficacy Assessments 
5.1.1. 
Efficacy Assessments for cUTI or AP 
Primary Endpoint 
The primary endpoint for cUTI or AP is defined differently by the EMA and FDA. The primary 
endpoint for the EMA is proportion of subjects in the mCRE-MITT Population that 
demonstrate microbiological eradication (See Table 2). The primary endpoint for the FDA is 
the proportion of subjects in the mCRE-MITT Population who demonstrate a response of 
overall success at the TOC visit (See Table 2).  
To meet primary endpoints for either EMA or FDA definitions, a subject’s gram-negative 
antimicrobial therapy to treat the baseline infection cannot be altered (other than dose 
adjustment or modification of BAT based on susceptibility of baseline pathogen within the 
first 72 hours after first dose of study drug) after randomization due to concerns of 
microbiological failure, clinical failure, or tolerability AND must meet the criteria in Table 2. 
Table 2. Primary Endpoint Definitions By Regulatory Agency – cUTI and AP 
Parameter 
Analysis for EMA 
Analysis for FDA 
Outcome measure 
Microbiological eradicationa) 
Overall Success (Clinical cureb) and 
microbiological eradicationa)) 
Efficacy time 
point(s) 
TOCc) 
TOCc) 
a. 
Microbiological eradication is defined as the demonstration that the bacterial pathogen(s) found at 
baseline is reduced to <103 CFU/mL of urine for EMA and <104 CFU/mL of urine for FDA. 


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b. Clinical cure is defined as complete resolution or significant improvement of the baseline signs and 
symptoms of cUTI or AP such that no further antimicrobial therapy is warranted. 
c. 
The TOC visit occurs 7 days (±2 days) post-EOT (Day 12 to Day 23). 
CFU = colony-forming unit; EMA = European Medicines Agency; EOT = End of Treatment; FDA = Food 
and Drug Administration; TOC = Test of Cure. 
Secondary Endpoints 
• The all-cause mortality rate in the mCRE-MITT and m-MITT Populations at Day 28; 
• Proportion of subjects in the m-MITT and ME Populations who demonstrate a response of 
overall success at the TOC visit; 
• Proportion of subjects in the mCRE-MITT, m-MITT, CE, CRE-ME, and ME Populations 
with a clinical outcome of cure at Day 3, EOT, TOC, and LFU; 
• Proportion of subjects in the mCRE-MITT, m-MITT, CRE-ME, and ME Populations with 
a microbiological outcome of eradication at Day 3, EOT, TOC, and LFU; 
• Relapse/recurrence rates of baseline cUTI or AP at the LFU visit; and 
• Per-pathogen outcome in the mCRE-MITT, m-MITT, CRE-ME, and ME Populations at 
Day 3, EOT, TOC, and LFU. 
5.1.2. 
Efficacy Assessments for cIAI 
Primary Endpoint  
The primary endpoint for cIAI for both the EMA and the FDA is the proportion of patients 
with a clinical outcome of cure in the mCRE-MITT population at TOC visit, approximately 
Day 28.   
To meet the primary endpoint, a subjects’ gram-negative antimicrobial therapy to treat the 
baseline infection cannot be altered (other than dose adjustment or modification of BAT based 
on susceptibility of baseline pathogen within the first 72 hours after first dose of study drug) 
after randomization due to concerns of microbiologic failure, clinical failure, or tolerability. In 
addition, subjects cannot require any further unplanned surgical or radiologic intervention after 
randomization until TOC due to concerns of microbiologic failure or clinical failure.   
Secondary Endpoints  
• The all-cause mortality rate in the mCRE-MITT and m-MITT Populations at Day 28; 
• Proportion of subjects in the mCRE-MITT, m-MITT, CE, CRE-ME, and ME Populations 
with a clinical outcome of cure at Day 3, EOT, TOC, and LFU;  
• Proportion of subjects in the mCRE-MITT, m-MITT, CE, CRE-ME, and ME Populations 
with a clinical outcome of cure at TOC, where the use of an aminoglycoside beyond 
72 hours in subjects with a pathogen susceptible to meropenem-vaborbactam is assigned 
to failure;  
• Relapse/recurrence rates of baseline cIAI at the LFU visit; and  
• Per-pathogen outcome in the mCRE-MITT, m-MITT, CRE-ME, and ME Populations at 
Day 3, EOT, TOC, and LFU. 


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5.1.3. 
Efficacy Assessments for HABP and VABP 
Primary Endpoint (Combined for HABP/VABP and Bacteremia) 
The primary endpoint for HABP and VABP is the all-cause mortality rate in the mCRE-MITT 
Population at Day 28 for all subjects with HABP and VABP, combined with all subjects with 
bacteremia (not related to cUTI/AP, cIAI or HABP/VABP). 
Secondary Endpoints 
• The all-cause mortality rate in the mCRE-MITT and m-MITT Populations at Day 28; 
• The proportion of subjects in the mCRE-MITT Population who demonstrate a clinical 
outcome of cure at the TOC visit. 
A clinical outcome of cure is defined as: 
- 
A subject whose gram-negative antimicrobial therapy to treat the baseline infection 
is not altered (other than dose adjustment or modification of BAT based on 
susceptibility of baseline pathogen within the first 72 hours after first dose of study 
drug) after randomization due to concerns of microbiological failure, clinical 
failure, or tolerability AND  
- 
Complete resolution or significant improvement of the baseline signs and 
symptoms of HABP or VABP such that no further antimicrobial therapy is 
warranted; 
• Proportion of subjects in the mCRE-MITT, m-MITT, CE, CRE-ME, and ME Populations 
with a clinical outcome of cure at Day 3, EOT, TOC, and LFU; 
• Proportion of subjects in the mCRE-MITT, m-MITT, CE, CRE-ME, and ME Populations 
with a clinical outcome of cure at TOC, where the use of an aminoglycoside beyond 
72 hours in subjects with a pathogen susceptible to meropenem-vaborbactam is assigned 
to failure; 
• Per-pathogen outcome in the mCRE-MITT, m-MITT, CRE-ME, and ME Populations at 
Day 3, EOT, TOC, and LFU; 
• Relapse/recurrence rates of baseline bacterial pneumonia at the LFU visit; 
• Total ventilator days measured from time of randomization; 
• Change in the partial pressure arterial oxygen to fraction of inspired oxygen (PaO2:FiO2) 
ratio from baseline to Day 3, Day 7, and EOT; and 
• Time (days) to extubation in subjects who are on the ventilator at baseline (i.e., Day 1). 
5.1.4. 
Efficacy Assessments for Bacteremia 
Primary Endpoint 
The primary endpoint for bacteremia is the all-cause mortality rate in the mCRE-MITT 
Population at Day 28 for all subjects with HABP and VABP, combined with all subjects with 
bacteremia (not related to cUTI/AP, cIAI or HABP/VABP). 


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Secondary Endpoints 
• The all-cause mortality rate in the mCRE-MITT and m-MITT Populations at Day 28;  
• The proportion of subjects in the mCRE-MITT Population who demonstrate a response of 
overall success at the TOC visit. 
For subjects whose gram-negative antimicrobial therapy to treat the baseline infection is 
not altered (other than dose adjustment or modification of BAT based on susceptibility of 
baseline pathogen within the first 72 hours after first dose of study drug) after 
randomization due to concerns of microbiological failure, clinical failure, or tolerability, a 
response of success is defined by clearance of bacteremia (microbiological eradication) 
and a clinical assessment of cure.  
Clearance of bacteremia (microbiological eradication) is defined as the demonstration that 
bacterial pathogen(s) found at baseline is absent with repeat culture. 
Clinical cure is defined as complete resolution or significant improvement of the baseline 
signs and symptoms of bacteremia, such that no further antimicrobial therapy is warranted. 
• Proportion of subjects in the m-MITT, CRE-ME, and ME Populations who demonstrate a 
response of overall success at the TOC visit;  
• Proportion of subjects in the mCRE-MITT, m-MITT, CE, CRE-ME, and ME Populations 
with a clinical outcome of cure at Day 3, EOT, TOC, and LFU; 
• Proportion of subjects in the mCRE-MITT, m-MITT, CE, CRE-ME, and ME Populations 
with a clinical outcome of cure at TOC, where the use of an aminoglycoside beyond 
72 hours in subjects with a pathogen susceptible to meropenem-vaborbactam is assigned 
to failure; 
• Proportion of subjects in the mCRE-MITT, m-MITT, CRE-ME, and ME Populations with 
a microbiological outcome of eradication at Day 3, EOT, TOC, and LFU;  
• Relapse/recurrence rates of baseline bacteremia at the LFU visit;  
• Per-pathogen outcome in the mCRE-MITT, m-MITT, CRE-ME, and ME Populations at 
Day 3, EOT, TOC, and LFU; and 
• Time to bacterial clearance in mCRE-MITT, m-MITT, CRE-ME, and ME Populations. 
Exploratory analyses will be conducted based on subject evaluability and may include clinical 
and microbiological responses in various analysis populations at EOT, TOC, and LFU. 
 
 
 
 
 
 
 
 
 


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5.1.6. 
Clinical Outcome 
Clinical outcome will be used to determine a response of success for subjects with cIAI, HABP 
or VABP. Clinical outcome, as a component of an assessment of overall response, will also be 
used to determine a response of success for subjects with cUTI or AP (FDA only), or 
bacteremia. The Investigator will be provided with a choice of clinical outcomes based on 
definitions to make a clinical assessment of the subject at the Day 3, Day 7, EOT, TOC, and 
LFU visits. The Investigator will assign a clinical outcome as defined in Table 3.  
If all symptoms present at baseline are classified as mostly resolved or continuing (decreased), 
with no new onset symptoms, such that no further surgical intervention (cIAI only) or 
antimicrobial therapy is warranted, the subject will have a clinical outcome of cure at Day 7, 
EOT, TOC, and LFU visits. Subjects with lessening, incomplete resolution, or no worsening 
of these symptoms (i.e., continuing [decreased or no change] and resolved), who still warrant 
antimicrobial therapy, will have a clinical outcome of improvement at Day 3 and Day 7. 
Subjects with worsening of symptoms or the development of new onset symptoms sufficient 
to require initiation of non-study antimicrobials (and/or for cIAI subjects unplanned surgical 
procedures/percutaneous drainage), in addition to the criteria in Table 3 will have a clinical 
outcome of failure. In addition to the above components of clinical outcome, subjects with 
HABP or VABP will be monitored for oxygen requirements and ventilator settings per site 
standard of care to evaluate clinical outcome. 


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Table 3. 
Criteria for Clinical Outcome 
Category 
Criteria 
Cure 
Complete resolution or significant improvement of the baseline signs and 
symptoms, such that no further surgical intervention (cIAI only) or antimicrobial 
therapy is warranted. This outcome category will only be used at Day 7, EOT, 
TOC, and LFU visits. 
Improvement 
Lessening, incomplete resolution, or no worsening of baseline clinical signs and 
symptoms, but continued therapy is warranted. This outcome category will only 
be used at Day 3 and Day 7 visits. 
Failure 
Subjects who experience any one of the following:  
• 
At any study visit, worsening of baseline clinical signs and symptoms or the 
development of new clinical signs and symptoms of infection, sufficient to 
stop study medication and initiate non-study antimicrobial or for cIAI 
require unplanned surgical procedures or percutaneous drainage; 
• 
Surgical site wound infection (cIAI only); 
• 
At TOC and LFU visits, persistence, incomplete resolution of baseline 
clinical signs and symptoms of infection;  
• 
Withdrawal from the study due to an adverse event or due to lack of clinical 
improvement; or 
• 
Death of the subject during the study. 
Indeterminate 
Clinical outcome cannot be determined. 
EOT = End of Treatment; LFU = Late Follow-up; TOC = Test of Cure. 
If the Principal Investigator’s and Blinded Investigator’s assessments of clinical outcome are 
different, the adjudicated results from the blinded adjudication committee (BAC) are used. 
However, since BAC only adjudicate the clinical outcome at TOC visit per the Charter, if there 
are discrepancies between blinded and unblinded assessments at the visits other than TOC, the 
assessments from the unblinded investigator will be used. 
5.1.7. 
Microbiologic Outcome 
The microbiologic outcome will be used, as a component of an assessment of overall 
response, to determine a response of success for subjects with cUTI or AP (FDA only), or 
bacteremia. The microbiologic outcome will be used to determine a response of success for 
subjects with cUTI or AP for the EMA. The criteria for microbiological outcome for subjects 
with cUTI or AP are defined in Table 4, and the sponsor’s algorithm for microbiologic 
assessment is included in Appendix 1.  
 


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Table 4. 
Criteria for Microbiologic Outcome for cUTI or AP 
Category 
Criteria 
Eradication 
• 
Eradication is the demonstration that the bacterial pathogen(s) found at 
baseline is reduced to <104 CFU/mL on urine culture for FDA or 
<103 CFU/mL for EMA 
• 
AND a negative blood culture (after positive blood culture at baseline). 
Persistence 
• 
Persistence is the demonstration at EOT that 1 or more of the bacterial 
pathogen(s) found at baseline remains 104 CFU/mL of urine culture for 
FDA or 103 CFU/mL for EMA 
• 
OR a positive blood culture. 
Recurrence 
• 
Recurrence is the isolation of the same baseline bacterial pathogen(s) from 
culture after a response of eradication  
• 
OR a positive blood culture with the same baseline organism that was 
identified as a uropathogen after a response of eradication. 
Indeterminate 
• 
An indeterminate outcome will occur if there is no culture or the culture 
cannot be interpreted for any reason. 
AP = acute pyelonephritis; CFU = colony-forming unit; cUTI = complicated urinary tract infection; 
EMA = European Medicines Agency; EOT = End of Treatment; FDA = Food and Drug Administration. 
 
The criteria for microbiological outcome for subjects with bacteremia are presented in Table 5. 
Table 5. 
Criteria for Microbiologic Outcome for Bacteremia 
Category 
Criteria 
Eradication 
• 
Eradication is the demonstration that the bacterial pathogen(s) found at 
baseline is absent with repeat blood culture. 
Persistence 
• 
Persistence is the demonstration at EOT that the bacterial pathogen(s) found 
at baseline is present with repeat blood culture. 
Recurrence 
• 
Recurrence is the isolation of the same baseline bacterial pathogen(s) from 
blood culture after a response of eradication.  
Indeterminate 
• 
An indeterminate outcome will occur if there is no blood culture or the blood 
culture cannot be interpreted for any reason. 
EOT = End of Treatment. 
5.1.8. 
Overall Response 
Overall response will be used to determine a response of success for subjects with cUTI or 
AP (FDA only or bacteremia. This efficacy measure is derived from a composite of the 
clinical outcome and the microbiological outcome.  
The algorithm for overall response at the TOC visit is summarized in Table 6. 


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Table 6. 
Overall Response at Test of Cure (TOC) Visit 
Clinical 
Outcome 
Microbiologic Outcome 
Eradication 
Persistence 
Recurrencea 
Indeterminate 
Cured 
Success 
Failure 
Failure 
Success based on 
presumed eradicationb 
Failure 
Failure 
Failure 
Failure 
Failure based on 
presumed persistencec 
Indeterminate 
Failed if clinical 
outcome for any 
previous visit = failed; 
otherwise = 
indeterminate 
Failure 
Failure 
Failed if clinical 
outcome for any 
previous visit = failed; 
otherwise = 
indeterminate 
a. 
For an outcome of recurrence, subjects must have documented prior eradication at any prior time point.  
b. Presumed eradication occurs when there is no material available for culture, and the subject has an 
investigator assessment of clinical outcome of cure. 
c. 
Presumed persistence occurs when there is no material available for culture, or no culture was obtained, 
and the subject has an investigator assessment of clinical outcome of failure. 
5.1.9. 
Overall Mortality Rate 
The overall all-cause mortality rate across all indications will also be evaluated.  
5.2. 
Safety Assessments 
Safety assessments will include adverse events, clinical laboratory evaluations (including 
analysis of changes in renal function), vital signs, physical examinations, and 
electrocardiograms (ECGs). 
5.2.1. 
Adverse Events 
An adverse event is defined as any untoward medical occurrence deemed clinically relevant 
by the Investigator in a clinical investigation subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment. An adverse event 
can therefore be any unfavorable and/or unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an investigational 
medicinal product, whether or not related to the investigational medicinal product. All adverse 
events, including observed or volunteered problems, complaints, or symptoms, are to be 
recorded and entered on the appropriate eCRF. Adverse events will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA, Version 17.0). The severity of all adverse 
events will be graded according to the current National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE). 
5.2.2. 
Clinical Laboratory Evaluations 
Blood samples for serum chemistry and hematology analyses will be collected as specified by 
the Schedule of Procedures (Table 1).  
Eligibility criteria related to laboratory assessments (i.e., screening laboratory assessments) 
will be processed/analyzed by a local laboratory within 48 hours of randomization and must 
include, at a minimum, AST, ALT, total bilirubin, creatinine, white blood cell (WBC) count 
with differentials, platelet count, and leukocyte esterase (LCE) in urine. 


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All other study-related analyses will be performed by the central laboratory. 
The chemistry, hematology, and urinalysis parameters assessed in this study include the 
following: 
• Chemistry: creatinine, estimated creatinine clearance, blood urea nitrogen, AST, ALT, 
alkaline phosphatase, total bilirubin, uric acid, lipase, amylase, albumin, total protein, 
glucose, sodium, potassium, chloride, carbon dioxide, calcium, and phosphorus. 
• Hematology: complete blood count (red blood cell count, and white blood cell (WBC) 
count with differentials. 
• Urinalysis: dipstick analysis of protein, glucose, ketones, bilirubin, blood, nitrites, LCE, 
and urobilinogen; microscopic evaluation for red blood cells, WBCs, bacteria, and casts; 
specific gravity; and pH. 
For women of childbearing potential, a serum and urine pregnancy test will be performed 
before the first dose of study drug, however, only urine results are required to initiate treatment. 
A urine and serum pregnancy test will be performed at EOT or early termination. 
5.2.3. 
Vital Signs 
Vital signs, including blood pressure, heart rate, respiratory rate, and temperature, will be 
measured at the indicated visits. 
5.2.4. 
Electrocardiograms (ECGs) 
Twelve-lead ECGs will be performed per the Schedule of Procedures (Table 1) in triplicate, at 
least 1 minute apart, after the subject has been in the supine position for at least 10 minutes. 
The ECG will include all 12 standard leads and should be recorded at a paper speed of 25 
mm/sec. The following ECG parameters will be recorded:  
• PR interval,  
• QRS interval,  
• Heart rate,  
• RR interval,  
• QT interval, and  
• QTc interval. 
All ECGs must be evaluated by a qualified physician for the presence of abnormalities. If 
clinically indicated per the Investigator for a safety event, a 12-lead ECG will be performed 
according to site standards and recorded in the electronic data capture (EDC) database 
according to the EDC guidelines. 
5.2.5. 
Acute Kidney Injury Evaluations 
Analysis of the changes in serum creatinine as a marker of changes in renal function will be 
performed using the Risk, Injury, Failure, Loss, or End-Stage (RIFLE) criteria for serum 
creatinine, as follows:  


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• Class 1: Risk – increase in serum creatinine > 1.5 times baseline value 
• Class 2: Injury – increase in serum creatinine > 2 times baseline value 
• Class 3: Failure – increase in serum creatinine > 3 times baseline value, OR an acute 
increase in serum creatinine >44 umol/L from baseline >354 umol/L 
• Class 4: Complete loss of kidney function for over 4 weeks 
• Class 5: End-stage – complete loss kidney function for over 3 months    
Note that as the duration of this study is approximately 4 weeks, Class 4 and 5 are not 
applicable in this study. Only the first three categories will be analyzed.  
 
5.2.6. 
Physical Examination  
A complete physical examination must include source documentation of skin, head and neck, 
heart, lung, abdomen, extremities, back/flank/costo-vertebral angle tenderness, and 
neuromuscular assessments. Height and weight will be included at screening. Demographic 
data including name, sex, age, race, weight, and alcohol use will be recorded at screening. A 
limited, symptom-based, physical examination will be performed at other indicated visits. If a 
subject does not display symptoms, no limited physical examination needs to be performed.  
Clinically significant physical examination findings (as determined by the Investigator) noted 
during a preceding physical examination (complete or limited) should be followed until 
resolution. 
Physical examinations may be performed at various unscheduled time points if deemed 
necessary by the Investigator. 
5.3. 
Medical History 
Relevant medical history, surgical history, and allergies will be collected at screening. 
Medical/surgical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA, Version 17.0). 
5.4. 
Prior and Concomitant Medications 
All relevant medications used in the 14 days prior to first dose of study drug and any 
medications used for standard subject care during the study are to be recorded. Concomitant 
treatments (non-pharmacological treatments) which include any surgical or diagnostic 
procedures will be captured in the source documents. Prior and concomitant medications will 
be coded using the World Health Organization (WHO) Drug Dictionary (June 2014). 
5.5. 
Pharmacokinetic Assessments 
Pharmacokinetic sampling will be completed in subjects randomized to meropenem-
vaborbactam only. Samples will be collected for PK analysis on Day 1 within 30 minutes and 
2 to 3 hours after the end of the first infusion. On Day 3 and Day 5, PK samples will be collected 
within 30 minutes after the end of one of that day’s infusions. Samples will be taken as close 
to the 30-minute mark as possible and within the 1-hour window 2 to 3 hours after the end of 


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the selected infusion. 
If subject is on a ventilator at the time of PK sampling, ventilator settings should be noted at 
the time of the blood draw. 
6. 
ANALYSIS POPULATIONS 
The following analysis populations will be included in the analyses. A schematic summary of 
the analysis populations is provide in Figure 2. 
6.1. 
Intent-to-Treat Population  
The Intent-to-Treat (ITT) Population for efficacy will include all subjects screened and 
randomized to study drug (meropenem-vaborbactam or BAT). 
6.2. 
Modified Intent-to-Treat Population  
The Modified Intent-to-Treat (MITT) Population will include subjects who meet the ITT 
criteria and receive at least 1 dose of study drug as randomized.  
6.3. 
Safety Population  
The Safety Population will include subjects who meet the ITT criteria and receive at least one 
dose of study drug, based on the actual treatment received.  
6.4. 
Microbiological Modified Intent-to-Treat Population  
The Microbiological Modified Intent-to-Treat (m-MITT) Population will include subjects 
who meet the MITT criteria and have a baseline gram negative bacterial pathogen(s).  
6.5. 
Microbiological Carbapenem-resistant Enterobacteriaceae Modified Intent-to-
Treat Population  
The Microbiological Carbapenem-resistant Enterobacteriaceae Modified Intent-to-Treat 
(mCRE-MITT) Population will include subjects who meet the m-MITT criteria and who 
have a baseline Enterobacteriaceae that is confirmed to be meropenem-resistant.  The 
mCRE-MITT is the primary efficacy population. 
6.6. 
Clinical Evaluable Population  
The Clinical Evaluable (CE) Population will include subjects who meet the MITT criteria, as 
well as the following criteria:  
• Have no key inclusion or exclusion violations;  
• Obtain a clinical outcome (cure, improvement, or failure) at EOT and a clinical 
outcome of cure or failure at TOC, unless criteria for failure on clinical outcome were 
met at an earlier time point; 
• Receive ≥80% of expected IV doses for the completed treatment duration, miss no 
more than 1 IV dose in the first 48 hours of treatment, and miss no more than 2 
consecutive IV doses overall; and  


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• Receive ≥3 days of study drug (and for cIAI adequate source control) if classified as a 
failure on clinical outcome, or receive ≥5 days of study drug (and for cIAI adequate 
source control) if classified as a cure on clinical outcome. 
6.7. 
Microbiological Evaluable Population  
The Microbiological Evaluable (ME) Population will include subjects who meet the m-MITT 
criteria, as well as the following criteria: 
• Have no key inclusion or exclusion violations;  
• Obtain a clinical outcome (cure, improvement, or failure) and a microbiological 
outcome (eradication or persistence) at EOT and an overall outcome of cure or failure 
at TOC, unless criteria for failure on clinical outcome were met at an earlier time point; 
• Receive ≥80% of expected IV doses for the completed treatment duration, miss no 
more than 1 IV dose in the first 48 hours of treatment, and miss no more than 2 
consecutive IV doses overall; and  
• Receive ≥3 days of study drug (and for cIAI adequate source control) if classified as a 
failure on overall outcome, or receive ≥5 days of study drug (and for cIAI adequate 
source control) if classified as a cure on overall outcome. 
6.8. 
Carbapenem-resistant Enterobacteriaceae Microbiological Evaluable 
Population  
The Carbapenem-resistant Enterobacteriaceae Microbiological Evaluable Population           
(CRE-ME) Population will include subjects who meet the ME criteria and who have a baseline 
Enterobacteriaceae that is confirmed to be meropenem-resistant. 
6.9. 
Pharmacokinetics Population  
The Pharmacokinetics (PK) Population will include subjects who meet the MITT criteria and 
have at least one plasma PK sample drawn. 
 
 
 
 
 
 
 
 
 
 


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Figure 2: Statistical Analysis Populations 
 
Pharmacokinetic (PK) 
Population 
• Have at least one plasma 
PK sample drawn 
CRE Microbiologic 
Evaluable (CRE-ME) 
Population 
• Meets all ME evaluability 
criteria  
• Has a confirmed Meropenem 
resistant Enterobacteriaceae 
infection 
Microbiological CRE 
Modified Intent-to-Treat 
(mCRE-MITT) Population 
• Meets all m-MITT 
evaluability criteria  
• Has a confirmed Meropenem 
resistant Enterobacteriaceae 
infection 
Microbiological Modified 
Intent-to-Treat (m-MITT) 
Population 
• baseline bacterial 
pathogen(s) 
Screen failure 
Drop no-med 
subjects 
Clinical Evaluable (CE) 
Population 
Meets all MITT 
Evaluability Criteria: 
• Have no key 
inclusion/exclusion 
violations 
• Clinical Outcome of (C/I/F) 
at EOT 
• Clinical Outcome of (C/F) at 
TOC (unless F at earlier time 
point) 
• Receive >80% of expected 
IV doses 
• Miss no more than 1 dose in 
1st 48 hours of treatment 
• Miss no more than 
2 consecutive IV doses 
• >3 days for failure, ≥5 days 
for cure 
Screened Population 
Intent-to-Treat (ITT) 
Population 
Modified Intent-to-Treat 
(MITT) Population 
• Receive ≥1 dose of Study Drug 
Microbiological Evaluable 
(ME) Population 
Meets all m-MITT 
evaluability criteria and: 
• Have no key 
inclusion/exclusion violations 
• Clinical Outcome of (C/I/F) and 
Microbiological Outcome of 
(E/P) at EOT 
• Overall Outcome of (C/F) at 
TOC (unless F at earlier time 
point) 
• Receive >80% of expected IV 
doses 
• Miss no more than 1 dose in 1st 
48 hours of treatment 
• Miss no more than 
2 consecutive IV doses 
• >3 days for failure, ≥5 days for 
cure 
C = Cure; E = Eradication; EOT = End of Treatment; F = Failure; I = Improvement; IV = intravenous; P = Persistence; 
PK = pharmacokinetic; TOC = Test of Cure 


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7. 
STATISTICAL ANALYSIS  
7.1. 
General Statistical Considerations 
All summary statistics will be presented by treatment group. For continuous variables, the 
number of observations (n), mean, standard deviation (SD), median, minimum, and maximum 
will be provided. For categorical variables, the frequency and percentage in each category will 
be displayed. 
For summary statistics, the mean and median will be displayed to one decimal place greater 
than the original value and the measure of variability (e.g. standard deviation) will be displayed 
to two decimal places greater than the original value. All analyses will be performed using 
SAS® Version 9.3. 
7.2. 
Handling of Dropouts/Missing Data 
Subjects who dropped out or had missing outcome data will be included in the denominator 
for response rate calculation. A clinical failure occurring at an earlier time point will be carried 
forward to the subsequent visits. Refer to Table 3 for more details. 
Missing values for the other variables will not be imputed and only observed values will be 
used in data analysis and presentation. 
7.3. 
Baseline Definition 
For all efficacy and safety endpoints, baseline is defined as the last measurement or assessment 
prior to the first dose of study drug.  
For microbiological data, the algorithm for baseline pathogen(s) determination is presented in 
Table 7.   
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 7  
Baseline CRE Pathogen(s) Determination  
KNOWN CRE Subjects 
Screening  
Day 1 
Baseline Selection 
CRE pathogen 
CRE pathogen 
Day 1 will be considered as Baseline  
CRE pathogen 
non-CRE pathogen 
Screening will be considered as 
Baseline 
CRE pathogen  
No growth 
Screening will be considered as 
Baseline 
SUSPECTED CRE Subjects 
CRE pathogen 
CRE pathogen 
Day 1 will be considered as Baseline 
Non-CRE pathogen 
CRE pathogen 
Day 1 will be considered as Baseline 
CRE pathogen (within 3 days 
of Day 1) 
Non-CRE pathogen  
Screening will be considered as 
Baseline 
CRE pathogen (within 3 days 
of Day 1) 
No growth 
Screening will be considered as 
Baseline 
Non-CRE pathogen (within 3 
days of Day 1) 
Non-CRE pathogen  
Day 1 will be considered as Baseline 
(in m-MITT, not mCRE-MITT ) 
Non-CRE pathogen (within 3 
days of Day 1) 
No growth 
Screening will be considered as 
Baseline (in m-MITT, not mCRE-
MITT ) 
No Growth (or growth >3 
days of Day 1) 
No Growth 
Missing (Not in m-MITT or mCRE-
MITT) 
7.4. 
Subject Disposition 
Subject disposition will be summarized for the MITT Population for each treatment group and 
in total. The following subject disposition categories will be included in the summary for the 
MITT Population: 
• Subjects who completed the study treatment/ BAT, 
• Subjects who did not complete the treatment/ BAT, 
• Subjects who completed the study, and 
• Subjects who did not complete the study. 
For subjects who did not complete the treatment/ BAT, and subjects who did not complete the 
study, a summary will be provided by reason of discontinuation. 
The above display will be repeated for the ITT population if the difference between the number 
of subjects in the ITT and the MITT population is greater than 2.  
The following subject disposition categories will be included in the summary for the ITT 
Population: 
• Subjects who received study drug/ BAT, 
• Subjects who did not receive study drug/ BAT, 


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• Subjects who completed the study, and 
• Subjects who did not complete the study. 
In addition, the total number of subjects for each defined statistical population and disposition 
group will be tabulated overall and by infection type. Number and percent of patients with 
reasons leading to exclusion from the m-MITT and mCRE-MITT population, as specified in 
Section 6.4 and Section 6.5, will also be presented.  
7.5. 
Demographic and Baseline Characteristics  
Demographic and baseline characteristics will be summarized descriptively for the MITT, m-
MITT, and mCRE-MITT Populations by treatment group and overall. Age, weight, height, 
body mass index (BMI), and creatinine clearance will be summarized descriptively (n, mean, 
standard deviation, median, minimum, and maximum). Gender, race, ethnicity,  age group 
(<65,  ≥65, 65- < 75, and ≥75 years),  alcohol usage, region, creatinine clearance group at 
baseline (<10 mL/min, >=10-19 mL/min, >=20-29 mL/min, >=30-49 mL/min, and >=50 
mL/min), diabetes status, systemic inflammatory response syndrome (SIRS) status (yes and no), 
Charlson Comorbidity score (≤2, 3, 4, and 5) at baseline, and immunocompromised (yes and 
no) will be summarized with contingency tables. The algorithm to determine 
immunocompromised is included in Appendix 2.  
7.6. 
Baseline Infection Characteristics  
Baseline infection characteristics will be summarized with descriptive statistics for the MITT, 
m-MITT and mCRE-MITT populations. Infection type (cUTI/AP, cIAI, HABP/VABP, and 
bacteremia), CRE status (known CRE / suspected CRE), and prior treatment failure (yes/no) 
will be summarized to show the number and percentage of subjects in each category. The 
clinical conditions associated with the indication and sign and symptoms experienced by 
subjects at baseline will be summarized for each indication with contingency tables.   
7.7. 
Medical History  
Medical and surgical history will be summarized for the MITT Population for each treatment 
group and in total by system organ class (SOC) and preferred term.  
All medical and surgical history will be listed by subject.  
7.8. 
Prior and Concomitant Medications  
Prior medications will include medications used before the first dose of study drug. Any 
medications used on or after the first dose of study drug will be included as concomitant 
medications. The number and percentage of subjects taking concomitant medications which 
started prior to the first dose of study drug and continued during the treatment period will be 
summarized for the MITT and m-MITT Populations by anatomic therapeutic chemical (ATC) 
Level 2 class and preferred term for each treatment group.  The number and percentage of 
subjects receiving new concomitant medications, i.e., those started on or after the first dose of 
study drug will also be summarized by ATC Level 2 class and preferred term for each treatment 
group.  


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The number and percentage of subjects taking prior antibiotics will be summarized for the 
MITT, m-MITT, and MCRE-MITT Populations by ATC Level 2 class and preferred term for 
each treatment group. In addition, prior antibiotics used within 24 hours prior to the first dose 
of study drug will be summarized by ATC Level 2 class and preferred term. Other prior 
medications will be summarized similarly.     
Prior antibiotics along with the duration of prior antibiotics will be listed by subject. 
The number and percentage of subjects receiving concomitant procedures or non-drug therapy 
will also be summarized by ATC Level 2 class and preferred term for each treatment group. 
All prior and concomitant medications and procedures will be listed by subject.  
7.9. 
Dosing and Extent of Exposure  
Overall extent of exposure in days will be calculated as the last dose date minus the first dose 
date of study drug plus 1. The overall extent of exposure to study drug will be summarized for 
the MITT, m-MITT, CE, mCRE-MITT and ME Populations by treatment group with 
descriptive statistics. In addition, contingency tables will be provided to show the number and 
percentage of subjects in each treatment group with exposure in the following categories: <7 
days, 7 - <10 days, 10 - 14 days, and >14 days. 
The overall compliance rate to study drug will be calculated as the total number of doses 
received divided by the total number of doses expected then multiplied by 100. The total 
number of expected doses is the number of medication days multiplied by the number of 
expected doses per day. Number of medication days is the total number of days from the date 
of the first infusion of study drug to the date of the last infusion of study drug. 
Percent compliance will be calculated using the following formula: 
days
 
medication
 
of
number 
 
 total
*
day 
per 
 
doses
 
expected
100
*
received
 
doses
 
of
 
no.
compliance
%

 
The overall compliance rate will be summarized with summary statistics by treatment group 
and overall for the MITT Population. In addition, contingency tables will be provided to show 
the number and percentage of subjects in each treatment group with compliance in the 
following categories: <80% and ≥80%. 
The total number of doses received will also be summarized by treatment group using 
descriptive statistics.  
7.10. 
Efficacy Analyses 
The efficacy analyses will be structured and presented by indications. However, a summary 
table including all primary efficacy endpoints for all indications will be presented along with 
their 95% two-sided exact binomial confidence intervals for m-MITT and mCRE-MITT 
populations. For indications with less than 8 total patients, only listings will be presented, but 
not tables. Due to limited sample size for the interim analysis, only m-MITT and mCRE-
MITT populations will be analyzed.  


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7.10.1. 
Analyses of Overall Response 
Success rate of overall response will be calculated as the proportion of subjects with a response 
of overall success.  For cUTI/AP and cIAI, overall success is defined as clinical cure and 
microbiological eradication. For bacteremia, overall success is defined as clinical cure and 
clearance of bacteremia (microbiological eradication). 
The following success rates will be calculated: 
• Success rate at TOC visit for subjects with cUTI or AP (by FDA definition) 
• Success rate at TOC visit for subjects with Bacteremia 
Success rates at TOC will be summarized by infection type for the mCRE-MITT and m-MITT 
Populations. The 95% two-sided exact binomial confidence intervals of the success rates will 
also be presented.  
In addition, the following success rates will be summarized: 
• Success rate for subjects with cUTI or AP (by FDA definition) per baseline pathogen  
at TOC 
• Success rate for subjects with Bacteremia per baseline pathogen  at TOC 
7.10.2. 
Analyses of Clinical Response 
The clinical outcome will be categorized as cure, improvement, failure, and indeterminate. 
Cure rate of clinical response will be calculated as the proportion of subjects with clinical 
outcome of cure reported by investigator. The following cure rates will be calculated: 
• Cure rate at Day 3, EOT, TOC, and LFU for subjects with cUTI or AP 
• Cure rate at Day 3, EOT, TOC, and LFU for subjects with cIAI 
• Cure rate at Day 3, EOT, TOC, and LFU for subjects with HABP or VABP 
• Cure rate at Day 3, EOT, TOC, and LFU for subjects with Bacteremia 
Cure rates will be summarized descriptively by infection type at Day 3, EOT, TOC, and LFU 
for the mCRE-MITT and m-MITT Populations. The 95% two-sided exact binomial confidence 
intervals of the cure rates will also be presented.  
In addition, the number and percentage of subjects in each clinical response category (cure, 
improvement, failure, and indeterminate) will be summarized by infection type per baseline 
pathogen and for each scheduled visit. 
Clinical response will be assessed by the Principal Investigator (PI). In addition, at each site a 
Blinded Investigator (BI) will be assigned to assess each subject’s outcome at the EOT and 
TOC visits. A blinded adjudication committee will also be formed to independently evaluate 
clinical outcome data in cases where the PI and BI’s assessment of outcome differ.  
The clinical response will be analyzed using the assessment from the PI. In case the PI and 
BI’s assessment of outcome differ, the assessment from the blinded adjudication committee 
will be used in the analysis.     
 


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Source Control 
An independent assessor will review adequacy of source control in all cIAI patients. A 
sensitivity analysis will be performed based for subjects with adequate and inadequate source 
control (see details in Section 7.12). 
7.10.3. 
Analyses of Microbiological Outcome 
Microbiological Responses 
Microbiological responses will be summarized for the mCRE-MITT and m-MITT Populations. 
The microbiological outcome will be categorized as eradication, persistence, recurrence, and 
indeterminate.  
Microbiological eradication rate is calculated as the proportion of subjects with 
microbiological eradication. Relapse of cUTI or AP is defined as isolation of the same baseline 
bacterial pathogen(s) from culture after eradication, OR a positive blood culture with the same 
baseline organism that was identified as an uropathogen after eradication, which is 
accompanied by new or worsening signs and symptoms of infection since the previous visit 
requiring alternative antimicrobial therapy in the time period after EOT. Relapse of bacteremia 
is defined as isolation of the same baseline pathogen(s) from blood culture after eradication 
which is accompanied by new or worsening signs and symptoms of infection since the previous 
visit requiring alternative antimicrobial therapy in the time period after EOT. 
The criteria of microbiological outcome is defined in Section 5.1.7. 
The following microbiological responses will be calculated: 
• Microbiological eradication rate at Day 3, EOT, TOC, and LFU for subjects with cUTI 
or AP, using both FDA and EMA definitions   
• Microbiological eradication rate by pathogen at Day 3, EOT, TOC, and LFU for 
subjects with cUTI or AP, using both FDA and EMA definitions 
• Microbiological eradication rate at Day 3, EOT, TOC, and LFU for subjects with cIAI  
• Microbiological eradication rate by pathogen at Day 3, EOT, TOC, and LFU for 
subjects with cIAI 
• Microbiological eradication rate at Day 3, EOT, TOC, and LFU for subjects with 
HABP or VABP  
• Microbiological eradication rate by pathogen at Day 3, EOT, TOC, and LFU for 
subjects with HABP or VABP 
• Microbiological eradication rate at Day 3, EOT, TOC, and LFU for subjects with 
Bacteremia 
• Microbiological eradication rate by pathogen at Day 3, EOT, TOC, and LFU for 
subjects with Bacteremia 
• Relapse/Recurrence rate of baseline cUTI or AP at LFU for the subjects with cUTI or 
AP 
• Relapse/Recurrence rate of baseline cIAI at LFU for the subjects with cIAI 


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• Relapse/Recurrence rate of baseline bacterial pneumonia at LFU for the subjects with 
HABP or VABP 
• Relapse/Recurrence rate of baseline bacteremia at LFU for the subjects with 
Bacteremia 
Microbiological eradication rates will be summarized descriptively by infection type at Day 3, 
EOT, TOC, and LFU. The 95% two-sided exact binomial confidence intervals of the 
microbiological eradication rate will also be presented.  Microbiological eradication rates by 
pathogen will be summarized similarly. 
Relapse/recurrence rate will be summarized at after EOT. 
In addition, microbiological responses will be summarized by infection type showing the 
number and percentage of subjects in each microbiological outcome category at each 
scheduled visit. 
 
Microbiological Characteristics 
Microbiological characteristics including culture and susceptibility testing results from the 
central laboratory based on urine specimens, respiratory tract specimens, and blood and other 
tissue specimens will be summarized for the m-MITT and mCRE-MITT Populations. 
The baseline pathogens isolated from all specimens will be summarized with contingency 
tables by specimen source to show the number and percentage of subjects with the specific 
pathogen isolated. 
The minimum inhibitory concentration (MIC) will be summarized by pathogen and by 
antibiotics using descriptive statistics (number of isolates, 50th percentile [MIC50], 90th 
percentile [MIC90], and range) for the two antibiotics: meropenem and meropenem-
vaborbactam (vaborbactam fixed at 8 mcg/mL). The distribution of MIC will be summarized 
with contingency table to show the number and percentage of subjects in each MIC level for 
each pathogen by treatment and overall.  
For subjects who had overall success, clinical cure, and microbiologic eradication, a 
contingency table will be presented by scheduled visit, baseline pathogen and actual MIC for 
the m-MITT and mCRE-MITT populations. Both FDA and EMA’s criteria for microbiologic 
eradication will be summarized.  
Fold change in MIC is defined as the ratio of post-baseline MIC over baseline MIC. For 
meropenem, meropenem-vaborbactam MIC, the number and percentage of subjects with at 
least 4 fold increase of MIC will be summarized and listed by baseline pathogen for each post-
baseline visit. A distribution will also be presented for the actual fold increase in MIC if the 
increase is at least 4 fold.  
 
7.10.4. 
All-Cause Mortality Rate 
The following all-cause mortality rate will be calculated: 
• All-cause mortality rate at Day 28 for the subjects with cUTI or AP 


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• All-cause mortality rate at Day 28 for the subjects with cIAI 
• All-cause mortality rate at Day 28 for the subjects with HABP or VABP 
• All-cause mortality rate at Day 28 for the subjects with Bacteremia 
• All-cause mortality rate at Day 28 for the subjects with HABP or VABP, combined 
with all subjects with Bacteremia (not related to cUTI/AP, cIAI or HABP/VABP) 
All-cause mortality rate at Day 28 based on Kaplan-Meier estimates along with the 95% 
confidence interval will be presented overall and by indication for the mCRE-MITT and m-
MITT Populations. Subject whose survival status is unknown due to early termination or lost 
to follow up will be censored at the last day the subject was known to be alive. 
7.10.5. 
Analyses of Other Efficacy Endpoints 
The following efficacy endpoints will be summarized for the m-MITT and mCRE-MITT 
Populations. 
Total Ventilator Days 
Total ventilator days is defined as number of days from the date of the first dose of study drug 
to the date at which the ventilator is removed and remained off for all subsequent visits. Total 
ventilator days will be summarized with summary statistics by treatment group for the subjects 
with HABP or VABP. 
Partial Pressure Arterial Oxygen to Fraction of Inspire Oxygen 
The partial pressure arterial oxygen to fraction of inspire oxygen (PaO2:FiO2) at Day 3, Day 
7, and EOT, and the change from baseline will be summarized by treatment group for the 
subjects with HABP or VABP. 
Time-to-Event Efficacy Endpoints 
The following time-to-event efficacy endpoints will be summarized using Kaplan-Meier 
method. Median time to each event as well as the 95% confidence interval will be presented.  
• Time (days) to extubation in subjects who are on the ventilator at baseline for the 
subjects with HABP or VABP 
• Time to bacterial clearance in the mCRE-MITT and m-MITT Populations for all 
subjects with bacteremia at baseline, regardless whether enrolled under indication of 
bacteremia.  
Time to extubation is defined as number of days from the date of the first dose of study drug 
to the last date at which the ventilator is removed. Subjects who were on the ventilator at 
baseline but discontinued from the study without extubation will be considered censored. 
Time to bacterial clearance is defined as number of days from the date of the first dose of study 
drug to the date at which bacterial pathogen(s) found at baseline is absent with repeat culture. 
For days where the culture assessment is missing, the last assessment will be carried forward 
to the missing days. If EOT is the date at which bacterial pathogen(s) is first found absent, no 
repeat culture is required. Subjects discontinued from the study prior to bacterial clearance will 
be considered censored. 


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7.13. 
Subgroup Analyses 
For subjects with cUTI/AP or bacteremia, overall responses at TOC using FDA criteria, 
clinical responses and microbiological responses at Day 3, EOT, TOC, and LFU using both 
FDA and EMA criteria will be summarized by the following subgroups for m-MITT and 
mCRE-MITT populations based on baseline characteristics: 
• age group (<65, >=65, 65- < 75, and ≥75 years),  
• gender,  
• race,  
• region,  
• creatinine clearance group (<10 mL/min, >=10-19 mL/min, >=20-29 mL/min, >=30-
49 mL/min, and >=50 mL/min),  
• diabetes status,  
• 
systemic inflammatory response syndrome (SIRS) status,  
• Charlson Comorbidity score (≤2, 3, 4, and 5),  
• status of immunocompromised.   
7.14. 
Safety Analyses 
All safety summaries and analyses will be performed on the Safety Population. All subjects 
will be summarized based on the actual treatment received.  
All safety analyses will be performed for all subjects combined, and for subjects with cUTI/AP 
only.  
7.14.1. 
Adverse Events 
Treatment-emergent adverse events (TEAEs) are adverse events with start date and time on or 
after the first dose of study drug.   
An overview of adverse events will be provided which summarizes the incidence of the 
following information: 
• All TEAEs,  
• All TEAEs sorted by the frequency of total occurrence 


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• Drug-related TEAEs, 
• Maximum severity of TEAEs,  
• Deaths, 
• Serious adverse events (SAEs), and 
• Discontinuation due to TEAEs 
• Drug related SAEs. 
• AE of special interests (AESI).  
The following AESI will be summarized: 
- 
Hypersensitivity 
- 
Seizure 
- 
Pseudomembranous colitis/CDAD. 
The search term for these AESIs are included in Appendix 3.  
 
Number and the percentage of subjects who experienced at least one TEAE will be presented 
by system organ class and preferred term. Drug-related TEAEs, withdrawals due to TEAEs, 
and all SAEs will be summarized in the same manner.  
Summaries will be provided by worst grade for the number and percentage of subjects with 
TEAEs and for subjects with drug-related TEAEs by system organ class and preferred term. 
Although a subject may have two or more TEAEs, the subject is counted only once within a 
System Organ Class and Preferred Term category. The same subject may contribute to two or 
more preferred terms in the same System Organ Class category. 
A list of subjects who have serious adverse events (SAEs), a list of subjects who discontinue 
from study drug with reasons for discontinuation, and a list of death with primary cause will 
be provided. All adverse events will be listed.  
7.14.2. 
Clinical Laboratory Evaluations 
Laboratory test results (hematology, serum chemistry, and urinalysis) at each scheduled visit 
and change from baseline will be summarized by treatment group.   
Shift tables from baseline to each scheduled post-baseline visit will be provided for urinalysis, 
chemistry and hematology parameters.  The following categories will be used: low, normal, 
and high based on the reference range. 
The number and percentage of subjects with predefined potentially clinically significant (PCS) 
laboratory abnormalities at post baseline evaluations will be presented by treatment group for 
selected laboratory parameters. The percentages will be calculated relative to the number of 
subjects with non-PCS values at Baseline and at least one post-baseline assessment for the 
selected laboratory parameters. 
The thresholds for the predefined changes and clinically significant laboratory abnormalities 
for selected parameters are listed in Table 8. 


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Table 8. 
Criteria for Potential Clinically Significant Abnormal Lab Tests 
 
 
Parameter 
Lower limit 
Upper limit 
Hematology 
 
 
Red Blood Cell Count 
 0.75× LLN 
≥ 1.25×ULN 
WBC’s Count 
<2.0 x 109/L 
 
Neutrophils Count 
< 1.0 x 109/L 
 
Lymphocyte count  
< 0.5 x 109/L  
 
Hematocrit 
≤0.75x LLN 
≥1.25x ULN 
Hemoglobin 
≤11.5 g/dL Male 
≤9.5 g/dL Female 
≥18.0 g/dL Male 
≥16.0 g/dL Female 
Platelet count 
≤75 x 109/L 
 
≥700 x 109/L 
Serum Chemistry 
 
 
BUN 
 
≥10.7 mmol/L 
Calcium 
≤7.0 mg/dL 
≥15.5 mg/dL 
CPK 
 
≥3x ULN 
Creatinine 
 
≥2.0 mg/dL 
Glucose  
≤50 mg/dL 
≥180 mg/dL  
Potassium 
≤3.0 mmol/L 
≥5.5 mmol/L 
Sodium 
≤125 mmol/L 
≥150 mmol/L 
Liver Function Tests (LFTs) 
 
Alanine Transaminase (ALT/SGPT) ≥ 3x, 5x, 10x and 20x ULN 
Aspartate Transaminase (AST/SGOT) ≥ 3x, 5x, 10x and 20x ULN 
ALT or AST ≥ 3x, 5x, 10x, or 20x ULN 
Total bilirubin ≥ 1.5x and 2x ULN 
Alkaline Phosphatase (ALP) ≥ 1.5x and 3x ULN 
ALT/AST ≥ 3x ULN and Total bilirubin ≥ 2x ULN;  
Potential Hy’s Law cases: ALT or AST ≥3×ULN, Total bilirubin ≥2×ULN, and ALP ≤ 2×ULN 
 
 
LLN: lower limit of the standard reference (normal) range. 
ULN: upper limit of the standard reference (normal) range. 
 
 
 


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A listing will be provided for the PCS values. All clinical laboratory data will be listed. Values 
outside the normal ranges will be flagged. 
7.14.3. 
Vital Signs 
Descriptive statistics will be provided for the vital signs (blood pressure, heart rate, and 
respiratory rate) and changes from baseline for each scheduled visit.   
The number and percentage of subjects with PCS changes in vital signs will be presented by 
treatment group, based on the following thresholds: 
• Respiratory Rate ≤10 rpm; 
• Respiratory Rate ≥30 rpm; 
• Systolic blood pressure ≥180 mm Hg and increase ≥20 mm Hg from Baseline; 
• Diastolic blood pressure ≥110 mm Hg and increase ≥15 mm Hg from Baseline; 
• Systolic blood pressure ≤90 mm Hg and decrease ≥20 mm Hg from Baseline; 
• Diastolic blood pressure ≤50 mm Hg and decrease ≥15 mm Hg from Baseline; 
• Heart rate ≥120 bpm with increase ≥15 bpm from Baseline; 
• Heart Rate ≤50 bpm with decrease ≥15 bpm from Baseline. 
7.14.4. 
12-Lead ECG 
The statistical analysis plan for the ECG measurements will be documented in a separate file 
and analysis results will be submitted in a separate report.  
All ECG measurements and the overall interpretation will be listed by subject. 
7.14.5. 
Acute Kidney Injury  
The incidence of acute kidney injury as defined by RIFLE criteria at day 3, day 7 and EOT as 
well as the maximum RIFLE grade achieved and the time to incidence of acute kidney injury 
will be summarized by treatment group for all subjects.   
7.14.6. 
Physical Examination 
Physical examination findings will be listed by subject. 
7.15. 
Pharmacokinetic Concentration Analyses 
Plasma PK concentrations will be listed by subject.  
7.16. 
Protocol Deviations 
Determination of major protocol deviations will be based on blinded data review and finalized 
prior to the database lock. A list of all protocol deviations will be included in the study report. 


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7.17. 
Interim Analyses 
Forty-one subjects (25 meropenem- vaborbactam, 16 BAT) were included for this interim 
analysis. The goal of the interim analysis is to provide efficacy and safety data to support the 
NDA filing of Study 505, and there is no go/no go decision based on this analysis. 
 
Enrollment will continue until at least 45 subjects (30 meropenem- vaborbactam, 15 BAT) 
with cUTI or AP are documented to have a CRE organism at baseline and until at least 30 
subjects with cIAI with a documented CRE organism at baseline (20 meropenem-
vaborbactam, 10 BAT) are enrolled. Once the specified number of subjects are enrolled in 
the cUTI and/or cIAI indications, data from these subjects may be submitted to regulatory 
agencies in support of a marketing application, and the enrollment of additional subjects into 
the specific indication(s) where enrollment was met may be stopped. 
 
 
 


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8. 
APPENDICES  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
   
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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HABP/VABP 
1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 


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 or 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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8.2. 
Appendix 2  
Algorithm to Determine Immunocompromised Patients 
Statistics to programmatically make a list of patients who meet any of the following criteria:  
 
1.  In Medical History: Any patients with the following terms in medical history:  
• Leukemia 
• Lymphoma 
• Transplant 
• Immunocompromised 
• Splenectomy 
2.  In Con Medications any patients with the following ATC 2 terms:  
• Glucocorticoids 
• Selective Immunosuppressants 
• Calcineurin inhibitors 
 
3. In laboratory data: Any patients with an absolute neutrophil count (ANC) less than 1000 
cells/mm3 at baseline. 
 
The list of subjects meeting any of the above criteria with treatment allocation blinded will 
be further reviewed by the medical team for consistency with the following definition: 
 
Immunocompromised status was defined as any patients with any: 
 
• Underlying lymphoma, leukemia, prior transplant or splenectomy. 
• Active receipt of any immunosuppressants including calcineurin inhibitors, and 
selective immunosuppressants. 
• Active receipt of high doses of systemic steroids (equivalent to > 20mg prednisone 
daily) for the purposes of prevention of rejection or immunosuppression. 
• Active receipt of bone marrow ablative chemotherapy 
 
 
 
 
 
 
 
 
 
 
 


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8.3. 
Appendix 3  
SMQ for AESI Search Terms Hypersensitivity