An Investigator Initiated, Phase II Single-Center, Randomized, Open-Label, Prospective, Study To Determine The Impact Of Serial Procalcitonin On Improving Antimicrobial Stewardship And On The Efficacy, Safety, And Tolerability Of Imipenem-Cilastatin-Relebactam Plus/Minus Vancomycin Or Linezolid Versus Standard Of Care Antipseudomonal Beta-Lactams Plus/Minus Vancomycin Or Linezolid As Empiric Therapy In Febrile Neutropenic Adults With Cancer
Phase: PHASE2
Conditions: Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm
Sponsor: M.D. Anderson Cancer Center

 
 
 
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MD Anderson IND Sponsor Cover Sheet 
  
Protocol ID 
2020-0074 
Protocol Title 
An Investigator Initiated, Phase II Single-Center, Randomized, Open-
Label, Prospective, Study To Determine The Impact Of Serial 
Procalcitonin On Improving Antimicrobial Stewardship And On The 
Efficacy, Safety, And Tolerability Of Imipenem-Cilastatin-Relebactam 
Plus/Minus Vancomycin Or Linezolid Versus Standard Of Care 
Antipseudomonal Beta-Lactams Plus/Minus Vancomycin Or Linezolid 
As Empiric Therapy In Febrile Neutropenic Adults With Cancer  
 
Protocol Phase 
 II 
Protocol Version 
8 
Version Date 
06/20/2022 
  
Protocol PI 
Issam Raad, M.D. 
Department 
Infectious Diseases 
  
IND Sponsor 
MD Anderson Cancer Center 
IND # 
155191 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AN INVESTIGATOR INITIATED, PHASE II SINGLE-CENTER, 

 
 
 
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RANDOMIZED, OPEN-LABEL, PROSPECTIVE, STUDY TO 
DETERMINE THE IMPACT OF SERIAL PROCALCITONIN ON 
IMPROVING ANTIMICROBIAL STEWARDSHIP AND ON THE 
EFFICACY, SAFETY, AND TOLERABILITY OF IMIPENEM-
CILASTATIN-RELEBACTAM PLUS/MINUS VANCOMYCIN OR 
LINEZOLID VERSUS STANDARD OF CARE ANTIPSEUDOMONAL 
BETA-LACTAMS PLUS/MINUS VANCOMYCIN OR LINEZOLID AS 
EMPIRIC THERAPY IN FEBRILE NEUTROPENIC ADULTS WITH 
CANCER  
 

 
 
 
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TABLE OF CONTENTS 
1.0 
TABLE 2–1. SCHEDULE OF ASSESSMENTS AND PROCEDURES ........................9 
2.0 
LIST OF IN-TEXT TABLES ...........................................................................................11 
3.0 
LIST OF IN-TEXT FIGURES .........................................................................................12 
4.0 
LIST OF ABBREVIATIONS ..........................................................................................13 
5.0 
ETHICAL CONSIDERATIONS ....................................................................................16 
5.1 
Institutional Review Board .................................................................................16 
5.2 
Ethical Conduct of The Study .............................................................................16 
5.3 
Patient Information and Informed Consent ........................................................16 
6.0 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ....................17 
7.0 
INTRODUCTION ............................................................................................................18 
7.1 
Background and Study Rationale .......................................................................18 
7.2 
Clinical Overview ...............................................................................................19 
The activity of imipenem against Gram-negative bacteria is either retained or enhanced 
with the addition of relebactam. Significant increases in activity of imipenem with the 
addition of relebactam are observed against imipenem non-susceptible and b-lactamase 
(ESBL, KPC, and serine carbapenemase) producing Enterobacteriaceae (2- to 128-fold 
MIC reductions) and against P. aeruginosa (eightfold MIC reduction). Clinical trials 
completed to date are summarized in Table (12 ), including two imipenem–relebactam 
phase II clinical trials for the treatment of cIAI and cUTI/AP (NCT01506271 and 
NCT01505634). ..................................................................................................................19 
7.2.1 
Summary of Efficacy In Completed Clinical Studies ..........................................19 
7.3    
Summary of Safety ..............................................................................................20 
7.4  
In vitro Activity of Imipenem/relebactam and Comparator Agents ...................21 
8.0 
STUDY OBJECTIVES ....................................................................................................22 
9.0 
INVESTIGATIONAL PLAN .......................... ERROR! BOOKMARK NOT DEFINED. 
9.1 
Overall Study Design and Plan: Description .....................................................22 

 
 
 
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9.2 
This Section Intentionally Omitted .....................................................................25 
9.3 
Selection of Study Population .............................................................................25 
9.3.1 
Inclusion Criteria ...............................................................................................25 
9.3.2 
Exclusion Criteria...............................................................................................26 
9.3.3 
Removal of Patients from Therapy or Study Assessment ....................................27 
9.3.3.1 
Premature Discontinuation from Inpatient IV Study Drug Due To Safety .........27 
9.3.3.2 
Premature Discontinuation from Inpatient IV Study Drug Due To Insufficient 
Therapeutic Effect ...............................................................................................................28 
9.3.3.3 
Premature Discontinuation from Oral or IV Therapy ........................................28 
9.3.3.4 
Withdrawal from Study .......................................................................................28 
9.3.4  
Patient Replacement Procedures ........................................................................29 
9.4.1 
TREATMENTS ...............................................................................................................29 
9.4.1 
Treatment Group ................................................................................................29 
9.4.1.3 
Standard of Care Treatment Group ....................................................................30 
9.4.1.3 
Other Additional Antibacterial Therapy.............................................................31 
9.4.1.4 
Optional Oral or IV Therapy Switch ..................................................................33 
9.4.1.4.1  Criteria for Switching to Oral or IV Therapy ..................................................33 
9.4.4.4.2 Oral and IV Switch Therapy Options ................................................................34 
9.4.1.5 
Duration of Treatment ........................................................................................36 
9.4.2 
Identity of Investigational Products ...................................................................36 
9.4.3 
Method of Assigning Patients to Treatment Groups ..........................................38 
9.4.4  
Selection of Dosages in the Study .......................................................................38 
9.4.5 
Selection and Timing of Dose for Each Patient .................................................38 
9.4.5.1 
Dose Adjustments for Imipenem-Cilastatin-Relebactam ....................................39 

 
 
 
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9.4.5.2 
Dose Adjustments - Other Investigational Products ..........................................40 
9.4.6 
Blinding ..............................................................................................................40 
9.4.7 
Unblinding ..........................................................................................................40 
9.4.8 
Prior and Concomitant Therapy.........................................................................40 
9.4.9 
Monitoring Treatment Compliance ....................................................................40 
9.5 
EFFICACY AND SAFETY VARIABLES .....................................................................40 
9.5.1 
Primary and Secondary Efficacy Assessments ...................................................41 
9.5.1.2 
Microbiological Assessments .............................................................................41 
9.5.1.3 
Clinical Outcome of The Infection ......................................................................42 
9.5.2 
Safety Assessments ..............................................................................................42 
9.5.2.1 
Adverse Events ....................................................................................................43 
9.5.2.2 
Causality Assessment ..........................................................................................44 
9.5.2.3 
Serious Adverse Events (SAE) Reporting ...........................................................45 
9.5.2.5 
Clinical Laboratory Determinations ..................................................................48 
9.5.2.6 
Vital Signs, Body Weight, and Height ................................................................48 
9.5.2.7 
Chest Radiography .............................................................................................49 
9.5.2.8 
Physical Examination .........................................................................................49 
9.5.3 
Schedule of Assessments .....................................................................................49 
9.5.3.1 
Baseline ..............................................................................................................49 
9.5.3.2 
Study Days 1 To ≤ 14 ..........................................................................................51 
9.5.3.3 
End of Inpatient Intravenous Therapy ................................................................52 
9.5.3.4 
Test-of-Cure (Toc) ..............................................................................................52 
9.5.3.5 
Late Follow-Up...................................................................................................53 
Record Infection Symptoms, Including Recurring Or Worsening Symptoms Indicative of 

 
 
 
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Clinical Failure ..................................................................................................................53 
9.6 
DATA QUALITY ASSURANCE ....................................................................................55 
9.6.1 
Data Recording, Documentation and Monitoring ..............................................55 
9.6.2 
Data Recording and Documentation ..................................................................55 
9.7 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ............55 
9.7.1 
Analysis Sets .......................................................................................................55 
9.7.1.1 
Screened Analysis Set .........................................................................................57 
9.7.1.2 
Intent-To-Treat Analysis Set ...............................................................................57 
9.7.1.3 
Safety Analysis Set ..............................................................................................57 
9.7.1.4 
Modified Intent-To-Treat Analysis Set ...............................................................57 
9.7.1.5 
Microbiological Modified Intent-To-Treat Analysis Set ....................................57 
9.7.1.6 
Clinically Evaluable Analysis Set .......................................................................57 
9.7.1.7 
Microbiologically Evaluable Analysis Set ..........................................................58 
9.7.2 
Patient Disposition .............................................................................................58 
9.7.3 
Demographics and Other Baseline Characteristics ...........................................58 
9.7.4 
Extent of Exposure and Treatment Compliance .................................................59 
9.7.4.1 
Extent of Exposure ..............................................................................................59 
9.7.4.2 
Measurement of Treatment Compliance .............................................................59 
9.7.5 
Efficacy Analyses ................................................................................................60 
9.7.5.1 
Primary Efficacy Parameter ...............................................................................60 
9.7.5.2 
Secondary Efficacy Parameters..........................................................................60 
9.7.5.3 
Clinical Outcome Definitions .............................................................................61 
9.7.5.4 
Microbiological Response Definitions ...............................................................63 
9.7.5.5 
Emergent Infections ............................................................................................64 

 
 
 
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9.7.6 
Safety Analyses ...................................................................................................64 
9.7.6.1 
Adverse Events ....................................................................................................65 
9.7.6.2 
Clinical Laboratory Parameters ........................................................................65 
9.7.6.3 
Vital Signs ...........................................................................................................66 
9.7.6.4 
Chest Radiography .............................................................................................66 
9.7.6.5 
Stopping Rule ......................................................................................................66 
9.7.7 
Antimicrobial Stewardship  and Outcomes Research Analyses .........................68 
9.7.8 
Interim Analysis ..................................................................................................68 
9.7.9 
Determination of Sample Size .............................................................................68 
9.7.10 
Computer Methods .............................................................................................68 
9.8 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES ....69 
9.9 
PROTOCOL DEVIATIONS ...........................................................................................69 
10.0 
STUDY FUNDERSHIP ....................................................................................................69 
10.1 
STUDY TERMINATION ................................................................................................69 
10.2 
REPORTING AND PUBLICATION .............................................................................69 
11.0 
INVESTIGATOR OBLIGATIONS ................................................................................69 
11.1 
DOCUMENTATION .......................................................................................................69 
11.2 
USE OF INVESTIGATIONAL MATERIALS .............................................................70 
11.3 
CASE REPORT FORMS ................................................................................................70 
11.4 
RETENTION AND REVIEW OF RECORDS ..............................................................70 
11.5 
PATIENT CONFIDENTIALITY ...................................................................................70 
12.0 
APPENDICES ...................................................................................................................70 
APPENDIX I. ELEMENTS OF INFORMED CONSENT ...................................................70 
APPENDIX II. MD ANDERSON NEUTROPENIC FEVER INPATIENT ADULT 

 
 
 
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TREATMENT GUIDELINES ....................................................................................................73 
APPENDIX III. MD ANDERSON PNEUMONIA IN ADULT PATIENTS WITH 
CANCER TREATMENT GUIDELINES ..................................................................................82 
APPENDIX IV. POTENTIAL DRUG-INDUCED LIVER INJURY/HY’S LAW ..............92 
APPENDIX V. INVESTIGATORS BROCHURE . ERROR! BOOKMARK NOT DEFINED. 
PHL ...............................................................................................................................................93 
FOLLOW-UP AND REPORTING ............................................................................................93 
REFERENCE ...............................................................................................................................94 
13.0 
LITERATURE CITED ....................................................................................................96 

 
 
 
 
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1.0 
TABLE 2–1. SCHEDULE OF ASSESSMENTS AND 
PROCEDURES 
 
Assessment or Procedure 
Baselinea 
Treatment 
Follow-up 
Study Days 1 to ≤ 
14b 
EOIVc 
TOCd 
LFUe 
Informed consentf 
X 
Inclusion/exclusion criteria 
X 
Medical and surgical historyg 
X 
Height and weighth 
X 
Chest radiographyi 
X 
If clinically indicated 
Physical examination 
X 
Xj 
X 
X 
Xk 
Vital signsl 
X 
X 
X 
X 
Xk 
Prior/concomitant medicationsm 
X 
X 
X 
X 
X 
AEs and SAEs 
X 
X 
X 
X 
X 
Clinical outcome 
X 
X 
X 
Laboratory testsn 
X 
If clinically 
indicatedo 
Xp 
Absolute neutrophil count 
X 
Xq 
X 
 
Urine or Serum pregnancy testr 
X 
 
CrCl calculations 
X 
Xj 
if clinically 
indicated 
 
Blood culture 
X 
XT 
Xu 
as clinically indicated 
Urine culture/urine analysis (when clinically 
needed) 
X 
as 
clinically 
indicated 
 
as clinically indicated 
Other samples for culture from possible suspected 
infected site if clinically indicated t 
if clinically indicated 
Randomization 
X 
Study drug administration 
Xv 
X 
a 
Perform baseline assessments within 36 hours of enrollment. 
b 
Study Day 1 is the first day of inpatient IV study drug administration; subsequent study days are 
consecutive calendar days. Baseline and Study day 1 assessment could be combined if they occur on the 
same calendar day.. On  
Study Days 1 to ≤ 14, study drug administration applies to all patients, and assessments are to be performed 
for patients on inpatient IV study drug only. Treatment duration is 2 to 14 days with a minimum of 2 days 
(ie, 48 hours and a minimum of 8 doses for Imipenem-Cilastatin-Relebactam and SOC therapies, except 
piperacillin/tazobactam, which is a minimum of 8 doses) of inpatient IV study drug. 
c 
Perform EOIV assessments in person within 72 hours after administration of the last dose of inpatient IV 
study drug. A patient may be eligible to switch to oral or other simplified IV therapy after at least 48 hours of  
IV gram negative antimicrobial coverage and procalcitonin () downward drops by 30% from baseline or is 
below than 0.25   (Section 9.4.1.4). 
d 
Perform TOC assessments in person between Study Days 21 and 28. 
e 
Perform LFU assessments between Study Days 35 and 42. LFU assessments may be conducted via 
telephone for any patient who has not experienced clinical failure since TOC, did not have ongoing study 
drug related AEs or SAEs at TOC, or did not develop any study  drug related AEs or SAEs since TOC. If 
symptoms consistent with clinical failure or new study drug related AEs or SAEs are noted, or at the 

 
 
 
 
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discretion of the Investigator, the patient should be immediately scheduled for an in-person visit. Also, 
telephone visit is acceptable for patients who cannot present for a clinic visit. 
f 
Obtain written informed consent before initiating any study assessment or procedure. 
g 
Obtain a complete medical and surgical history, including all active conditions and all conditions 
diagnosed within the previous 3 months. 
h 
If height or weight is not obtained , use the last known or stated height and weight. 
i 
CXR (eg, portable anteroposterior film) or chest CT for patients with respiratory signs or symptoms. 
j 
 Every 3 days after first dose, while the patient is hospitalized and receiving inpatient IV study drug, 
whereby the week begins on the day of enrollment.   The patient could receive unscheduled assessment, if 
deemed necessary at the discretion of the investigator. The investigator can rely on the physical exam 
performed by a professionally trained physician or health professional licensed to perform physical 
examinations. 
k 
Do not perform if LFU is conducted via telephone. 
l 
Blood pressure (systolic and diastolic) and pulse rate, respiratory rate, oxygen saturation (if 
applicable), and highest daily temperature. 
m 
Record medications, including antimicrobials (ie, antibacterials, antivirals, antifungals, antiparasitics), over-
the- counter medications (eg, vitamins, herbal medications), and parenteral nutrition taken or received within 
30 days of first dose of inpatient IV study drug through LFU. 
n 
Refer to Section 9.5.2.5 for a detailed list of laboratory tests. Results from unscheduled laboratory tests will not 
be collected, unless associated with an SAE or AE leading to discontinuation of IV study drug. Any abnormal 
laboratory test possibly attributable to IV study drugs will be repeated at appropriate intervals until it returns to 
normal. 
o 
Perform on Study Day 7 if still on IV study drug. 
p 
At EOIV, perform laboratory tests if laboratory tests for EOIV is obtained ≥ 24 hours prior to the  last 
dose (if applicable). 
q 
Record absolute neutrophil count a minimum of 3 times per week while on study therapy (IV or oral). For 
patients who switch to oral or IV therapy, at the discretion of the Investigator, record absolute neutrophil 
count as clinically indicated between EOIV and TOC. 
r 
Women of childbearing potential only (including those who are fewer than 2 years postmenopausal); ensure test is 
negative before randomization within 5 days. 
s 
The estimated CrCl should be calculated with the Cockcroft-Gault formula using the actual weight. If 
weight is not obtained, use the last known or stated weight. 
t 
Obtain 1-2 sets of blood samples from an existing CVC, if present, and from a peripheral vein site if 
possible, preferably before antibiotics are administered. If no CVC is present, collect 1-2 blood cultures 
from separate venipuncture sites, preferably. Obtain blood samples for culture every other day until 
temperature is ≤ 100.4°F (38.0°C)  and cultures are negative. 
u 
If baseline cultures were positive, repeat blood cultures at EOIV if clinically indicated to determine 
microbiological response.  
v 
Administer study drug per Section 9.4.1. 
 
AE = adverse event; CrCl = creatinine clearance; CT = computed tomography; CVC = central venous catheter; 
CXR = chest radiography; EOIV = End of Inpatient Intravenous Therapy; IV = intravenous; LFU = Late 
Follow-up; SAE = serious adverse event; TOC = Test-of-Cure. 

 
 
 
 
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2.0 
LIST OF IN-TEXT TABLES 
  
Table 2–1. Schedule of Assessments and Procedures .................................. 13 
Table 9.4.1.3–1. Investigational Products ....................................................  32 
Table 9.4.5.1–1. Imipenem-Cilastatin-Relebactam  Dosage Adjustments for   
Renal Impairment ………………………………………………………..... 36 
Table 9.7.5.3–1. Clinical Outcome Definitions............................................  55 
Table 9.7.5.4–1. Microbiological Response Definitions ..............................  58 
Table 9.7.5.5–1. Emergent Infections...........................................................  58 

 
 
 
 
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3.0 
LIST OF IN-TEXT FIGURES 
Figure 9.1–1. Study Design ........................................................  
30 
Figure 9.7.1–1. Analysis Sets for Study  ................................. 
62 

 
 
 
 
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4.0 
LIST OF ABBREVIATIONS 
 
%fT > CT 
percent of time that free drug concentrations are above a threshold 
concentration over a dose interval 
 
%fT > MIC 
percent of time that free drug concentrations are above the 
minimum inhibitory concentration over a dose interval 
 
AE 
adverse event 
 
ALP 
alkaline phosphatase 
 
ALT 
alanine aminotransferase 
 
ANC 
absolute neutrophil count 
 
AmpC 
Ambler Class C 
 
AST 
aspartate aminotransferase 
 
CE 
clinically evaluable 
 
CFR 
Code of Federal Regulations 
 
cIAI 
complicated intra-abdominal infection 
 
CrCl 
creatinine clearance 
 
CT 
computed tomography 
 
cUTI 
complicated urinary tract infection 
 
CXR 
chest x-ray 
 
eCRF 
electronic case report form 
 
EDC 
electronic data capture 
 
EOIV 
End of Inpatient Intravenous Therapy 
 
ESBL 
extended-spectrum β-lactamase 

 
 
 
 
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FDA 
US Food and Drug Administration 
 
FR 
Federal Register 
 
GCP 
Good Clinical Practice 
 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
 
ICF 
informed consent form 
 
ICH 
International Conference on Harmonisation 
 
IMI 
Imipenem/cilastatin 
 
IND 
Investigational New Drug 
 
IRB 
Institutional Review Board 
 
ITT 
intent-to-treat 
 
IV 
intravenous, intravenously 
 
LAR 
legally authorized representative 
 
LFU 
Late Follow-up 
 
MDR 
multidrug resistant 
 
ME 
microbiologically evaluable 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
MITT 
modified intent-to-treat 
 
mMITT 
microbiological modified intent-to-treat 
 
MTZ 
metronidazole 
 
PCS 
potentially clinically significant 
 
PHL 
potential Hy’s Law 
 
PID 
patient identification 
 
PK 
pharmacokinetic 
 
PK/PD 
pharmacokinetic/pharmacodynamic 
 
q8h 
every 8 hours 

 
 
 
 
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q6h 
every 6 hours 
 
REL 
Relebactam 
RSM 
Regional Site Manager 
SAE 
serious adverse event 
SOC 
standard of care 
TEAE 
treatment-emergent adverse event 
TOC 
Test-of-Cure 
ULN 
upper limit of normal 

 
 
 
 
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5.0 
ETHICAL CONSIDERATIONS 
 
5.1 
Institutional Review Board 
 
Approval by the Institutional Review Board (IRB) before the start of the study will be the 
responsibility of the Investigator. A copy of the approval letter will be supplied to 
Merck, Inc. along with a roster of IRB members or the US Department of Health and Human 
Services general assurance number. During the course of the study, the Investigator will provide 
timely and accurate reports to the IRB on the progress of the study, at intervals not exceeding 1 
year (or as appropriate), and will notify the IRB of serious adverse events (SAEs) or other 
significant safety findings. The study protocol, informed consent form (ICF), information sheet 
advertisements, and amendments (if any) will be approved by the IRB in conformance with the 
CFR, Title 21, Part 56. 
 
 
5.2 
Ethical Conduct of the Study 
 
This clinical study will be conducted in accordance with the ethical principles that have their 
origins in the Declaration of Helsinki. 
 
This clinical study will comply with ICH Guidance on General Considerations for Clinical Trials 
(ICH-E8; 62 FR 66113, 17 Dec 1997) and Good Clinical Practice (ICH-E6; 62 FR 25692, 09 
May 1997), as well as Part 312 of the CFR. 
 
 
5.3 
Patient Information and Informed Consent 
 
Patients, after being given an explanation of the study, will give voluntary and written informed 
consent and HIPAA authorization (in compliance with 21 CFR, Parts 50 and 312) before 
participating in any study-related procedures. 
 
Each patient (or his or her legally authorized representative) will read, assent to an understanding 
of, and sign an instrument of ICF after having had an opportunity to discuss it with the study 
staff before signing; each patient will be made aware that he or she may withdraw from the study 
at any time. 
 
The informed consent statement contains all the elements of informed consent listed in Appendix 
I of this protocol. Signed copies of the ICF will be given to the patient, and both documents will 
be placed in the Investigator’s study files. 

 
 
 
 
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6.0 
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE 
 
This study will be performed at 1 study center in the United States (MD Anderson Cancer 
Center, Houston, Texas). 
 
The Investigator is responsible for ensuring that the study is conducted according to the signed 
Investigator statement, the investigational plan, GCP guidelines, and applicable regulations; for 
protecting the rights, safety, and welfare of patients under the Investigator’s care; and for the 
control of investigational products under investigation. An Investigator shall obtain the informed 
consent of each human patient prior to the patient enrolling in the study and/or prior to 
participating in any study-related activity. 
 
The Investigator must meet his or her obligations to the patients, ethics committee, Funder, and 
regulatory authorities by maintaining oversight and control of the study’s conduct and the study 
staff. It is the responsibility of the Investigator to ensure that any and all delegated duties be 
assigned to qualified staff by education, experience, and licensure (in accordance with local 
regulations) and that the Investigator oversight is documented and assessment of their 
capabilities and performance consistent with the study investigational plan. The Investigator will 
be responsible for the management of the study, including maintaining the study file and the 
patient records, corresponding with the IRB, and completing the electronic case report forms 
(eCRFs). 
 

 
 
 
 
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7.0 
INTRODUCTION 
 
7.1 
Background and Study Rationale 
 
 
Infections caused by multidrug-resistant Gram-negative pathogens, ESBL-producing 
Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp., are difficult to treat and 
associated with high mortality (1-5).  Carbapenems fulfil a critical role in the treatment of serious 
bacterial infections due to these pathogens, both as empirical therapy in settings with high 
background levels of antibiotic resistance and as definitive therapy for confirmed MDR strains 
(6-10). The increasing prevalence of carbapenem-resistant bacterial pathogens is therefore a 
major global health threat, with the US CDC considering carbapenemresistant 
Enterobacteriaceae, one of only three bacterial threats at the highest hazard level (11-13). The 
most common carbapenem resistance mechanism is the production of carbapenemases, which are 
b-lactamase enzymes able to hydrolyse carbapenem-class antibacterials (14).  
 Resistance can also be mediated by other b-lactamases combined with additional mechanisms, 
such as porin loss and/or efflux pump expression (7, 15-18). 
 
Among various strategies, the most successful in increasing the life span of -lactam antibiotics 
has been their combination with new agents capable of inhibiting a broad spectrum of –
lactamases (10). Relebactam  is a -lactamase inhibitor that inhibits two different classes of -
lactamases: class A -lactamases (serine-containing -lactamases, such as the Klebsiella 
pneumoniae carbapenemase) and class C -lactamases (such as AmpC cephalosporinases) (7) 
Relebactam is suitable for combination with the well-established carbapenem 
imipenem/cilastatin (IMI): inhibiting AmpC frequently restores Pseudomonas aeruginosa 
susceptibility to imipenem but not other carbapenems, neither agent is subject to efflux in P. 
aeruginosa, and their pharmacokinetic/pharmacodynamic profiles complement each other (9, 10).  
Combining relebactam with IMI (IMI/REL) can restore IMI activity against many imipenem-
nonsusceptible gram-negative pathogens, including extended-spectrum β-lactamase (ESBL)-, 
AmpC-, and KPC-producing Enterobacteriaceae (19, 20). Two phase 2 trials found IMI/REL 
safe and no less effective than IMI for complicated intraabdominal and urinary tract infections 
(14, 21-23). In addition the Pivotal RESTORE-IMI 2 Phase 3 Study of Merck’s RECARBRIO™ 
(imipenem, cilastatin, and relebactam) in Hospital-Acquired and Ventilator-Associated Bacterial 
Pneumonia (HABP/VABP). This trial met Primary Endpoint. For both the primary and 
secondary efficacy end points, IMI/REL was non-inferior (p <0.001) to PIP/TAZ. The rates of 
adverse events (AEs) in the safety population (IMI/REL 226/266 [85.0%] vs PIP/TAZ 233/269 
[86.6%]), as well as therapy discontinuations due to both overall AEs and specifically due to 
drug-related AEs, were similar across both treatment arms. Diarrhea, increase alanine 
aminotransferase, and increased aspartate aminotransferase were the most common AEs (6/266 
[2.3%] each). Therefore IMI/REL is an efficacious and well-tolerated treatment option for 
HABP/VABP.  Pharmacokinetic/pharmacodynamic analyses (21, 24) confirmed 500 mg IMI 
plus 250 mg REL as the optimum IMI/ REL dose for further clinical evaluation. 
 
Therefore, the novel β-lactamase inhibitors relebactam are being developed to address the need 
for agents with activity against carbapenem-resistant Gram-negative, such as Imipenem–
Relebactam. This antibiotic (Imipenem-Cilastatin-Relebactam) will be compared to standard of 

 
 
 
 
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care other anti-pseudomonal beta-lactams (e.g.Cefepime, Meropenem or 
Piperacillin/Tazobactam) in patients with neutropenia and fever. This study uses Procalcitonin 
(PCT) as a theragnostic biomarker that promotes antimicrobial stewardship and the need to 
switch and streamline these broad spectrum IV antibiotics by 48-72 hours in most of the cases. 
PCT has been studied by our group in cancer patients in the setting of neutropenic fever and has 
been shown to be a useful tool for assessing the response to antimicrobial therapy particularly 
between 48 and 72 hours (25-31). Furthermore, it has been highly studied in high risk patients 
such as critically ill patients and patients with lower respiratory tract infections and was found to 
be a useful tool for antimicrobial stewardship and for streamlining antimicrobial therapy (to 
either oral regimen or simplified IV regimen) or discontinuing antimicrobial therapy (32-35). 
Hence, it is being used in this current study for antimicrobial stewardship to prevent unnecessary 
prolonged use of broad spectrum antimicrobial therapy.  
 
 
7.2 
Clinical Overview 
The activity of imipenem against Gram-negative bacteria is either retained or enhanced with the 
addition of relebactam. Significant increases in activity of imipenem with the addition of 
relebactam are observed against imipenem non-susceptible and b-lactamase (ESBL, KPC, and 
serine carbapenemase) producing Enterobacteriaceae (2- to 128-fold MIC reductions) and 
against P. aeruginosa (eightfold MIC reduction). Clinical trials completed to date are 
summarized in Table (12 ), including two imipenem–relebactam phase II clinical trials for the 
treatment of cIAI and cUTI/AP (NCT01506271 and NCT01505634).  
 
7.2.1 
Summary of Efficacy In Completed Clinical Studies 
The efficacy, tolerability, and safety of imipenem–relebactam has been studied for the treatment 
of cIAI in a global, double-blind, randomized, phase II, non-inferiority trial (NCT01506271) 
(Table II) (21). Imipenem/cilastatinrelebactam (500/500/250 mg and 500/500/125 mg) were 
compared to imipenem/cilastatin alone (500/500 mg), administered IV (t’ 30 min) q6 h for 4–14 
days. The dose of imipenem was adjusted for renal insufficiency and/or low body weight 
according to the approved label at the time of the trial, and the dose of relebactam was adjusted 
proportionally. In this study, 351 patients were BLOCK randomized (1:1:1) . Clinical response in 
the ME population at EFU and LFU was similar to the response seen at DCIV, and was similar 
across all three treatment groups (Table II). 
 
The efficacy, tolerability, and safety of imipenem–relebactam has been studied for the 
treatment of cUTI and AP in a global, double-blind, randomized, phase II, non-inferiority trial) 
(14). Imipenem/cilastatin-relebactam (500/500/250 mg and 500/500/125 mg) was compared to 
imipenem/cilastatin alone (500/500 mg), administered IV (t’ 30 min) q6 h with optional oral 
step-down to ciprofloxacin after at least 4 days of IV therapy. The total treatment duration was 
a maximum of 14 days. The dose of imipenem was adjusted for renal insufficiency and/or low 
body weight according to the approved label at the time of the trial, and the dose of relebactam 
was adjusted proportionally. In this study, 302 patients were block randomized 1:1:1.  
The primary outcome was a favorable microbiological response in the ME population at DCIV. 
Microbiological response was determined based on urine culture results on follow-up relative 
to the pathogen(s) isolated at baseline. The ME population was defined as subjects with an 

 
 
 
 
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eligible diagnosis of cUTI or AP, a prestudy culture growing at least one Gram-negative 
enteric and/or anaerobic pathogen at a sufficient quantity, and no significant protocol 
deviations, who received at least 4 days of IV study therapy.  
The ME population at DCIV included 77.2% of randomized patients. A non-inferiority margin 
was set at ≥ 15% for the lower bound of the 95% CI, with 87% power to determine non-
inferiority of imipenem–relebactam compared to imipenem alone. Microbiological response in 
the ME population at DCIV (primary outcome) for the relebactam arm 250 mg was 95.5 versus 
98.7% for imipenem alone, a difference of − 3.1% (95% CI − 11.3 to 3.2), while response for 
the relebactam 125 mg arm was 98.6 versus 98.7% for imipenem alone (95% CI − 6.4 to 5.9). 
Therefore, both regimens were non-inferior to imipenem alone for the primary outcome.  
 
 
 
 
7.3    
Summary of Safety  
 
 
In a Phase II study comparing the treatment of cUTI and AP, drug-related adverse events 
occurred in 10.1, 9.1, and 9% of patients for treatment with imipenem/cilastatin-relebactam 
500/500/250 mg, imipenem/cilastatin-relebactam 500/500/125 mg, and imipenem/cilastatin 
500/500 mg, respectively (14). No deaths occurred; however, serious treatment-emergent 
adverse events were reported in 3.0, 1.0, and 3.0%, respectively. The most common treatment-
emergent adverse events included nausea, headache and diarrhea, which were relatively similar 
in all three treatment groups (range of 2.0–7.1%). Treatment-related adverse events leading to 
discontinuation occurred in four patients, 2 (2%), 1 (1%), and 1 (1%) in the three treatment 
groups, respectively, due to diarrhea, rash, nausea, and diarrhea. One patient in the relebactam 
250 mg group experienced AST elevations ≥ 5× ULN, determined to be drug related.

 
 
 
 
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7.4  
In vitro Activity of Imipenem/relebactam and 
Comparator Agents 

 
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8.0 
STUDY OBJECTIVES 
 
Primary: 
• To evaluate the efficacy of imipenem–cilastatin-relebactam plus/minus vancomycin, 
daptomycin or linezolid vs  standard of care (SOC) plus/minus vancomycin, daptomycin or 
linezolid as empiric therapy in febrile neutropenic adults with cancer with respect to favorable 
clinical response at End of Inpatient Intravenous Therapy (EOIV) in the Modified Intent-to-
Treat (MITT) Analysis Set. 
 
• To evaluate the safety and tolerability of imipenem-cilastatin–relebactam plus/minus 
vancomycin, daptomycin, or linezolid compared with SOC plus/minus vancomycin, daptomycin 
or linezolid as empiric therapy in febrile neutropenic adults with cancer. 
 
 
 
Secondary: 
• To evaluate the efficacy of imipenem-cilastatin–relebactam plus/minus vancomycin, 
daptomycin  or linezolid compared with SOC plus/minus vancomycin, daptomycin or linezolid 
as empiric therapy in febrile neutropenic adults with cancer with respect to the following: 
 
○ Favorable clinical response at EOIV in the mMITT and Clinically Evaluable (CE) analysis sets. 
 
○ Favorable clinical response at TOC (ie, 21 to 28 days after start of IV therapy) and LFU (ie, 35 
to 42 days after start of IV therapy) in the MITT Analysis Set. 
 
○ Favorable clinical response by baseline Gram-negative pathogen at EOIV, TOC, and LFU in the 
mMITT and CE analysis sets. 
 
○ Favorable microbiological response by patient and by baseline Gram-negative pathogen at EOIV, 
TOC, and LFU in the mMITT and ME analysis sets. 
 
○ Infection-related mortality rate at TOC and LFU in the MITT and mMITT analysis sets. 
 
○ 30-day all-cause mortality rate in the MITT and mMITT analysis sets. 
 
• To evaluate the role of PCT in promoting antimicrobial stewardship resulting in the switch of 
most patients from the broad spectrum agents (Imipenem/Cilastatin/Relebactam & SOC) to a 
more simplified IV or oral  antibiotic therapy within 48-72 hours. 
 
9.0 Investigational Plan: 
9.1 
Overall Study Design and Plan: Description 
 
This clinical study will be a single-center, randomized, open-label, parallel-group study 
comparing imipenem-cilastatin–relebactam plus/minus vancomycin, daptomycin or linezolid 
with SOC plus/minus vancomycin, daptomycin or linezolid as empiric therapy in febrile 
neutropenic adults with cancer. The total duration of study therapy will be 2 to 14 days; a 
minimum of 2 days (ie, 48 hours of IV antimicrobial gram negative coverage is required; 

 
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duration of treatment is discussed in Section 9.4.1.5. IV study drug is defined as the IV 
treatment for Gram-negative coverage (or SOC) that the patient is receiving for the 
neutropenic febrile episode). A switch to open-label oral or IV therapy may be allowed after at 
least 48 hours IV gram negative antimicrobial coverage per Section 9.4.1. Doses of SOC 
antibiotics given before signing informed consent will be counted. 
Gram positive antimicrobial coverage (ie vancomycin, linezolid or daptomycin) is optional and 
can be given if clinically indicated at the discretion of the primary team or emergency center 
physician. Gram positive antimicrobial coverage can also be switched at any time during the 
study.  
 
 
 
 
 

 
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IV SOC plus/minus 
Vancomycin, 
Daptomycin or 
Linezolid 
IV SOC plus/minus Vancomycin, Daptomycin 
li
lid
 
 
Figure 9.1–1. 
Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IV Imipenem relebactam 
Plus/minus Vancomycin, 
Daptomycin or Linezolid 
IV Imipenem relebactam plus/minus Vancomycin, 
Daptomycin or Linezolid 

 
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9.2 
This Section Intentionally Omitted 
 
9.3 
Selection of Study Population 
 
 
9.3.1 
Inclusion Criteria 
 
To be eligible to participate in the study, a patient must meet the following criteria: 
 
1. Has provided written informed consent, and has the willingness and ability to comply with all 
study procedures 
 
2. Male or female, ≥ 18 years old 
 
3. Patients with neutropenic fever who have existing malignancy or have undergone hematopoietic 
stem cell transplantation. Neutropenic fever is defined as the presence of neutropenia defined by: 
1) Absolute neutrophil count (ANC) < 500 cells/mm3 or has an ANC that is expected to decrease 
to < 500 cells/mm3 within 48 hours of trial entry and fever defined as: 2) Single oral temperature 
measurement of > 100.4°F (38.0°C)  
 
4. Requires hospitalization for IV empiric antibiotic therapy 
 
5. If female: 
 
○ Not breastfeeding 
 
○ Agrees to not attempt to become pregnant during the study 
 
 

 
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o Is surgically sterile or at least 2-years postmenopausal, or if of childbearing potential, has negative 
screening serum or urine pregnancy test within 5 days 
 
○ If of childbearing potential (including being < 2 years postmenopausal), is willing to practice 
sexual abstinence or use an effective dual form of contraception with her partner (eg, 2 barrier 
methods, barrier method plus hormonal method) during treatment and up 28 days post treatment.  
 
 
9.3.2 
Exclusion Criteria 
 
Patients who meet any of the following criteria will not be eligible to participate in the study: 
 
1. History of any hypersensitivity or allergic reaction to any carbapenem 
 
2. Fever suspected to be caused by a noninfectious cause (eg, fever related to drug or blood product 
administration) 
 
3. Confirmed fungal infection (eg, Pneumocystis jirovecii etiology in patients with pneumonia) that 
justifies adding additional empiric antimicrobial therapy (eg, antifungals) 
 
4. Confirmed viral infection that justifies adding additional empiric antiviral therapy (eg, 
ganciclovir, foscarnet) 
 
5. Evidence of significant hepatic impairment (any of the following): 
 
○ Known acute viral hepatitis 
 
Alanine aminotransferase (ALT) level > 5 times the upper limit of normal (× ULN).  
Total bilirubin > 3 × ULN unless isolated hyperbilirubinemia is directly related to the acute 
infection or due to known Gilbert disease 
○ Manifestations of end-stage liver disease, such as ascites or hepatic encephalopathy 
 
6. Known to be human immunodeficiency virus positive 
 
7. Severely impaired renal function, defined as creatinine clearance (CrCl) ≤ 30 mL/min estimated 
by the Cockcroft-Gault formula (Section 9.5.3.1) 
 
8. Expected requirement for hemodialysis while on study therapy 
 
9. Received > 36 hours of IV antibacterial therapy (with study drugs) within 72 hours of the 
initiation of inpatient IV study drug for treatment of suspected infection. Antibiotic prophylaxis 
and oral antibiotics is allowed. Prophylactic use of antiviral or antifungal medication is 
permitted. 
 
10. Past or current history of epilepsy or seizure disorder; exception: well-documented febrile 
seizure of childhood 
 
11. Evidence of immediately life-threatening disease, progressively fatal disease, or life expectancy 
of 3 months or less (eg, moribund or with shock unresponsive to fluid replacement) 

 
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12. Unable or unwilling to adhere to the study-specified procedures and restrictions 
 
13. Any condition that would make the patient, in the opinion of the Investigator, unsuitable for the 
study (eg, would place a patient at risk or compromise the quality of the data   
 
14. Participation in any other ongoing imipenem-cilastatin–relebactam trial. 
 
15. Prior participation on this trial  
 
 
9.3.3 
Removal of Patients from Therapy or Study 
Assessment 
 
Patients should be encouraged to complete all study assessments. However, a patient may be 
discontinued from inpatient IV study drug or oral or IV therapy or may withdraw consent to 
participate in this study at any time without penalty or loss of benefits to which the patient is 
otherwise entitled. 
 
 
A premature discontinuation from the study will occur when a patient who signed the ICF, 
regardless of circumstances, ceases participation in the study, before the completion of all study 
assessments (ie, before completing all protocol-stipulated activities). In addition, patients can be 
prematurely discontinued from the study after careful consideration for one of the reasons listed 
in Section 9.3.3.4. 
 
Follow-up of patients prematurely discontinued from inpatient IV study drug or oral or IV 
therapy or withdrawn from the study will be conducted as described below. 
 
 
9.3.3.1 
Premature Discontinuation from Inpatient IV Study 
Drug Due To Safety 
 
Reasons: Possible reasons for premature discontinuation from study drug administration 
due to safety include, but are not limited to: 
 
Occurrence of a related, possibly or probably related AE that, in the opinion of the Investigator, 
warrants the patient’s permanent discontinuation from IV study drug 
 
Known pregnancy or breastfeeding during the study therapy administration period.  
 
The patient meets criteria for drug-induced liver injury per Appendix V, at the discretion of the 
Investigator 
 
Investigator determines that it is in the best interest of the patient to discontinue study drug, due 
to reasons other than an adverse event (AE) 
 
Assessments and Procedures: A patient who is prematurely discontinued from inpatient 
IV study drug (ie, before the anticipated full course of study therapy required for effective 
treatment of febrile neutropenia) for safety reasons should have EOIV assessments conducted 

 
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and undergo safety assessments at TOC and LFU. 
 
Clinical Outcome Assessment: See Table 9.7.5.3–1 
 
 
9.3.3.2 
Premature Discontinuation from Inpatient IV Study 
Drug Due To Insufficient Therapeutic Effect 
 
Reasons: Possible reasons for discontinuation from study drug due to insufficient therapeutic 
effect include, but are not limited to: 
 
Clinical worsening: A patient who shows signs of clinical worsening may be prematurely 
discontinued from inpatient IV study drug at any time. If the Investigator deems the benefit-to-
risk ratio of inpatient IV study drug continuance acceptable, administration of at least 48 hours is 
encouraged before discontinuation. 
 
Lack of clinical progress: For a patient who is stable, yet does not show signs of improvement, 
the Investigator is encouraged to continue inpatient IV study drug for at least 48 hours before 
such a patient is considered a clinical failure and is prematurely discontinued from IV study drug 
 
Assessments and Procedures: A patient who is prematurely discontinued from inpatient IV 
study drug due to insufficient therapeutic effect should have EOIV assessments conducted and 
undergo safety assessments at TOC and LFU. If a patient is discontinued from inpatient IV study 
drug due to insufficient therapeutic effect and is switched to an alternative IV antibiotic, that 
therapy should be recorded. 
 
Clinical Outcome Assessment: See Table 9.7.5.3–1. 
 
9.3.3.3 
Premature Discontinuation from Oral or IV Therapy 
 
A patient who is prematurely discontinued from oral or IV therapy for any reason will not have 
protocol assessments conducted until TOC (ie, there is no scheduled visit between EOIV and 
TOC). At an unscheduled visit or at TOC, whichever occurs first, record the date of and reason 
for discontinuation. See Table 9.7.5.3–1 for clinical outcome definitions at TOC. 
 
9.3.3.4 
   Withdrawal from Study 
 
Reasons: Possible reasons for withdrawal from study depend on the timing of the withdrawal, 
and include, but are not limited to: 
 
Before administration of first dose of study therapy: 
 
Screen failure (failure to meet inclusion/exclusion criteria) 
 
Withdrawal of consent at any time during the study period. 
 
AE 
 
Protocol violation 

 
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Lost to follow-up 
 
Study terminated by Funder 
 
Site terminated by Funder 
 
Investigator determines that it is in the best interest of the patient to withdraw from the 
study protocol, due to reasons other than an AE 
 
An AE should not be a reason for withdrawal from study after study drug has been administered. 
The patient may be discontinued from study drug due to an AE, in which case they should be 
encouraged to stay in the study for follow-up safety assessments. 
 
Note: If death was due to an AE, then the AE is the reason for discontinuing study drug and death 
is the reason for withdrawal from study. If the death is due to lack of efficacy, then lack of 
efficacy is the reason for discontinuing study drug, and death is the reason for withdrawal from 
study. 
 
 
Assessments and Procedures: Patients may withdraw from the study, or be withdrawn at the 
request of the Investigator or Funder. A patient who is withdrawn completely from the study 
during inpatient IV study drug or oral or IV therapy should be encouraged to undergo, if 
possible, EOIV (if on inpatient IV study drug) or TOC (if on oral or IV therapy) assessments on 
the day of withdrawal. Patients withdrawn from the study need not undergo subsequent TOC 
efficacy assessments (if on inpatient IV study drug) or LFU (if on oral or IV therapy) 
assessments. 
 
Clinical Outcome Assessment: A patient withdrawn from the study who is not assessed as a 
clinical failure should be assessed as indeterminate at all subsequent outcome evaluation time 
points (Table 9.7.5.3–1). 
 
9.3.4  
Patient Replacement Procedures 
 
Randomized patients who are withdrawn and have received at least one dose of study drug will 
not be replaced. Patients who withdraw consent prior to receiving any dose of study drug will be 
replaced by an evaluable patient. 
 
 
 
9.4.1 
TREATMENTS 
 
Treatments Administered 
 
 9.4.1 
Treatment Group 
 
As shown in Table 9.4.1.3-1, patients randomized to the Imipenem-Cilastatin-Relebactam 

 
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treatment group will receive: 
 
Imipenem-Relebatam: 500 mg Imipenem, 500 mg cilastatin and  250 mg of Relebactam IV over 
30 min Q6 hours 
 
IV Imipenem/Cilastatin/Relebactam (minimum of 8 doses) 
 
Gram positive antimicrobial coverage (ie vancomycin, linezolid or daptomycin) is optional and 
can be given if clinically indicated at the discretion of the primary team or emergency center 
physician. Gram positive antimicrobial coverage can also be switched at any time during the 
study.  
Daptomycin could be given if there is no evidence of pneumonia. 
 
Patient may continue on the study drug up to 14 days if clinically indicated by the assessment of 
the treating physician   
 
Patients may receive other additional therapy as discussed in Section 9.4.1.3. Patients may be 
eligible to switch to outpatient IV or oral therapy, as discussed in 
Section 9.4.1.4. 
 
 
 
9.4.1.3 
Standard of Care Treatment Group 
 
As shown Table 9.4.1.3–1, patients randomized to the SOC treatment group will receive: 
 
One of the following IV therapies: 
 
Cefepime (minimum of 6 doses) 
 
Meropenem (minimum of 6 doses) 
 
Piperacillin/tazobactam (minimum of 8 doses) 
 
Doses given before signing informed consent will be counted if antibiotics remain the same 
(dose and frequency) after signing informed consent. 
 
Gram positive coverage is optional as clinically indicated with IV vancomycin, daptomycin or 
linezolid (oral linezolid is allowed). Daptomycin could be given if there is no evidence of 
pneumonia. 
 
Patients may receive other additional therapy as discussed in Section 9.4.1.3. Patients may be 
eligible to switch to outpatient IV or oral therapy, as discussed in 
Section 9.4.1.4. 
 
 

 
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9.4.1.3 
Other Additional Antibacterial Therapy 
 
Patients in either treatment group may receive other additional therapy as needed (Table 9.4.1.3–
1) at the discretion of the primary physician or Investigator, per the MD Anderson Neutropenic 
Fever Inpatient Adult Treatment Guidelines (Appendix II; or Appendix III for patients with 
documented or suspected pneumonia), as follows: 
 
Double Gram-negative coverage should be considered with complicated tissue-based infections, 
neutropenic enterocolitis, pneumonia, and perirectal infections; if indicated, add Tobramycin, 
Amikacin Ciprofloxacin, Minocycline, Tigecycline, Doxycycline, or Bactrim.   
Table 9.4.1.3–1 
 
Additional antibacterial therapy may be added at any time during the study for management of 
complications or if antibacterial resistance is suspected or proven 
 
A Switch to a Once-Daily Gram- Negative IV Agent for the Purposes of Outpatient Or Home IV 
Treatment Is Allowed After 48 Hours As Described In Table 9.4.1.3–1 
 
 
Empirical Treatment of patients with colitis, abdominal symptoms or C. Difficile with Oral 
Vancomycin or Metronidazole (IV or oral) May Be Added at any time during the study. 
 
 
Table 9.4.1.3–1. Investigational Products 
 
Investigational 
Product 
Dosagea and Route 
Form and Strength 
Supplier 
 Treatment Group: 
Imipenem-
Cilastatin-
Relebactam 
500 mg Imipenem, 500 mg 
Cilastatin  and  250 mg of 
Relebactam IV over 30 min 
Q6h  
Investigational 
FRI 
PLUS/MINUS one of the following adjunctive Gram-positive therapies (optional): 
Vancomycinb 
15 mg/kg (rounded to nearest 
250-mg dose) IV q12h  
(+/– 30 min) 
Commercial Supply as per FDA approved 
package insert 
MDA 
Linezolidb 
600 mg IV (or oral) q12h  
Commercial Supply as per FDA approved 
package insert 
MDA 
Optional for Either Treatment Group (IV Gram-Positive Adjunctive Therapy Switch at any time for 
Patients With Suspected Line Infections and/or Bacteremia) 
Daptomycinb 
6-8 mg/kg IV q24h 
Commercial Supply as per FDA approved 
package insert 
MDA 
Standard of Care (Comparator) Treatment Group: 

 
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ONE of the following: 
Cefepime 
2 g IV q8h  
Commercial Supply as per FDA approved 
package insert 
MDA 
Meropenem 
1 g IV q8h  
Commercial Supply as per FDA approved 
package insert 
MDA 
Piperacillin/tazo 
bactam 
4.5 g IV q6h  
Commercial Supply as per FDA approved 
package insert 
MDA 
PLUS/MINUS one of the following adjunctive Gram-positive therapies (optional): 
Vancomycinb 
15 mg/kg (rounded to nearest 
250-mg dose) IV q12h  
Commercial Supply as per FDA approved 
package insert 
MDA 
Linezolidb 
600 mg IV (or oral) 
q12h 
 
Commercial Supply as per FDA approved 
package insert 
MDA 
Optional for Either Treatment Group (IV Gram-Negative Therapy Switch After at Least 48 Hours 
of IV  Gram-Negative antimicrobial coverage) 
Ceftriaxone 
2 g IV q24h 
Commercial Supply as per FDA approved 
package insert 
MDA 
Ertapenem 
1 g IV q24h 
Commercial Supply as per FDA approved 
package insert 
MDA 
Optional for Either Treatment Group (IV Gram-Positive Adjunctive Therapy Switch at any time for 
Patients With Suspected Line Infections and/or Bacteremia) 
Daptomycinb 
6-8 mg/kg IV q24h 
Commercial Supply as per FDA approved 
package insert 
MDA 

 
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Table 9.4.1.3–1. Investigational Products 
 
Investigational 
Product 
Dosagea and Route 
Form and Strength 
Supplier 
Optional for Either Treatment Group (Adjunctive Double Gram-Negative Therapy): 
Tobramycinc 
7 mg/kg IV q24h 
Commercial Supply as per FDA approved 
package insert 
MDA 
Optional for Either Treatment Group (Adjunctive Double Gram-Negative Therapy): 
Amikacinc 
15 - 20 mg/kg IV q24h 
Commercial Supply as per FDA approved 
package insert 
MDA 
Ciprofloxacinc 
400 mg IV q8h 
Commercial Supply as per FDA approved 
package insert 
 
MDA 
Minocyclin 
100mg q12h 
Commercial Supply as per FDA approved 
package insert 
MDA 
Tigecycline 
100 mg/day (day 1- day 2 on) 
50 mg q12h 
Commercial Supply as per FDA approved 
package insert 
 
MDA 
Doxycycline 
100 mg q12h 
Commercial Supply as per FDA approved 
package insert 
 
MDA 
Bactrim 
5-20mg/kg/day   
Commercial Supply as per FDA approved 
package insert 
MDA 
a 
Dosages shown for patients with normal renal/hepatic function. Appropriate dosage modifications for 
renal function will be made per Section 9.4.5.1-1 
b 
Per the MD Anderson Neutropenic Fever Inpatient Adult Treatment Guidelines (Appendix II) or, for patients 
with documented or suspected pneumonia, the MD Anderson Pneumonia in Adult Patients with Cancer 
Treatment Guidelines (Appendix III). 
c 
As needed for double Gram-negative coverage per the MD Anderson Neutropenic Fever Inpatient 
Adult Treatment Guidelines (Appendix II). 
  
Imipenem Cilastatin Relebactam; IV = intravenous; MDA = MD Anderson; q6h = every 6 hours; q8h = every 
8 hours; q12h = every 12 hours; q24h = every 24 hours. 
 
All antibiotic doses and infusion time will be administered according to standard doses and time 
of administration defaulted in EPIC system.  
 
Subsequent antibiotic doses may be administered according to MDACC policy (Standard 
28Medication Administration Time Policy (UTMDACC Institutional Policy # CLN1091) timed 
on the next whole hour. If unable to administer a dose at scheduled time, give the next dose 
ASAP (according to MDACC institutional policy # 1091, Standard medication administration 
Exception list attachment). Once the delay has been resolved, re-time future doses to coincide 
with the most recent administration time. 
 
 
 
 
9.4.1.4 
            Optional Oral or IV Therapy Switch 
 
 
9.4.1.4.1  
Criteria for Switching to Oral or IV Therapy 
 
A switch to oral or IV therapy may be allowed after at least 48 hours  of  IV gram negative 
antimicrobial coverage if all of the following criteria are met: 
 
Oral therapy or IV therapy (for outpatient or home administration) is clinically indicated 

 
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Patient received at least 48 hours of IV gram negative antimicrobial coverage. 
 
EOIV clinical signs and symptoms have been assessed 
 
Patient has the ability to maintain oral intake 
 
Patient is clinically stable 
 
Patient is afebrile 
 
Improvement in clinical signs and symptoms of infection from baseline 
 
Patient has negative blood culture (taken within past 24 hours) (for patients with positive blood 
cultures at baseline with a gram negative organism) 
 
.  
 
For Patients Who Are Randomized To SOC, Doses Given Before Signing The Informed Consent 
Will Be Counted If Antibiotics Remain The Same (Dose and Frequency) After Signing The 
Informed Consent.  
 
Exploratory: We will evaluate how often repeat PCT at 48-72 hours after study drug initiation 
has dropped by ≥ 30 % from baseline (day 0= start of therapy) or PCT level within 48-72 hours 
is below 0.25. This will not be considered a switching criterion and if not met will not constitute 
a protocol deviation. This is an exploratory criterion that will be evaluated to explore the role of 
PCT used as a biomarker in adjunct to the clinical judgement to guide antibiotic therapy. 
 
 
9.4.4.4.2 
Oral and IV Switch Therapy Options 
 
After completion of at least 48 hours of IV gram negative antimicrobial coverage, the patient 
may be switched to an appropriate combination of oral and/or IV therapy such as: 
 
Linezolid (oral) 
 
Ampicillin 
 
Amoxicillin 
 
Amoxicillin/clavulanate (oral) 
 
Minocycline (oral) 
 
Ciprofloxacin (oral) 
 
Levofloxacin (oral) 

 
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Cefpodoxime (Oral) 
 
Trimethoprim/sulfamethoxazole (oral) 
 
Ceftriaxone (IV) 
 
Ertapenem (IV) 
 
Daptomycin (IV) 
 
Vancomycin (IV) 
 
The specific combination chosen is at the discretion of the Investigator in accordance with local 
SOC and should provide coverage for isolated pathogens and appropriate empirical therapy in the 
absence of microbiological data. 

 
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Consult the package inserts, labels, and local dosing guidelines regarding storage, administration, 
maximum doses, contraindications (eg, drug-drug interactions), warnings, precautions, and 
adverse drug reactions reported with the use of oral or IV therapies. 
 
9.4.1.5 
Duration of Treatment 
 
The total duration of study therapy will be 2 to 14 days; a minimum of 2 days (ie, 48 hours) of IV 
gram negative antimicrobial coverage is required. After at least 2 days (ie, 48 hours [of  IV gram 
negative antimicrobial coverage, the Investigator will assess if inpatient IV study drug should be 
continued or a switch to oral or IV therapy is warranted (Section 9.4.1.4). After at least 48 hours 
(ie, 2 days, typically on or after Study Day 2) of antibiotic therapy (IV plus oral), the Investigator 
will assess if inpatient IV study drug or oral or IV switch therapy should be continued or if all 
therapy should be discontinued. 
 
Duration of therapy is at the discretion of the Investigator, considering clinical response, presence 
of clinically and /or microbiologically documented infections, and signs of bone marrow 
recovery. 
 
An assessment of clinical outcome will be made at the end of all study therapy as defined in 
Section 9.7.5.3. 
 
9.4.2 
Identity of Investigational Products 
 
Investigational product Imipenem-Cilastatin-Relebactam contains  Imipenem, Cilastatin and 
Relebactam, which will be administered together in a single infusion bag. A single vial filled 
with the sterile crystalline form of Imipenem (500 mg), cilastatin 500mg, and the sterile 
crystalline form of Relebactam (250mg) for IV administration. The crystalline powders are 
reconstituted using saline or various dextrose solution for Injection, resulting in a concentrate 
solution. An amount of this solution, corresponding to the dose to be administered, is withdrawn 
from the vial and transferred into an infusion bag containing 100 mL saline. 
 
Preparation of RECARBRIO Solution for Intravenous Administration 
RECARBRIO is supplied as a dry powder in a single-dose vial that must be constituted and 
further diluted using aseptic technique prior to intravenous infusion. To prepare the infusion 
solution, contents of the vial must be constituted with the appropriate diluent as instructed below. 
A list of appropriate diluents is as follows: 
• 
0.9% Sodium Chloride Injection, USP 
• 
5% Dextrose Injection, USP 
• 
5% Dextrose Injection, USP + 0.9% Sodium Chloride Injection, USP 
• 
5% Dextrose Injection, USP + 0.45% Sodium Chloride Injection, USP 
• 
5% Dextrose Injection, USP + 0.225% Sodium Chloride Injection, USP 
RECARBRIO has low aqueous solubility. To ensure complete dissolution of RECARBRIO it is  
important to adhere to the following instructions: 
Step 1) For diluents available in 100 mL prefilled infusion bags, proceed to step 2. For diluents 
not available in 100 mL prefilled infusion bags, aseptically withdraw 100 mL of the desired 
diluent and transfer it to an empty infusion bag, then proceed to step 2. 

 
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Step 2) Withdraw 20 mL (as two 10 mL aliquots) of diluent from the appropriate infusion bag 
and constitute the vial with one 10 mL aliquot of the diluent. The constituted suspension is for 
intravenous infusion only after dilution in an appropriate infusion solution. 
Step 3) After constitution, shake vial well and transfer resulting suspension into the remaining 80 
mL of the infusion bag. 
Step 4) Add the second 10 mL aliquot of infusion diluent to the vial and shake well to ensure 
complete transfer of vial contents; repeat transfer of the resulting suspension to the infusion 
solution before administering. Agitate the resulting mixture until clear. 
Constituted solutions of RECARBRIO range from colorless to yellow. Variations of color within 
this range do not affect the potency of the product. 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration, whenever solution and container permit. Discard if discoloration or 
visible particles are observed. 
 
The above instructions for preparation of RECARBRIO solution for intravenous administration 
must be followed for all patients, irrespective of the intended patient’s renal function. The 
volume of this prepared RECARBRIO solution to be administered to patients is determined 
based on renal function [see Dosage and Administration]. 
 
Preparation of RECARBRIO Solution for Intravenous Administration in Patients with Renal 
Impairment  
For patients with renal impairment, prepare a reduced dose of RECARBRIO (1 gram, 0.75 
grams, or 0.5 grams) by preparing a 100 mL solution containing 1.25 grams (as described above) 
then withdrawing and discarding the excess according to Table 2. 
Table 2: Preparation of Reduced RECARBRIO Doses for Intravenous Administration in Patients 
with Renal Impairment 
 
 
Creatinine 
Clearance 
(mL/min) 
Dosage of RECARBRIO 
(imipenem/cilastatin/relebactam
) 
After preparation as 
instructed above, remove 
from the 100 mL prepared 
bag the volume indicated 
below and discard 
Resulting volume 
that provides the 
indicated reduced 
dose 
60 to 89 
1 gram (imipenem 400 mg, 
cilastatin 
400 mg, and relebactam 200 
mg) 
20 mL 
80 mL 
30 to 59 
0.75 grams (imipenem 300 mg, 
cilastatin 300 mg, and 
relebactam 
150 mg) 
40 mL 
60 mL 
15 to 29 or 
ESRD on 
hemodialysis 
0.5 grams (imipenem 200 mg, 
cilastatin 200 mg, and 
relebactam 
100 mg) 
60 mL 
40 mL 
 

 
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With the exception of Imipenem-Cilastatin-Relebactam all other study drugs (IV or oral) will be 
commercially labeled. All inpatient IV study drug and oral and IV therapies should be kept in a 
secure place under appropriate storage conditions, as specified on the drug labeling and package 
insert. 
 
Upon completion of the study or termination of the site, all used and unused study drugs that 
were supplied by the funder will be destroyed according to the standard operating procedures of 
MD Anderson. 
 
9.4.3 
Method of Assigning Patients to Treatment Groups 
 
After patient enrollment, randomization will be conducted by the clinical coordinator on an 
institutional Clinical Trial Conduct (CTC) website, developed by the Department of Biostatistics.  
At the end of the study, 50% patients will be divided equally at the end of the study between both 
arms. If the patient is started on one of the three agents, we will continue the same agent if he is 
assigned to SOC arm. The choice of the antibiotic will be kept at the discretion of the primary 
team. 
 
Patients in SOC arm will be analyzed as one treatment group in the intent to treat analysis and 
other analysis.   
 
At the time of signing the ICF and consenting to participate in this study. The first patient to sign 
the ICF at the study center will be assigned the first accession number, and each subsequent 
patient will be assigned the next sequential number. This patient identification number will be 
used to identify the patient at all phases of the study. 
 
 
9.4.4  
Selection of Dosages in the Study 
 
The dosages of each investigational product are shown in Table 9.4.1.3–1 and, if applicable, in 
the MD Anderson Neutropenic Fever Inpatient Adult Treatment Guidelines (Appendix II) or, for 
patients with documented or suspected pneumonia, in the MD Anderson Pneumonia in Adult 
Patients with Cancer Treatment Guidelines 
(Appendix III). 
 
The dose of Imipenem-Cilastatin-Relebactam that was selected for this study was based on 
clinical trial for the treatment of cIAI and cUTI table II  
 
The dosages of the other investigational products are considered SOC and are used in current 
treatment of febrile neutropenic patients at MD Anderson, as shown in the MD Anderson 
Neutropenic Fever Inpatient Adult Treatment Guidelines (Appendix II) or, for patients with 
documented or suspected pneumonia, in the MD Anderson Pneumonia in Adult Patients with 
Cancer Treatment Guidelines (Appendix III). 
 
9.4.5 
Selection and Timing of Dose for Each Patient 
 
Investigational products will be administered per Table 9.4.1.3–1 and, if applicable, per the MD 
Anderson Neutropenic Fever Inpatient Adult Treatment Guidelines (Appendix II) or, for patients 

 
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with documented or suspected pneumonia, in the MD Anderson Pneumonia in Adult Patients 
with Cancer Treatment Guidelines (Appendix III). 
 
9.4.5.1 
Dose Adjustments for Imipenem-Cilastatin-
Relebactam 
 
In the case of renal impairment, at any time, the dose of Imipenem-Cilastatin-Relebactam 
(including the initial dose) may be adjusted by the pharmacist or designee per the dosage 
regimen in Table 9.4.5.1–1. At any time, the dose of Imipenem-Cilastatin-Relebactam may be 
readjusted to the appropriate dosage when renal function improves. If a patient’s estimated CrCl 
(as calculated using the Cockcroft-Gault formula [Section 9.5.3.1]) decreases to ≤ 30 mL/min 
during the treatment period, the Study Physician should be contacted immediately to discuss if 
continuation of study drug therapy is appropriate and to discuss additional dose adjustments for 
CrCl ≤ 30 mL/min. 
 
 
 
 
 
 
Table 9.4.5.1–1.  Dosage Adjustments for Renal Impairment 
 
Dosage Adjustments In Patients With Renal Impairment 
Dosage adjustment is recommended in patients with renal impairment. Patients who have a CLcr 
less than 90 mL/min require dosage reduction of RECARBRIO (Table I). For patients with 
fluctuating renal function, CLcr should be monitored. 
 
Table I: Dosage of RECARBRIO for Adult Patients with Renal Impairment 
Estimated CLcr 
(mL/min)a 
Recommended Dosage of RECARBRIO 
(imipenem/cilastatin and relebactam) (mg)b 
Dosing Interval 
60 to 89 
1 gram (imipenem 400 mg, cilastatin 400 mg, 
and relebactam 200 mg) 
Every 6 hours 
30 to 59 
0.75 grams (imipenem 300 mg, cilastatin 300 
mg, and relebactam 150 mg) 
Every 6 hours 
15 to 29 
0.5 grams (imipenem 200 mg, cilastatin 200 
mg, and relebactam 100 mg) 
Every 6 hours 
End Stage Renal 
Disease (ESRD) on 
Hemodialysisc 
0.5 grams (imipenem 200 mg, cilastatin 200 
mg, and relebactam 100 mg) 
Every 6 hours 
aCLcr calculated using the Cockroft-Gault formula  
bAdminister by IV over 30 minutes.  
cAdministration should be timed to follow hemodialysis.  
RECARBRIO is provided as a single vial in a fixed-dose combination; the dose for each 
component will be adjusted equally during preparation [see Preparation of RECARBRIO 

 
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Solution for Intravenous Administration in Patients with Renal Impairment]. 
 
Patients with CLcr less than 15 mL/min should not receive RECARBRIO unless hemodialysis is 
instituted within 48 hours. There is inadequate information to recommend usage of 
RECARBRIO for patients undergoing peritoneal dialysis.  Imipenem, cilastatin, and relebactam 
are cleared from the circulation during hemodialysis. For patients maintained on hemodialysis, 
administer RECARBRIO after hemodialysis and at intervals timed from the end of that 
hemodialysis session. 
9.4.5.2 
Dose Adjustments - Other Investigational Products 
 
For all other investigational products, appropriate dosage modifications for renal function will be 
made per the respective package insert or institutional guidelines. 
 
 
9.4.6 
Blinding 
 
This study will be conducted as an open-label investigation; no blinding of assigned treatment 
will occur. 
 
 
9.4.7 
Unblinding 
 
Not applicable. 
 
9.4.8 
Prior and Concomitant Therapy 
 
All prior (taken or received within 30 days before the first dose of IV study drug) and 
concomitant (taken during the study) medications, including but not limited to, antimicrobials (ie, 
antibacterials, antivirals, antifungals, antiparasitics), over-the-counter medications (eg, vitamins, 
herbal medications), and parenteral nutrition, will be documented on the appropriate screens of 
the eCRF (concomitant meds will be captured in subjects medical record in Epic). 
 
Concomitant use of the following is not permitted: 1) potentially effective systemic antibacterial 
therapy; 2) any drug known to exhibit a contraindicated drug-drug interaction with any of the 
study therapies or a labeled contraindication to use of any study therapies. 
 
All other concomitant medications and nutrients necessary for the health and well-being of the 
patient are permitted. 
 
9.4.9 
Monitoring Treatment Compliance 
 
Treatment compliance will be closely monitored by recording the date, time, and whether or not 
each dose of inpatient IV study drug or IV switch therapy was infused and, if applicable, 
whether or not each intended dose of oral switch therapy was taken. 
 
 
 
9.5 
EFFICACY AND SAFETY VARIABLES 
 

 
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9.5.1 
Primary and Secondary Efficacy Assessments 
 
 
Primary Efficacy Assessment 
 
The Investigator’s assessment of clinical response will be used to determine the primary efficacy 
assessment. The Investigator should consider the entirety of the patient’s clinical course and 
current status, including an evaluation of infection signs and symptoms (eg, fever, neutropenia), 
radiological findings (if applicable), and physical examination in order to classify the patient’s 
clinical response at EOIV according to the definitions listed in Table 9.7.5.3–1. The investigator 
could rely on physical exam performed by a professionally trained physician or health 
professional licensed to perform physical examinations.  
The investigator will use the serial PCT levels drawn at baseline and at 48-72 hours as an adjunct 
to the clinical judgement to guide antibiotic therapy and prevent unnecessary prolonged therapy 
with broad spectrum agents (Imipenem/Cilastatin/Relebactam & SOC). 
 
 
Secondary Efficacy Assessments 
 
Clinical Assessments 
The Investigator’s assessment of clinical response at EOIV, TOC, and LFU will be used to 
determine the secondary clinical efficacy endpoints according to the definitions listed in Table 
9.7.5.3–1. 
 
 
Microbiological and Molecular Assessments 
A patient’s microbiological response at EOIV, TOC, and LFU will be determined 
programmatically based on individual outcomes for each baseline pathogen according to the 
definitions listed in Table 9.7.5.4–1. 
 
 
9.5.1.2 
Microbiological Assessments 
 
 
Blood Samples for Culture 
 
Blood samples for culture will be obtained at the following time points, preferably before the 
next scheduled dose of study antibiotics is administered: 
 
Baseline 
 
Study Days 1 to ≤ 14: every other day until temperature is ≤ 100.4°F (38.0°C) and blood cultures 
are negative and PCT is < 0.25 or dropped by 30% or more within 48 -72 hours compared to 
baseline on Day 0 (start of therapy). PCT will be collected at baseline and at 48-72 hours after 
study drug initiation. 
 
EOIV: if baseline cultures were positive (to determine microbiological response) 
 
TOC and LFU: as clinically indicated per the discretion of the Investigator (eg, if clinical 

 
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worsening and/or persistence of fever or other signs or symptoms consistent with clinical 
failure) 
 
Blood cultures should be repeated upon knowledge of a positive result from any visit until 
sterilization is confirmed. 
 
When blood cultures are required, 1-2 sets of blood samples should be obtained from an existing 
central venous catheter, if present, and from a peripheral vein site if patient agrees. If no central 
venous catheter is present, collect 1-2 blood cultures from separate venipuncture sites. 
 
Culture, organism identification, and susceptibility testing will be conducted at the local 
laboratory. All pathogens will be tested for susceptibility to all drugs used. 
 
Microbiological samples for blood cultures will be collected, processed, and stored in 
accordance with local procedures (refer to Microbiology Manual). 
 
 
 
 
 
 
 
Other Samples for Culture 
 
Culture specimens from other sites of suspected infection should be obtained as clinically 
indicated. 
 
Culture, organism identification, and susceptibility testing will be conducted at the local 
laboratory. All pathogens will be tested for susceptibility to all drugs used. 
 
Microbiological samples will be collected, processed, and stored in accordance with local 
procedures (refer to Microbiology Manual). 
 
 
9.5.1.3 
Clinical Outcome of the Infection 
 
Per the Schedule of Assessments and Procedures (Table 2–1), the Investigator or sub-
investigator is to assess the Clinical Outcome at EOIV, TOC and LFU. 
 
 
9.5.2 
Safety Assessments 
 
 
Throughout the clinical trial, each patient will be observed for adverse reactions.  All patients 
will be monitored for the development of study-related adverse events through the entire study 
period including the thirty (30) days following the last dose of study drug. Any serious, 
unexpected adverse event(s) will be reported to the funder and IRB per policy, and reported to 
the FDA accordingly. Patients who have received at least one dose of the study drug will be 
included in the safety analysis. Patients who withdraw consent prior to receiving any dose of 
study drug, will not be included in the analysis and will be replaced by an evaluable patient. 
Evaluation done by the primary team and the attending physician following the patient are 

 
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acceptable.  
 
9.5.2.1 
Adverse Events 
 
Recording of Adverse Events.   
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study drug even if the event is not considered to be related 
to study drug. Medical conditions/diseases present before starting study drug are only considered 
adverse events if they worsen after starting study drug. Abnormal laboratory values or test results 
constitute adverse events only if they induce clinical signs or symptoms, are considered clinically 
significant, or require therapy. 
 
Reportable adverse events for this protocol will be documented into the Adverse Events log 
(source document) and entered into the case report form in RedCap according to the Recommended 
Adverse Event Guidelines for Phase II  Protocols (please refer to chart on page 46). The patients’ 
records will be reviewed and only reportable AEs (AEs of any grade that are possibly, probably 
and definitely related to the study drug, and any AE grade 3 or above regardless of their attribution 
to study drug) will be documented in the AE log and case report form”. The Investigator or 
physician designee is responsible for verifying and providing source documentation for all 
reportable adverse events and assigning the attribution for each event for all subjects enrolled on 
the trial. AEs not recorded on the AE log and case report form are considered grade 1 or 2 and 
unrelated or unlikely related to the study drug. This recording will apply to all patients enrolled on 
the protocol including future, current and previously enrolled patients. Labs that are not deemed 
clinically significant by the investigator will not be reported as AEs. Additionally, the Investigator 
is responsible for providing appropriate treatment for the event and for adequately following the 
event until resolution for all adverse events for subjects enrolled. 
 
Version 5.0 of the Common Toxicity Criteria for adverse events will be used to assess AEs and 
SAE (please refer to Section 9.5.2.1) 
• Attribution - the determination of whether an adverse event is related to a medical 
treatment or procedure.  
• Definite - the adverse event is clearly related to the investigational agent(s). 
• Probable - the adverse event is likely related to the investigational agent(s). 
• Possible - the adverse event may be related to the investigational agent(s). 
• Unlikely - The adverse event is doubtfully related to the investigational agent(s). 
• Unrelated - The adverse event is clearly NOT related to the investigational agent(s). 
 
 
Study subjects should be instructed to report all adverse events to the Investigator.  In addition, 
the Investigator should seek to elicit any clinical or objective reactions by specific questioning 
and, as appropriate, by examination.  Information on all adverse events should be recorded on the 
case report form.  All clearly related signs, symptoms and abnormal diagnostic procedures 
should be grouped together and recorded as a single diagnosis.  The component parts of the 
diagnosis may be listed for verification.  For each adverse, the Investigator is to assess the 
severity of the reaction, and to determine the relationship to study drug.  In addition, the duration 

 
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will be noted, and whether intermittent or continuous also documentation of the outcomes and 
what was done with study drug is needed.  
Events not included in the NCI CTCAE will be scored as follows: 
• Grade 1: Mild: discomfort present with no disruption of daily activity, no treatment 
required beyond prophylaxis. 
• Grade 2: Moderate: discomfort present with some disruption of daily activity, require 
treatment. 
• Grade 3: Severe: discomfort that interrupts normal daily activity, not responding to first 
line treatment.  
• Grade 4: Life Threatening: discomfort that represents immediate risk of death 
 
 
 
Please note medical procedures scheduled prior to consenting, but occurring during the study 
should not be captured as AEs, but should be listed in the medical history if related to a pre-
existing condition. 
 
Any worsening of the infection under study because of lack of therapeutic effect of any study 
drug is captured as an efficacy analysis variable and is not to be considered an AE, unless the 
event is an SAE resulting in death (Section 9.5.2.3). 
 
Pregnancies should not be automatically assessed as AEs. 
 
9.5.2.2 
Causality Assessment 
 
The Investigator or physician designee is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for each event for all subjects 
enrolled on the trial. Assessments done by the primary team following the patient are acceptable. 
 
Is there a reasonable possibility the investigational product caused the event? 
 
 
Yes: 
There Is Evidence To Suggest A Causal Relationship Between The Investigational 
Product and The Ae; Ie: 
 
○ There is a reasonable temporal relationship between the investigational product and the event, 
and/or 
 
○ The event is unlikely to be attributed to underlying/concurrent disease, other investigational 
products, or other factors, and/or 
 
○ Positive dechallenge and/or rechallenge exist 
 
No: 
There Is No Evidence To Suggest A Causal Relationship Between The 
Investigational Product and The Ae, Ie: 
 
○ There is no reasonable temporal relationship between the investigational product and the event, 

 
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or 
 
○ The patient did not take the investigational product, or 
 
○ The event is likely to be attributed to underlying/concurrent disease, other investigational 
products, or other factors, or 
 
○ The event is commonly occurring in the (study) population independent of investigational 
product exposure 
 
 
9.5.2.3  
Serious Adverse Event (SAE) Reporting Requirements for M D Anderson Sponsored 
Single Site IND Protocols 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following 
outcomes: 
  
• Death 
• A life-threatening adverse event 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• A congenital anomaly/birth defect. 
  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
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 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
  
• Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
• All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined 
in “The University of Texas M. D. Anderson Cancer Center Institutional Review Board 
Policy on Reporting Adverse Events for Drugs and Devices”. 
• Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws 
consent.  
• Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, or there 

 
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has been acceptable resolution of the event. 
• All SAEs, expected or unexpected/ initial or follow up, must be reported to the IND 
Office within 5 working days of knowledge of the event regardless of the attribution. 
• Death or life-threatening events that are unexpected, possibly, probably or definitely 
related to drug must be reported (initial or follow up) to the IND Office within 24 hours 
of knowledge of the event  
• Additionally, any serious adverse events that occur after the 30 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
• The electronic SAE application (eSAE) will be utilized for safety reporting to the IND 
Office and MD Anderson IRB.  
• All events reported to the supporting company must also be reported to the IND Office 
  
Reporting to FDA: 
• Serious adverse events will be forwarded to FDA by the IND Sponsor according to 21 
CFR 312.32. 
  
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy.  
 
 
 
 
Emergency room visits that do not result in hospitalization should be evaluated for one of the 
other serious outcomes to determine whether they qualify as SAEs. 
 
Preplanned hospitalizations (eg, elective procedures for preexisting conditions that did not 
worsen, such as cosmetic surgery and hysterectomy) are excluded from SAE reporting. 
 
Any worsening of the infection under study because of lack of therapeutic effect of any study 
drug is captured as an efficacy analysis variable and is not to be considered an SAE, unless the 
event results in death. 
Pregnancy will be reported to the IND Office via eSAE application as “Other Important Medical 
Event 
 
This study will collect adverse events according to phase II guidelines on the table below: 

 
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Reporting to the sponsor:  
Serious Adverse Event and Suspected Unexpected Serious Adverse Reaction, Potential Incident 
Reporting: Principal Investigator shall forward to Merck’s Global “Merck GPV”) group, any SAE 
or SUSAR, including, but not limited to, all initial and follow-up information involving any Study 
subject in the Study. Notification shall be in the form of a completed CIOMS I/MedWatch (or 
other mutually agreed upon format such as eSAE) within two (2) business days of but not longer 
than three (3) calendar days of receipt of the information. The phrase “business days” means a day 
in which Institution has regular business operations and would exclude weekends and holidays 
observed by Institution’s administrative staff. This information shall be transmitted to Merck. All 
information shall be transmitted in the English language and contain the reporter’s name and the 
Study subject identifier code.  
 
The below terms shall be defined as follows: 
 
“Adverse Event” or “AE” shall mean any untoward medical occurrence in a Study subject who is 
administered the Study Drug regardless of whether or not a causal relationship with the Study 
Drug exists. By way of example and without limitation, an AE can be any unfavorable and 
unintended sign (for example, an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of the Study Drug. 
 
“Serious Adverse Event” or “SAE” shall mean any untoward medical occurrence in a Study 
subject who is administered the Study Drug that results in death, a life- threatening drug 
experience, requires inpatient hospitalization or prolongation of existing hospitalization, results in 
persistent or significant disability/incapacity, or is a congenital anomaly/birth defect, cancer, or is 
a new cancer if the cancer is the condition of the study, or overdose. Other important medical 
events that may jeopardize the patient or may require intervention to prevent one of the outcomes 
listed previously should also be considered “serious”. 

 
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“Suspected Unexpected Serious Adverse Reaction” or “SUSAR” shall mean any Serious 
Adverse Event, the nature, severity or frequency of which is not consistent with information in the 
most current investigator’s brochure, or with respect to a marketed product the most current 
Summary of Product Characteristics (SPC) or Package Insert. 
 
 
9.5.2.5 
Clinical Laboratory Determinations 
 
Blood sample and urine culture/urine analysis (when clinically needed) will be collected 
according to the Schedule of Assessments and Procedures (Table 2-1). Specific labs important to 
the analysis will only be entered in REDCap and include procalcitonin, white blood cell count 
(WBC), absolute neutrophil count (ANC), hemoglobin, platelet count, alanine aminotransferase 
(ALT), albumin, alkaline phosphatase, creatinine, and total bilirubin. 
 
Women of childbearing potential (including those who are fewer than 2 years postmenopausal) 
will be required to have a serum or urine pregnancy test at baseline (within 5 days). The test 
must be negative before randomization. If the serum test results cannot be obtained before 
randomization, a urine pregnancy test may be used for enrollment. 
 
The following clinical laboratory levels will be measured (those marked with an asterisk [*] are 
required for eligibility): 
 
Hematology:  Basophils (absolute count and %), eosinophils (absolute count and %), erythrocyte 
count, hematocrit, hemoglobin, leukocytes (absolute count and differential), lymphocytes 
(absolute count and %), monocytes (absolute count and %), neutrophils (absolute count* and %), 
immature neutrophils (bands; %), platelet count, red blood cell indices (mean corpuscular 
volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration) 
 
Chemistry:  Albumin, ALT*,  bilirubin* (total), blood urea nitrogen, calcium, creatinine*, 
electrolytes (ie, bicarbonate, chloride, potassium, sodium), glucose, Procalcitonin (which will be 
repeated between 48-72 hours after initiation of therapy).   
 
Urinalysis if clinically indicated: 
Appearance (color, clarity), bilirubin, blood, glucose, 
ketones, leukocyte esterase, nitrite, pH, protein, specific gravity, urobilinogen, and urine 
microscopy (ie, red blood cells, white blood cells, casts, crystals, bacteria, yeast cells, parasites) 
 
Other:  pregnancy test* 
The MD Anderson local laboratory will be used to evaluate all urine and blood samples. Results 
from unscheduled laboratory tests will not be collected, unless associated with an 
SAE or AE leading to discontinuation of IV study drug. EXCEPTION: At the discretion of the 
Investigator, unscheduled ANC values will be recorded as clinically indicated while on oral or IV 
Switch therapy (ie, between EOIV and TOC). 
 
Any abnormal laboratory test possibly attributable to inpatient IV study drug will be repeated at 
appropriate intervals until stabilization. 
 
9.5.2.6 
Vital Signs, Body Weight, and Height 
 

 
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Vital signs will be recorded at every visit; the parameters are: 
 
Blood pressure: systolic and diastolic  
 
Pulse rate 
 
Respiratory rate 
 
Oxygen saturation: patients with respiratory signs or symptoms 
 
Temperature: record highest daily temperature 
 
Body weight and height will be measured at baseline. If height or weight is not obtained, the last 
known or stated height and weight may be used. 
 
9.5.2.7 
Chest Radiography 
 
A chest x-ray (CXR) (posteroanterior and lateral) or chest computed tomography (CT) scan will 
be obtained at baseline for patients with respiratory signs or symptoms. If the patient’s condition 
does not allow for a standard posteroanterior and lateral examination, a portable anteroposterior 
CXR is acceptable. Chest radiography will be obtained postbaseline, ie, at EOIV, TOC, or LFU 
if clinically indicated. 
 
9.5.2.8 
Physical Examination 
 
A complete physical examination will be conducted by a professionally trained physician or 
health professional licensed to perform physical examinations. 
 
9.5.3 
Schedule of Assessments 
 
The schedule of study assessments and procedures is tabulated by visit in Table 2–1. The 
descriptions of the procedures to be performed at each visit are provided below. 
 
9.5.3.1 
Baseline 
 
Baseline procedures must be completed within 24 hours before the start of the first dose of 
inpatient IV study drug. Any protocol-required eligibility laboratory evaluations already done as 
part of the patient’s regular medical care within 24 hours before the start of the inpatient IV 
study drug infusion on Study Day 1 do not have to be repeated to determine patient eligibility. 
 
At baseline, informed consent will be obtained, a review of inclusion/exclusion criteria will be 
conducted to determine the patient’s eligibility for enrollment, and study procedures will be 
reviewed with the patient and/or caregiver, and the legally authorized representative (if different 
from the caregiver). After signing the ICF, the patient will be assigned a unique PID number (or 
accession number) (see Section 9.4.3). If, after review of the inclusion/exclusion criteria, it is 
determined that the patient is eligible to enter the study, the patient will be randomized according 
to the randomization procedures in Section 9.4.3. 
 
At baseline, the following procedures will be performed: 
 
Obtain written informed consent per Section 5.3 

 
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Verify that inclusion criteria are met and none of the exclusion criterion apply 
 
Obtain medical and surgical history including all active conditions and all conditions diagnosed 
within the previous 3 months 
 
Abnormal baseline labs will not be captured as baseline AEs or medical history as deemed not 
clinically significant pertaining to our protocol. A changing in the grade of the abnormal labs 
during study treatment will be captured as AEs if clinically significant. 
 
Obtain height and weight (if height or weight is not obtained, use the last known or stated height 
and weight) 
 
Perform CXR (eg, portable anteroposterior film) or chest CT for patients with respiratory signs 
or symptoms (per Section 9.5.2.11) 
 
Perform complete physical examination 
 
Record vital signs (blood pressure and pulse rate, respiratory rate, oxygen saturation [if 
applicable], highest daily temperature) 
 
Record prior medications, including antimicrobials (ie, antibacterials, antivirals, antifungals, 
antiparasitics), over-the-counter medications (eg, vitamins, herbal medications), and parenteral 
nutrition taken or received within 30 days of first dose of inpatient IV study drug. 
 
Evaluate and record infection signs and symptoms  
 
Laboratory assessments: 
Collect blood and urine samples for clinical laboratory determinations per Section 9.5.2.5. 
 
Record ANC 
 
Collect blood sample for pregnancy test (females of childbearing potential only, including those 
who are fewer than 2 years postmenopausal); ensure test is negative before randomization. If the 
serum test results cannot be obtained before randomization within 5 days, a urine pregnancy test 
may be used for enrollment 
 
Estimate CrCl using the following Cockcroft-Gault formula (use actual body weight and 
conventional units; if weight is not obtained, use the last known or stated weight): 
 
Males: CrCl= (140 – age in years) X weight in kg / 72 X serum creatinine (mg/dL) 
 
Female: CrCl= 0.85 X (140-age in years) X weight in kg / 72 X serum creatinine (mg/dL) 
Microbiological assessments: 
 
 
Collect blood sample for culture and PCT per Section 9.5.1.2 (See pages 33-34). 
 
 
If clinically indicated, collect other samples for culture per Section 9.5.1.2 

 
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Randomize patient after verifying that the patient meets all study inclusion criteria and no 
exclusion criteria 
 
 
9.5.3.2 
Study Days 1 To ≤ 14 
 
Study Day 1 is the calendar day that inpatient IV study drug is first administered. Baseline and 
Study day 1 assessment could be combined if they occur on the same calendar day. 
 
On Study Days 1 to ≤ 14, administer study therapy to all patients and conduct the following 
assessments and procedures daily while the patient is hospitalized and receiving IV study drug, 
unless otherwise specified: 
 
Perform complete physical examination twice a week after first dose of inpatient IV study 
drug, at least every 3 days, whereby the week begins on the day of enrollment. The physical 
examination will be conducted by a professionally trained physician or health professional 
licensed to perform physical examinations. Patients may have unscheduled visit sooner 
than the scheduled date if deemed necessary by the investigator. 
 
Record vital signs (blood pressure and pulse rate a, respiratory rate, oxygen saturation [if 
applicable], highest daily temperature) 
 
Record new concomitant medications 
 
Review and record AEs and SAEs 
 
Evaluate and record infection signs and symptoms  
 
Laboratory assessments: 
 
Collect blood and urine samples for clinical laboratory determinations (Section 9.5.2.5) if 
clinically indicated 
 
On Study Day 7 +/- 24 hours, if still on IV study drug, collect blood and urine samples for 
clinical laboratory determinations (Section 9.5.2.5). 
 
Record ANC a minimum of 3 times per week while on study therapy (IV or oral) 
 
Record estimated CrCl every 3 days after first dose of inpatient IV study drug 
beginning on Study Day 1 
 
Microbiological assessments: 
 
Obtain blood samples (per Section 9.5.1.2) for culture every other day until temperature is ≤ 
100.4°F (38.0°C) and cultures are negative 
 
If clinically indicated, collect other samples for culture per Section 9.5.1.2. 
 

 
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Administer study therapies per Section 9.4.1 and Table 9.4.1.3–1 
 
 
9.5.3.3 
End of Inpatient Intravenous Therapy 
 
Conduct EOIV assessments within 72 hours after administration of the last dose of inpatient IV 
study drug. 
 
Administer the last dose of inpatient IV study drug, and conduct the following assessments and 
procedures in all patients, unless otherwise specified: 
 
If clinically indicated, perform CXR (eg, portable anteroposterior film) or chest CT for patients 
with respiratory signs or symptoms 
 
Perform complete physical examination 
 
Record vital signs (blood pressure and pulse rate, respiratory rate, oxygen saturation [if 
applicable], highest daily temperature) 
 
Record new concomitant medications 
 
Review and record AEs and SAEs 
 
Evaluate and record infection signs and symptoms per Section 9.5.1.3 
 
Assess clinical outcome per Section 9.7.5.3 
 
Laboratory assessments: 
 
Collect blood and urine samples for clinical laboratory determinations 
(Section 9.5.2.5) if laboratory tests for EOIV is performed ≥ 24 hours prior to EOIV (if 
applicable) 
 
Record ANC 
 
If clinically indicated, record estimated CrCl 
 
For patients on oral or IV therapy: At the discretion of the Investigator, record ANC as clinically 
indicated (ie, during an unscheduled visit between EOIV and TOC) 
 
Microbiological and molecular (PCT) assessments: 
 
If baseline blood cultures were positive, repeat blood cultures (per Section 9.5.1.2) 
 
If clinically indicated, collect other samples for culture (per Section 9.5.1.2) 
 
9.5.3.4 
Test-of-Cure (Toc) 
 
Conduct TOC assessments in person at any time between Study Days 21 and 28 (ie, 21 to 28 
days after the start of inpatient IV study drug). 

 
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For patients who were switched to oral or IV therapy: Assess if oral or IV therapy was completed 
and if not, record date of and reason for discontinuation 
 
If clinically indicated, perform CXR (eg, portable anteroposterior film) or chest CT for patients 
with respiratory signs or symptoms 
 
Perform complete physical examination 
 
Record vital signs (blood pressure and pulse rate, respiratory rate, oxygen saturation [if 
applicable], highest daily temperature) 
 
Record new concomitant medications 
 
Review and record AEs and SAEs 
 
Evaluate and record infection signs and symptoms per Section 9.5.1.3 
 
Assess clinical outcome per Section 9.7.5.3 
 
Laboratory assessments: 
 
Record ANC 
 
Microbiological assessments: 
 
If clinically indicated, collect blood sample for culture (per Section 9.5.1.2) 
 
If clinically indicated, collect other samples for culture (per Section 9.5.1.2) 
 
 
9.5.3.5 
Late Follow-Up 
 
Conduct LFU assessments any time between Study Days 35 and 42 (ie, 35 to 42 days after the 
start of inpatient IV study drug). The LFU may be conducted by telephone for any patient who 
has not experienced clinical failure since TOC, did not have ongoing study drug related AEs or 
SAEs at TOC, or did not develop study drug related AEs or SAEs since TOC. If symptoms 
consistent with clinical failure or new study drug related AEs or SAEs are noted, or at the 
discretion of the Investigator, the patient should be immediately scheduled for an in-person visit. 
Also, telephone visit is acceptable for patients who cannot present for a clinic visit. 
 
If LFU is conducted by telephone: 
 
Record new concomitant medications 
 
Review and record AEs and SAEs 
 
Record Infection Symptoms, Including Recurring or Worsening Symptoms 
 

 
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Indicative of Clinical Failure 
 
Note: If symptoms consistent with clinical failure or new AEs or SAEs are noted during the 
telephone interview, or at the discretion of the investigator, the subject should be immediately 
scheduled for an in-person visit 
 
Assess clinical outcome per Section 9.7.5.3 
 
If LFU is conducted in person: 
 
If clinically indicated, perform CXR (eg, portable anteroposterior film) or chest CT for patients 
with respiratory signs or symptoms 
 
Perform complete physical examination 
 
Record vital signs (blood pressure and pulse rate, respiratory rate, oxygen saturation [if 
applicable], highest daily temperature) 
 
Record new concomitant medications 
 
Review and record AEs and SAEs 
 
Evaluate and Record Infection Signs and Symptoms Per Section 9.5.1.3 
 
Assess clinical outcome per Section 9.7.5.3 
 
Microbiological assessment: In patients experiencing clinical failure after TOC or if 
clinically indicated, collect samples for culture per Section 9.5.1.2.2 
 
Any clinical findings obtained during the final examination or at premature discontinuation for 
any reason, including clinically significant laboratory abnormalities, will be followed until the 
condition returns to prestudy status, has resolved or stabilized, or can be explained as being 
unrelated to the investigational product. A follow-up visit, if one should be necessary, will take 
place within 30 days of investigational product termination. 

 
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9.6 
DATA QUALITY ASSURANCE 
 
 
9.6.1 
Data Recording, Documentation and Monitoring 
 
The Investigator and the study site staff will be responsible for data entry of patient data into 
REDCap.  The Investigator or designee will be responsible for approving all changes performed 
on the data, and endorsing the patient data within the system. This approval method will include 
applying an electronic signature linked to a uniquely assigned username and password that 
together will represent a traditional handwritten signature used in the past. 
 
 
9.6.2 
Data Recording and Documentation 
 
Data collection will involve the use of REDCap to which only authorized personnel will have 
access. Patient’s data are to be entered into the system by the Investigator or designee using their 
assigned user account. After data entry into the system by the Investigator or designee, a 
combination of manual and programmatic edit checks will be used to review the data for 
completeness, logic, and adherence to study protocol.  
 
After all data have been reviewed and all issues have been resolved, the database will be locked. 
 
All data collected in the context of this study will be stored and evaluated per regulatory 
requirements and applicable guidance for electronic records. Also, data will be stored and 
evaluated in such a way as to guarantee patient confidentiality in accordance with the legal 
stipulations applying to confidentiality of data. Study records (eg, copies of eCRFs, laboratory 
reports, patient diaries, regulatory documents, etc) will be retained at the site, along with 
adequate source documentation, according to FDA and ICH requirements. All study records 
must be available for., its authorized representatives, and the FDA or other health authorities. 
 
 
9.7 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
 
Descriptive statistics (number, mean, SD, median, minimum, and maximum) will be provided 
for continuous variables, and frequency distributions (counts and percentages) will be shown for 
categorical variables. All summary statistics will be presented by treatment group. In addition, 
the the summary statistics will be provided for all randomized patients that received any amount 
of inpatient IV study drug (MITT Analysis Set) and for the subgroup of patients with a pathogen 
identified (mMITT Analysis Set). Listings of individual patients’ data will also be produced. 
 
A comprehensive statistical analysis plan will be prepared and finalized before database lock and 
analysis of the data. 
 
9.7.1 
Analysis Sets 
 
Analysis sets are described below and displayed in Figure 9.7.1–1. 

 
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Figure 9.7.1–1. 
Analysis Sets for Study  
Screened 
Underwent Baseline Visit 
and received PID number 
 
 
Intent-to-Treat (ITT) 
All randomized 
 
Safety 
Received any amount of IV study drug 
      
 
    Modified Intent-to-Treat 
(MITT) 
        
   Met minimal disease criteria 
 
 
 
 
Clinically Evaluable(CE) 
Met all evaluability 
criteria 
 
 
    
 Microbiological Modified Inten-tto-Treat (mMITT) 
       ≥ 1 qualifying baseline bacterial pathoge,n irrespective of 
susceptibility to study therapies 
Microbiological Evaluable(ME) 
Met criteria for both mMITT and CE Analysis Sets 

 
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9.7.1.1 
Screened Analysis Set 
 
The Screened Analysis Set will consist of all patients who undergo the Baseline Visit and receive 
a PID number. 
 
9.7.1.2 
Intent-To-Treat Analysis Set 
 
The Intent-to-Treat Analysis Set will consist of all patients in the Screened Analysis Set who are 
randomized to a treatment group in the study. 
 
9.7.1.3 
Safety Analysis Set 
 
The Safety Analysis Set will be a subset of the ITT Analysis Set and will include all randomized 
patients who receive any amount of inpatient IV study drug. Patients will be analyzed according 
to the treatment actually received. 
 
9.7.1.4 
Modified Intent-To-Treat Analysis Set 
 
The MITT Analysis Set will be a subset of the ITT Analysis Set and will include all randomized 
patients who received any amount of inpatient IV study drug and meet minimal disease criteria 
(Inclusion Criterion 3). Patients will be analyzed according to randomized treatment group, 
regardless of treatment received. 
 
 
9.7.1.5 
Microbiological Modified Intent-To-Treat Analysis 
Set 
 
The mMITT Analysis Set will be a subset of the MITT Analysis Set and will include those 
patients for whom at least 1 qualifying bacterial pathogen was isolated from an appropriate 
microbiological specimen at baseline, irrespective of susceptibility to study therapies. 
 
9.7.1.6 
Clinically Evaluable Analysis Set 
 
The CE Analysis Set will be a subset of the MITT Analysis Set and will include patients who 
meet the following specific conditions for evaluability: 
 
Received at least 80% of the intended doses of inpatient IV study drug 
 
Received at least 48 hours of inpatient IV study drug to be considered an evaluable clinical 
failure, unless deemed a clinical failure based on a treatment-limiting AE 
 
Received at least 48 hours of IV gram negative antimicrobial coverage to 
be considered an evaluable clinical cure 
 
Did not receive any amount of inpatient IV study drug from the treatment arm to which the 
patient was not randomly assigned 
 
Had clinical outcome assessment at TOC (other than indeterminate) or was assessed as a clinical 
failure at EOIV (or at any time up to TOC) 
 
Did not receive > 36 hours of any potentially effective, systemic antibacterial therapy within 72 
hours before randomization for treatment of suspected infection. Any amount of prophylactic (in 

 
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the absence of an infection) antimicrobial (eg, antibacterial, antifungal, antiviral) therapy 
administered prior to starting study therapy is allowed. 
 
9.7.1.7 
Microbiologically Evaluable Analysis Set 
 
The ME Analysis Set will include patients who meet the criteria for both the CE and mMITT 
analysis sets. 
 
9.7.2 
Patient Disposition 
 
Patient disposition (enrollment, discontinuations from inpatient IV study drug, oral or IV 
therapy, and the study) by treatment group will be provided based on the ITT Analysis Set. The 
number of patients with a TOC and/or LFU visit will be summarized. Reasons for exclusion 
from study analysis sets will be summarized for the ITT Analysis Set. 
 
The number of patients in the Safety and ITT analysis sets will be summarized by treatment 
group. 
 
Screen failures (ie, patients screened but not randomized) and the associated reasons for failure 
will be tabulated overall. 
 
The number and percentage of patients who complete the treatment period and of patients who 
prematurely discontinue during the same period will be presented for each treatment group and 
pooled across treatment groups for the ITT Analysis Set. The reasons for premature 
discontinuation from the treatment period as recorded on the termination pages of the eCRF will 
be summarized (number and percentage) by treatment group for all randomized patients. 
 
9.7.3 
Demographics and Other Baseline Characteristics 
 
Demographics (eg, age, race, gender, body mass index), medical and surgical history, description 
of the infection, markers of disease severity and co-morbidities (eg, presence of bacteremia, renal 
impairment), type of malignancy, baseline assessment of the clinical signs and symptoms, and 
microbiological assessment of the primary infection site will be summarized by treatment group 
in the MITT Analysis Set. 
 
Prior medication is defined as any medication taken before the date of the first dose of 
investigational product. Concomitant medication is defined as any medication started on or after 
the date of the first dose of investigational product. Any prior medications stopped more than 3 
days before the date of the first dose of investigational product and any concomitant medications 
started after the date of the last dose of investigational product will not be presented in the 
summary tables, but will be included in the patient data listings. Medications that are ongoing at 
the time of first dose of inpatient IV study drug will be counted both as prior and concomitant. 
 
Both prior and concomitant medication use will be summarized by the number and proportion of 
patients in each treatment group receiving each medication within each therapeutic class for the 
Safety Analysis Set. Multiple administrations of the same medication to a patient will be counted 
only once for the given patient. Medication-related summaries will be presented separately by 
“systemic antimicrobial medications” and “other medications not in this class” subgroups. 
 

 
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9.7.4 
Extent of Exposure and Treatment Compliance 
 
 
9.7.4.1 
Extent of Exposure 
 
Exposure to inpatient IV study drug, oral and IV switch therapy will be summarized by 
treatment group for the Safety Analysis Set. Calendar days of exposure of inpatient IV only, 
oral or IV switch only, and overall (inpatient IV plus oral or IV switch) will be calculated as 
the number of calendar days on inpatient IV study drug/oral or IV switch therapy (ie the 
difference between the last dose of specified inpatient IV study drug/oral or IV switch therapy 
and the first dose of specified inpatient IV study drug/oral or IV switch therapy date and time 
converted to days + 1 day). For each type of exposure both descriptive statistics (number of 
patients, mean, SD, median, minimum, and maximum) and a frequency tabulation of days of 
specified study drug treatment by classes < 3 days, 3-5 days, 6-8 days, 9-14 days, and > 14 
days and oral therapy by classes < 3, 3, 4, 5 and > 5 days will be presented. 
 
The number and percentage of patients who switch to oral or IV therapy will be presented. 
Among this subset of patients, the number and percentage of patients receiving each specific 
protocol-approved oral or IV therapy will be summarized. Descriptive statistics will be provided 
for either the study day of switch to oral or IV therapy, as well as calendar days of oral or IV 
therapy (calculated as the date of last dose of the oral or IV therapy – date of the first dose of the 
oral or IV therapy + 1 day). 
 
 
Measurement of Treatment Compliance 
 
Each patient’s compliance with study therapy (inpatient IV or oral or IV switch) will be 
calculated based on the number of doses of study drug the patient would have been expected to 
receive based on the number of treatment days, the specific dosing regimen indicated for the 
given treatment, and the start and stop date and times of the first and last dose of each specific 
study therapy. Treatment compliance is defined as the number of doses actually received divided 
by the number of doses expected (× 100) over the time period of first dosing date and time to last 
dosing date and time. 
 
Three types of study therapy compliance will be calculated: IV study therapy compliance, all 
study therapies (both IV and oral) compliance, and, in the subgroup of patients who switch to 
oral or IV therapy, oral or IV therapy compliance. For each compliance measure, descriptive 
statistics (number of patients, mean, SD, minimum, median, and maximum value) and the 
number and percentage of patients whose compliance is < 80% versus ≥ 80% will be presented 
by treatment group for the Safety and MITT analysis sets. 

 
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9.7.5 
Efficacy Analyses 
 
The primary efficacy analysis will be based on the MITT analysis set at EOIV. The secondary 
efficacy analyses will be based on MITT, mMITT CE, and ME analysis sets at different time 
points (EOIV, TOC, and LFU). The clinical outcomes definitions with their time points are 
described on section 9.7.5.3. The baseline time point for the efficacy analyses is defined as the 
last measurement collected just before the first dose of inpatient IV study drug.  
The goal of the primary objective of the study is to show that the efficacy of Imipenem-
Cilastatin-Relebactam plus/minus vancomycin, daptomycin or linezolid is non-inferior to the 
standard of care (SOC) plus/minus vancomycin, daptomycin or linezolid as empiric therapy in 
febrile neutropenic adults with cancer with respect to favorable clinical response.  
 
 
The non-inferiority margin of efficacy is 10%. The rate of favorable clinical response will be 
estimated for each arm and the rate difference (treatment arm – control arm) and its two-sided 
95% confidence interval will be calculated. Non-inferiority of Imipenem-Cilastatin-Relebactam 
to the SOC will be declared if the lower confidence interval limit is greater than -10%.  
 
For each secondary efficacy parameter listed below (Sections: 9.7.5.1 and 9.7.5.2), a 2-sided  chi 
square tests or Fisher’s exact tests will be used to compare the two treatments. When appropriate, 
logistic model will be used to assess the relationship between the efficacy parameter and treatment, 
while adjusting for other factors.  
 
9.7.5.1 Primary Efficacy Parameter 
The primary efficacy parameter is the proportion of patients in the MITT Analysis Set with 
favorable clinical response at EOIV in accordance with Section 9.7.5.3 
 
9.7.5.2 Secondary Efficacy Parameters 
 
• The proportion of patients in the mMITT and CE analysis sets with favorable clinical 
response at EOIV 
 
• The proportion of patients in the MITT Analysis Set with favorable clinical response at 
TOC and LFU 
 
• The proportion of patients in the mMITT and CE analysis sets with favorable clinical 
response by baseline Gram-negative pathogen at EOIV, TOC, and LFU 
 
• The proportion of patients in the mMITT and ME analysis sets with a favorable 
microbiological response by baseline Gram-negative pathogen at EOIV, TOC, and LFU. 
A favorable microbiological response is defined as eradication or presumed eradication of 
the infecting pathogen among patients with microbiologically document infections 
 
• The proportion of patients in the MITT and mMITT analysis sets with infection-related 
mortality at TOC and LFU 
 
• The proportion of patients in the MITT and mMITT analysis sets with 30-day all-cause 
mortality 
 

 
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9.7.5.3 Clinical Outcome Definitions 
 
The definitions of Investigator-determined clinical outcome, by time point, are shown in 
Table 9.7.5.3–1. 
 
Successful antimicrobial stewardship (AS) outcome is considered to occur if ≥ 50% of the 
patients enrolled achieve clinical cure at TOC (as per table 9.7.5.3-1) with switch of the study 
drug or SOC to oral or simplified streamline IV therapy by 72 hours.  
 
Table 9.7.5.3–1. Clinical Outcome Definitions 
 
Applicable Time 
Point 
Outcome 
Definition 
EOIV 
Favorable clinical 
response 
Resolution of all acute signs and symptoms of the primary infection 
(primarily fever) or improvement to such an extent that no additional 
antibacterial therapy is required (ie, except for protocol-allowed 
adjunctive therapies and/or oral or IV switch) and such that no more 
than 14 days of total IV antibacterial therapy is required unless 
indicated for a complicated infection. 
TOCa 
Clinical cureb 
Sustained resolution of all acute signs and symptoms of the primary 
infection or continued improvement to such an extent that no further IV 
antibacterial therapy is required for the original episode. Another 
episode of neutropenic fever during the follow-up period will not be 
considered to be a failure unless the patient present for a relapse of 
the same documented infection that was present at baseline. 
LFUa 
Clinical cureb 
Sustained resolution of all acute signs and symptoms (or of symptoms 
only if LFU visit is conducted by telephone) of the primary infection 
or continued improvement to such an extent that no further IV 
antibacterial therapy is required for the original episode. Another 
episode of neutropenic fever during the follow-up period will not be 
considered to be a failure unless the patient present for a relapse of 
the same documented infection that was present at baseline.  

 
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EOIVa 
TOCa 
LFUa 
Clinical failure 
Patients who meet any of the following: 
• 
Has persistent fever (ie, a single oral temperature measurement of 
> 38.0°C [100.4°F]) 96 hours after the initiation of study drug. 
(NOTE: if the febrile neutropenia is documented to be caused by 
an invasive fungal or viral infection at any time during the study, 
the patient should be considered to have an indeterminate 
outcome for all clinical outcome assessments) 
• 
Has documented breakthrough gram negative bacteremia (ie, 
recurrence of bacteremia that resolved or occurrence of new 
bacteremia with gram negative organisms not present at 
baseline while the patient is receiving IV study drug) 
• 
Has a documented pathogen that is resistant to any study therapy 
received and requires alternative nonstudy antimicrobial therapy 
• 
Discontinuation of study therapy(ies) due to insufficient 
therapeutic effect including persistence, incomplete clinical 
resolution, or worsening in signs and symptoms of primary 
documented infection that requires alternative nonstudy 
antimicrobial  
therapy (Investigator is encouraged to continue study 
therapy[ies] for at least 48 hours before such a patient is 
considered a clinical failure and is prematurely discontinued from 
study therapy[ies].) 
• 
Developed shock, acute respiratory distress syndrome, 
disseminated intravascular coagulation, or multiorgan failure 
related to the primary infection 
• 
Discontinuation of study drug therapy(ies) due to an AE and 
requirement for alternative nonstudy antimicrobial therapy for 
the primary infection 

 
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Table 9.7.5.3–1. Clinical Outcome Definitions 
 
Applicable Time 
Point 
Outcome 
Definition 
• 
Died as a result of the primary infection 
 
EOIVa 
TOCa 
LFUa 
Indeterminate 
• 
Patients who developed a documented invasive fungal infection or 
a documented viral infection at any time during the study (Note: 
the documented fungal or viral infection must be the cause of the 
study qualifying episode of febrile neutropenia) 
• 
Study data are not available for evaluation of efficacy for any 
reason, including: 
o 
Death in which febrile neutropenia is clearly 
noncontributory 
o 
Lost to follow-up 
o 
Extenuating circumstances precluding classification as a 
clinical cure or clinical failure 
• 
Subjects withdrawn from the study not assessed as a clinical 
failure should be assessed as indeterminate at all subsequent 
outcome evaluation time points as noted in Section 9.3.3.3 
a 
A clinical failure at EOIV will be carried forward to TOC. A clinical failure at TOC will be carried forward 
to LFU. TOC evaluations include events between EOIV and TOC (including events through the end of 
oral or IV switch therapy, if applicable). LFU evaluations include events between TOC and LFU.  No 
scheduled assessment is performed at end of oral or IV switch therapy. 
b 
Favorable outcome at TOC or LFU. 
AE = adverse event; EOIV = End of Inpatient Intravenous Therapy; LFU = Late Follow-up; TOC = Test-of-
Cure. 
 
Perform EOIV assessments within 72 hours after administration of the last dose of inpatient IV study drug (Day 1-14).  
Perform TOC assessments between Study Days 21 and 28. 
Perform LFU assessments between Study Days 35 and 42.  
 
 
9.7.5.4 
Microbiological Response Definitions 
 
The timing and definitions of per-pathogen microbiological response are shown in 
Table 9.7.5.4–1. Per-patient microbiological response will be determined programmatically 
based on individual outcomes for each baseline pathogen. For a patient to have a favorable 
microbiological response, the outcome for each baseline pathogen must be favorable (eradicated 
or presumed eradicated). If the outcome for any pathogen is unfavorable (persistence or 
presumed persistence), the patient will be considered to have an unfavorable microbiological 
response. 
 
 

 
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Table 9.7.5.4–1. Microbiological Response Definitions 
 
Applicable 
Time Point 
Microbiological Response 
Definition 
EOIV 
TOC 
LFU 
Eradicationa 
Source specimen demonstrates absence of the original 
baseline pathogen 
EOIV 
TOC 
LFU 
Presumed eradicationa 
Source specimen was not available to culture and the 
patient was assessed as a clinical cure 
EOIV 
TOC 
LFU 
Persistence 
Source specimen demonstrates continued presence of 
the original baseline pathogen 
EOIV 
TOC 
LFU 
Presumed persistence 
Source specimen was not available to culture and the 
patient was assessed as a clinical failure 
EOIV 
TOC 
LFU 
Indeterminate 
Source specimen was not available to culture and the 
patient’s clinical response was assessed as 
indeterminate 
a 
Favorable outcome. 
EOIV = End of Inpatient Intravenous Therapy; LFU = Late Follow-up; TOC = Test-of-Cure. 
 
9.7.5.5 Emergent Infections 
 
Organisms or pathogens first appearing after baseline (emergent infections) are defined in 
 
Table 9.7.5.5–1 and will be summarized separately. 
 
 
 
Table 9.7.5.5–1. Emergent Infections 
 
Infection Category 
Definition 
Colonization 
Isolation of a new organism(s) different than any isolated at baseline from the site 
of infection in a patient who is assessed as a clinical cure 
Superinfection 
Isolation of a new pathogen(s) different than any isolated at baseline from the site 
of infection during treatment with study drug therapy, which is associated with 
emergence or worsening of signs and symptoms of infection 
New infection 
Isolation of a new pathogen(s) different than any isolated at baseline from the site 
of infection after completion of all study drug therapy, which is associated with 
emergence or worsening of signs and symptoms of infection 
 
 
Safety Analyses 
 
For the primary safety and tolerability objective, the incidence of TEAEs, SAEs, deaths, and 
discontinuations due to AEs will be summarized by treatment group, system organ class and 
preferred term according to the Medical Dictionary for Regulatory Activities, type, frequency, 
relationship to study therapy, and severity. Safety summaries will be presented using the Safety 

 
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Analysis Set, according to the treatment actually received. For each safety parameter, the last 
assessment made before the first dose of inpatient IV study drug will be used as the baseline for 
all analyses.  Descriptive statistics of observed results and the change from baseline will be 
presented for clinical laboratory results and vital signs. The incidence of potentially clinically 
significant (PCS) laboratory results will be summarized. A list of all TEAEs/SAEs that resulted 
in deaths will also be generated. The changes in clinical laboratory parameters and vital sign 
parameters in the Safety Analysis Set at each study visit that assessments will be performed.  
 
. 
 
 
 
9.7.6.1 Adverse Events 
 
An AE (classified by preferred term) that occurs during the treatment period will be considered a 
TEAE if it was not present before the date of the first dose of investigational product or was 
present before the date of the first dose of investigational product and increased in severity 
during the treatment period. If more than 1 AE is reported before the date of the first dose of 
investigational product and coded to the same preferred term, the AE with the greatest severity 
will be used as the benchmark for comparison with the AEs occurring during the treatment 
period that were also coded to that preferred term. An AE that occurs more than 30 days after the 
date of the last dose of investigational product will not be counted as a TEAE. 
 
The number and percentage of patients reporting TEAEs in each treatment group will be 
tabulated by system organ class and preferred term; by system organ class, preferred term, and 
severity; and by system organ class, preferred term, and causal relationship to the investigational 
product. If more than 1 AE is coded to the same preferred term for the same patient, the patient 
will be counted only once for that preferred term using the most severe and most related 
occurrence for the summarization by severity and by causal relationship to the investigational 
product. 
 
The distribution of TEAEs by severity and causal relationship to the investigational product will 
be summarized by treatment group. 
 
The incidence of common (eg, ≥ 2% of patients in any treatment group) TEAEs, on-therapy 
SAEs, and AEs leading to premature discontinuation of the investigational product will be 
summarized by preferred term and treatment group and will be sorted by decreasing frequency 
for the test treatment. In addition, the incidence of fatal on-therapy SAEs (ie, events that caused 
death) will be summarized separately by treatment group and preferred term. An SAE will be 
defined as an on-therapy SAE if it occurred on or after the date of the first dose of double-blind 
investigational product and within 30 days of the date of the last dose of investigational product. 
 
Listings will be presented for patients with SAEs, patients with AEs leading to discontinuation, 
and patients who die (if any). 
 
 
 
9.7.6.2 
Clinical Laboratory Parameters 
 
Descriptive statistics for clinical laboratory values (in SI units) and changes from the baseline 

 
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values at each assessment time point will be presented by treatment group for each clinical 
laboratory parameter. 
 
The number and percentage of patients with PCS post baseline clinical laboratory values will be 
tabulated by treatment group. The criteria for PCS laboratory values will be detailed in the 
statistical analysis plan. The percentages will be calculated relative to the number of patients with 
available non-PCS baseline values and at least 1 post baseline assessment. The numerator will be 
the total number of patients with available non-PCS baseline values and at least 1 PCS post 
baseline value. A supportive listing of patients with PCS post baseline values will be provided, 
including the PID number, and baseline and post baseline values. A listing of all AEs that occur 
in patients who have PCS laboratory values will also be provided. 
 
 
 
9.7.6.3 
Vital Signs 
 
Descriptive statistics for vital signs (ie, systolic and diastolic blood pressure, pulse rate, 
respiratory rate, oxygen saturation [if applicable], temperature) and changes from baseline values 
at each visit and at end of study will be presented by treatment group. 
 
Vital sign values will be PCS if they meet both the observed-value criteria and the change from 
baseline–value criteria detailed in the statistical analysis plan. The percentages will be calculated 
relative to the number of patients with baseline values and at least one postbaseline assessment. 
The numerator will be the total number of patients with available baseline values and at least one 
PCS postbaseline value. A supportive listing of patients with PCS postbaseline values will be 
provided, including the PID number, and baseline and postbaseline values. A listing of all AEs 
that occur in patients who have PCS vital sign values will also be provided. 
 
 
9.7.6.4 
Chest Radiography 
 
Readings of the baseline chest radiographs including the presence of pleural effusion, whether 
the pleural effusion was unilateral or bilateral, and whether the pulmonary infiltrate was uni- or 
multi-lobar and/or cavitated will be summarized by treatment group for the MITT Analysis Set. 
 
 
 
 
9.7.6.5 
Toxicity Stopping Monitoring Rule 
 
We monitor toxicity using the Bayesian optimal phase 2 (BOP2) design (Zhou, Lee and Yuan, 
2017)34. Toxicities used for this monitoring rule consist of severe (Grade ≥3) drug related 
adverse events leading to the discontinuation of the study drug. Toxicity monitoring will be 
carried out independently for the two arms,  in cohort size of 10. Specifically, let 𝑛 denote the 
interim sample size and 𝑁 denote the maximum sample size. Let 𝑝𝑡𝑜𝑥 denote the probability of 
toxicity and define the null hypothesis 𝐻0: 𝑝𝑡𝑜𝑥> 0.35, under which the treatment is deemed 
as unacceptable. Thus, we will stop enrolling patients and inspect the safety data for possible 
trial termination if 

 
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𝑃𝑟(𝑝𝑡𝑜𝑥≤0.35|𝑑𝑎𝑡𝑎) < 𝜆(𝑛
𝑁)
𝛼
, 
where 𝜆=0.86 and 𝛼=0.62 are design parameters optimized to maximize the probability of 
correctly concluding that a safe treatment is acceptable under the alternative hypothesis 
𝐻1: 𝑝𝑡𝑜𝑥= 0.2, while controlling the type I error rate (i.e., the probability of incorrectly 
concluding that an overly toxic treatment is acceptable) at 0.1. This optimization is performed 
assuming a vague prior Beta(0.35,0.65) for 𝑝𝑡𝑜𝑥. The above decision rule leads to the following 
optimal stopping boundaries: 
Table 9.7.6.5–1.  Optimized stopping boundaries 
# patients treated Stop if # toxicity >= 
10 
5 
20 
8 
30 
10 
40 
13 
50 
14 
 
Based on Table 9.7.6.5–1, we perform the interim analysis when the number of enrolled patients 
reaches 10, 20, 30, 40. When the total number of patients reaches the maximum sample size of 
50, we reject the null hypothesis and conclude that the treatment is acceptable if the number of 
toxicities are less than 14; otherwise we conclude that the treatment is unacceptable. 
 
Below are the operating characteristics of the design using the BOP2 web application, which is 
available at http://www.trialdesign.org. 
Table 9.7.6.5–2.   Operating characteristics 
Toxicity rate Early stopping (%) Claim acceptable (%) Sample size 
0.1 
0.22 
99.76 
49.9 
0.2 
9.75 
85.12 
47.3 
0.3 
52.57 
29.36 
36.0 
0.4 
90.64 
2.40 
22.6 
0.5 
99.44 
0.04 
15.2 
The Investigator is responsible for completing an efficacy/safety summary report and submitting 
it to the IND office Medical Affairs and Safety Group, for review and approval.   
 
This should be submitted after the first 10 evaluable patients per arm, complete in-patient 
intravenous therapy, and every 10 evaluable patients per arm, thereafter.  
 
A copy of the cohort summary should be placed in the Investigator’s Regulatory Binder under 
“funder correspondence”. 
 
 

 
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9.7.6.6 
Pregnancy Related Risk 
 
Birth Control Specifications: If you can become pregnant or father a child, you must use 2 forms of 
birth control. Acceptable forms of birth control include either 2 barrier methods (like a condom or 
diaphragm with spermicide) or 1 barrier method plus a hormonal method (such as birth control 
pills/injections/patches). 
 
Males: Tell the doctor right away if your partner becomes pregnant or suspects pregnancy while on 
study or within 28 days after your last dose of study drugs. If your partner/spouse becomes pregnant 
while you are on this study, the sponsor would like to collect information about the pregnancy. The 
study sponsor's contact information will be made available so that, if you and your partner wish to, 
you can share information about the outcome of the pregnancy with the sponsor. If you and/or your 
partner choose not to share this information, it will not result in any penalty or loss of benefits to 
which you are otherwise entitled. 
 
 
9.7.7 
Antimicrobial Stewardship and Outcomes Research 
Analyses 
 
Successful antimicrobial stewardship (AS) outcome is considered to occur if ≥ 50% of the 
patients enrolled achieve clinical cure at TOC (as per table 9.7.5.3-1) with switch of the study 
drug or SOC to oral or simplified streamline IV therapy by 72 hours.  
 
9.7.8 
Interim Analysis 
 
No futility interim analysis is planned for this study as Imipenem-Cilastatin-Relebactam has FDA 
approval for the treatment of HABP/VABP, and also approved for cUTI and cIAI, and Imipenem 
has over 35 years of clinical use and proven efficacy. Safety interim analysis is provided in 
Section 9.7.6.5. 
 
 
9.7.9 
Determination of Sample Size 
 
The primary objective of the study is determine the efficacy of Imipenem-Cilastatin-Relebactam 
plus/minus vancomycin, daptomycin or linezolid is non-inferior to the standard of care (SOC) 
plus/minus vancomycin, daptomycin or linezolid as empiric therapy in febrile neutropenic adults 
with cancer with respect to favorable clinical response.  The historical favorable clinical response 
for the SOC is approximately 65%. We expect that the favorable clinical response of Imipenem-
Cilastatin-Relebactam plus/minus vancomycin, daptomycin or linezolid is 80%. Given the non-
inferiority margin of 10% (i.e., if the favorable clinical response of Imipenem-Cilastatin-
Relebactam is >55%, it is deemed non-inferior to the SOC), the sample size of 50 patients per 
arm will have 80% power to establish the non-inferiority. This power calculation was performed 
using East with null response rate of 0.55, alternative response rate of 0.8, one-sided chi-squared 
test at significance level of 0.05. 
 
 
 
9.7.10 
Computer Methods 
 
Statistical analyses will be performed using SAS version 9.3. 

 
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9.8 
CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES 
 
No protocol amendment may be implemented (with the exceptions noted below) before it has 
been approved by the IRB. If the protocol is amended to eliminate or reduce the risk to patients, 
the amendment may be implemented before IRB review and approval. However, the IRB must be 
informed in writing of such an amendment, and approval must be obtained within reasonable 
time limits. 
 
 
9.9 
PROTOCOL DEVIATIONS 
 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
that is under the Investigator’s responsibility and oversight (as defined by regulations) without 
prior written IRB approval or favorable opinion of an appropriate amendment and that does not 
have a major impact on the patient’s rights, safety, or well-being, or on the integrity and 
authenticity of the study data. Deviations may include, but are not limited to, departure from 
inclusion/exclusion criteria, allowed concomitant medications, dosing or duration of treatment, 
failure to follow withdrawal criteria or perform the required assessments at specified time points, 
and scheduling of visits not in accordance with specifications. 
 
Deviating from the protocol is permitted only if absolutely necessary for the safety or clinical 
management of the patients.   
 
The IRB must be notified according to the criteria and time period dictated by the IRB associated 
with this study. 
 
 
10.0 
STUDY FUNDERSHIP 
 
MD Anderson Cancer Center IND office (Study Funder); Merck, Inc. (Supporting Company)   
 
10.1 
STUDY TERMINATION 
 
Merck, Inc. reserves the right to terminate the study in its entirety before study completion. 
 
 
10.2 
REPORTING AND PUBLICATION 
 
An integrated clinical and statistical report will be prepared at the completion of the study. 
Publication of the results by the Investigator will be subject to mutual agreement between 
the Investigator and Merck Institute, Inc., and will follow the current Applicable SOP on 
publications 
 
11.0 
INVESTIGATOR OBLIGATIONS 
 
 
11.1 
DOCUMENTATION 
 
The Investigator must maintain the following during the study: 

 
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A copy of the original IRB approval for conducting the study. If the study is ongoing, renewals 
must be submitted at yearly intervals. All subsequent modifications must be submitted and 
approved by the IRB, as stated in Section 5.1 
 
A copy of the IRB-approved ICF 
 
 
11.2 
USE OF INVESTIGATIONAL MATERIALS 
 
The Investigator will acknowledge that the investigational product supplies are investigational 
and as such must be used strictly in accordance with the protocol and only under the supervision 
of the Investigator or Sub-Investigators listed on Form FDA 1572. The investigational products 
must be stored in a secured place and must be locked. The MDA standard operating procedures 
for drug accountability will be followed. All unused investigational products will be destroyed 
according to the standard operating procedures at MD Anderson. It is the Investigator’s 
responsibility to ensure that patients return their investigational product. 
 
 
11.3 
CASE REPORT FORMS 
 
All patient data relating to the study will be recorded on REDCap. The Investigator is responsible 
for verifying that all data entries in the REDCap are accurate and correct. The Investigator must 
maintain and retain accurate documentation that supports the information entered for source 
document verification and possible regulatory inspection. 
 
 
11.4 
RETENTION AND REVIEW OF RECORDS 
 
Records and documents pertaining to the conduct of this study, including case report forms, 
source documents, consent forms, regulatory documents, clinical laboratory results, calibration 
logs, or reports (including, but not limited to, all local and central laboratory results and 
electrocardiogram reports), and medication inventory records in all formats (including, but not 
limited to, written, electronic, magnetic, and optical records, and scans, x-rays, and 
electrocardiograms) must be retained by the Investigator according to institutional policies.  
 
The Investigator must permit access to any documentation relating to the study upon request of 
the Funder or applicable regulatory authorities. If the Investigator for the study retires, relocates, 
or for other reasons withdraws from the responsibility of keeping the study records, custody must 
be transferred to a suitable alternate custodian employee of the institution or to a suitably 
qualified and responsible third party.  
 
11.5 
PATIENT CONFIDENTIALITY 
 
All patient records will only be identified by initials and accession number.  
 
 
12.0 
APPENDICES 
 
APPENDIX I. 
ELEMENTS OF INFORMED CONSENT 

 
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Procedures will comply with 21 CFR, Parts 50 and 312. Signed informed consent will be 
obtained from each patient participating in a clinical research study or from the patient’s legally 
authorized representative. This consent must include the following items: 
 
• A statement that the study involves research and an explanation of the purposes of the research; a 
description of the procedures to be followed and the identification of any procedures that are 
experimental; and the expected duration of the patient’s participation 
 
• A description of any reasonably foreseeable risks or discomforts to the patient 
 
• A description of any benefits to the patient or to others that may reasonably be expected from the 
research. If the patient is to be paid for participating in the study, the consent form must state the 
amount that he/she will receive and the schedule of payment (to ensure neither coercion nor 
undue influence) 
 
• A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the patient 
 
• A statement describing the extent, if any, to which confidentiality of records identifying the 
patient will be maintained and noting the possibility that the FDA; Merck, Inc.; the IRB; or an 
authorized contract research organization may inspect the records 
 
• For research involving more than minimal risk, an explanation of whether any medical treatment 
is available if injury occurs and, if so, what it consists of or where further information may be 
obtained 
 
• An explanation of whom to contact, including the relevant telephone number, for answers to 
pertinent questions about the research and the research patient’s rights and whom to contact in 
the event of a research-related injury to the patient. (Note: In some cases, it may be necessary to 
identify a person other than the Investigator as the contact. The guidance of the IRB may be 
required) 
 
• A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the patient is otherwise entitled, and that the patient may discontinue 
participation at any time without penalty or loss of benefits to which the patient is otherwise 
entitled.

 
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• A statement that the particular treatment or procedures may involve risks to the patient (or to the 
embryo or fetus if the patient is, or may become, pregnant) that are at present unforeseeable 
 
• The expected circumstances for which the patient’s participation may be terminated by the 
Investigator without regard to the patient’s consent 
 
• Any additional costs to the patient that may result from participation in the research 
 
• The consequences of a patient’s decision to withdraw from the research and procedures for an 
orderly termination of the patient’s participation 
 
• A statement that significant new findings developed during the course of the research that may 
relate to the patient’s willingness to continue participation will be provided to the patient 
 
• The approximate number of patients involved in the study 
 
• A statement of consent (eg, “I agree to participate . . .”) 
 
• A place for the patient’s signature and date of signing 
 
• A statement indicating that information about this study has been, or will be, entered into a 
databank that is publicly accessible at www.ClinicalTrials.gov. 
 
• A copy of the signed consent form must be given to the patient. All participants will be registered 
in the Clinical Oncology Research System (CORe). 
 
 
 
 
 
 
 
 
 

 
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APPENDIX II. 
MD ANDERSON NEUTROPENIC FEVER INPATIENT ADULT TREATMENT GUIDELINES 

 
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APPENDIX III. 
MD ANDERSON PNEUMONIA IN ADULT PATIENTS WITH CANCER TREATMENT 
GUIDELINES 
 
 

 
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APPENDIX IV. 
POTENTIAL DRUG-INDUCED LIVER INJURY/HY’S 
LAW 
 
IDENTIFICATION 
 
The Investigator is responsible for determining whether a patient meets the following potential 
Hy’s law (PHL) criteria at any point after initiation of study therapy (IV or oral). For a PHL case 
to meet Hy’s Law, the increases from baseline in AST or ALT and 
total bilirubin values, in the Investigator’s clinical judgment, should be temporally related to one 
another and to the administration of study drug, without an alternative explanation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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PHL 
 
AST or ALT ≥ 3 × ULN; total bilirubin ≥ 2 × ULN and ALP < 2 × ULN 
 
If there are increases from baseline in AST or ALT ≥ 3 × ULN  and total bilirubin ≥ 2 × ULN: 
 
• The Investigator must follow the instructions in this appendix 
 
• The investigative site must complete the appropriate screen(s) of the eCRF with the local 
laboratory test results 
 
 
FOLLOW-UP AND REPORTING 
 
If the Investigator determines that the patient has not met PHL criteria (has not had increases 
from baseline in AST or ALT ≥ 3 × ULN and total bilirubin ≥ 2 × ULN and ALP < 2 × ULN, at 
any point after initiation of study drug), the Investigator is to perform follow-up on subsequent 
laboratory results as required for patient care and per protocol Section 9.5.2.9.2. 
 
If the Investigator determines that the patient has met PHL criteria (has had AST or ALT ≥ 3 × 
ULN and total bilirubin ≥ 2 × ULN, and ALP < 2 × ULN, elevated from baseline at any point 
after initiation of study drug): 
 
• The Investigator should review the criteria for premature discontinuation of study drug due to 
elevated liver chemistry values, per protocol Section 9.3.3 
 
• Any PHL case should be handled as an SAE associated with the use of the drug and reported as 
an SAE per protocol Section 9.5.2.5 (ie, even before all other possible causes of liver injury have 
been excluded). It should be promptly reported before doing a full workup on the patient to rule 
out other etiologies 

 
 
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• The Investigator will investigate the etiology of the event and establish if another 
explanation/alternative cause other than drug-induced liver injury caused by the study drug is 
possible. The Funder may be contacted to discuss the work-up. 
 
• The investigative site must complete the appropriate screens of the eCRF 
 
If there is an alternative explanation or the liver chemistry values increased from baseline arenot 
temporally related to one another and to the initiation of study drug, the Investigator should 
update the PHL SAE to reflect the attributed underlying illness and reassign an appropriate 
causality assessment, per protocol Sections 9.5.2.5 and 9.5.2.2, respectively. 
 
If there is no alternative explanation and the liver chemistry values increased from baseline are 
temporally related to one another and to the initiation of study drug, the Investigator should 
update the PHL SAE to a Hy’s Law case (reported term ‘Hy’s Law’) and reassign a causality 
assessment of “related.” 
 
If, despite the Investigator’s attempts to conduct follow-up and the guidance provided in this 
appendix, there is an unavoidable delay of > 3 weeks in obtaining the information necessary to 
assess whether or not the case meets the criteria for a Hy’s case, then it is assumed that there is 
no alternative explanation until such time as an informed decision can be made. 
 
 
REFERENCE 
 
US Food and Drug Administration. Guidance for Industry. Drug-induced liver injury: 
Premarketing clinical evaluation. 2009 Jul. Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ 
Guidances/UCM174090.pdf. Accessed 2014 Oct 28. 
 
 
 
 
 

 
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Table  II 
 
Trial description 
n 
Treatment regimens 
Primary outcomes 
Primary outcome 
results n/N (%) 
Secondary outcomes 
Secondary outcome results 
n/N (%) 
Phase II treatment of 
cIAI (21) 
ClinicalTrials.gov 
ID: 
NCT01506271 
351 
Imipenem/relebactam 
500/250 mg IV (t’ 30 min) 
q6 h × 4–14 days 
Imipenem/relebactam 
500/125 mg IV (t’ 30 min) 
q6 h × 4–14 days 
Imipenem 
500 mg IV (t’ 30 min) 
q6 h × 4–14 days 
Clinical responsea in 
the MEbpopulation 
at DCIV 
Relebactam 250 mg: 
78/81 (96.3) 
Relebactam 125 mg: 
85/86 (98.8) 
Imipenem alone: 
79/83 (95.2) 
Clinical responsea at EFU 
(MEb) 
Relebactam 250 mg: 75/79 (94.9) 
Relebactam 125 mg: 81/86 (94.2) 
Imipenem alone: 78/81 (96.3) 
Clinical responsea at LFU 
(MEb) 
Relebactam 250 mg: 74/79 (93.7) 
Relebactam 125 mg: 81/85 (95.3) 
Imipenem alone: 75/79 (94.9) 
Microbiologic responsec at 
DCIV (MEb) 
Relebactam 250 mg: 81/83 (97.6) 
Relebactam 125 mg: 86/86 (100) 
Imipenem alone: 82/84 (97.6) 
Global responsed at 
28 days 
after randomization 
(MITTe) 
Relebactam 250 mg: 77/89 (86.5) 
Relebactam 125 mg: 86/96 (89.6) 
Imipenem alone: 78/92 (84.8) 
Phase II treatment of 
cUTI and AP (14) 
ClinicalTrials.gov 
ID: 
NCT01505634 
302 
Imipenem/relebactam 
500/250 mg IV (t’ 30 min) 
q6 h × 4–14 days 
Imipenem/relebactam 
500/500/125 mg IV (t’ 30 min) 
q6 h × 4–14 days 
Imipenem 
500/500 mg IV (t’ 30 min) 
q6 h × 4–14 days 
Optional oral step-down after 
4 days (all regimens): 
ciprofloxacin 500 mg BID 
Microbiological 
responsec in the 
MEbpopulation at 
DCIV 
Relebactam 250 mg: 
64/67 (95.5) 
Relebactam 125 mg: 
70/71 (98.6) 
Imipenem alone: 
74/75 (98.7) 
Microbiological 
responsec at 
EFU/LFU (MEb) 
Relebactam 250 mg: (61.5/68.3) 
Relebactam 125 mg: (68.1/65.2) 
Imipenem alone: (70.4/62.5) 
Clinical responsea at 
DCIV/EFU/LFU (MEb) 
Relebactam 250 mg: 
(97.1/89.1/88.7) 
Relebactam 125 mg: 
(98.7/91.8/87.3) 
Imipenem alone: (98.8/93.4/88.2) 
Microbiological 
responsec at 
DCIV for INS infections 
(MEb) 
Relebactam 250 mg: 10/10 (100) 
Relebactam 125 mg: 7/7 (100) 
Imipenem alone: 6/6 (100) 
 

 
 
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13.0 
LITERATURE CITED 
 
 
1. 
Prevention CfDCa. Antibiotic resistance threats in the United States 2013 [Available 
from: https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf. 
2. 
Cerceo E, Deitelzweig SB, Sherman BM, Amin AN. Multidrug-Resistant Gram-Negative 
Bacterial Infections in the Hospital Setting: Overview, Implications for Clinical Practice, and 
Emerging Treatment Options. Microb Drug Resist. 2016;22(5):412-31. 
3. 
Patel TS, Nagel JL. Clinical outcomes of Enterobacteriaceae infections stratified by 
carbapenem MICs. J Clin Microbiol. 2015;53(1):201-5. 
4. 
Pendleton JN, Gorman SP, Gilmore BF. Clinical relevance of the ESKAPE pathogens. 
Expert Rev Anti Infect Ther. 2013;11(3):297-308. 
5. 
Rottier WC, Ammerlaan HS, Bonten MJ. Effects of confounders and intermediates on the 
association of bacteraemia caused by extended-spectrum beta-lactamase-producing 
Enterobacteriaceae and patient outcome: a meta-analysis. J Antimicrob Chemother. 
2012;67(6):1311-20. 
6. 
American Thoracic S, Infectious Diseases Society of A. Guidelines for the management 
of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am 
J Respir Crit Care Med. 2005;171(4):388-416. 
7. 
Livermore DM, Warner M, Mushtaq S. Activity of MK-7655 combined with imipenem 
against Enterobacteriaceae and Pseudomonas aeruginosa. J Antimicrob Chemother. 
2013;68(10):2286-90. 
8. 
Organization WH. Global priority list of antibiotic-resistant bacteria to guide research, 
discovery, and development of new antibiotics 2017 [Available from: 
https://www.who.int/medicines/publications/global-priority-list-antibiotic-resistant-bacteria/en/. 
9. 
Rizk ML, Rhee EG, Jumes PA, Gotfried MH, Zhao T, Mangin E, et al. Intrapulmonary 
Pharmacokinetics of Relebactam, a Novel beta-Lactamase Inhibitor, Dosed in Combination with 
Imipenem-Cilastatin in Healthy Subjects. Antimicrob Agents Chemother. 2018;62(3). 
10. 
Rizk ML JP, Lasseter K, et al, editor Pharmacokinetics of MK-7655, a novel b-lactamase 
inhibitor (BLI), in combination with imipenem/cilastatin (IPM/CIL) in subjects with impaired 
renal function. 52nd Interscience Conference on 
Antimicrobial Agents and Chemotherapy (ICAAC); 2012; San Francisco, CA. 
11. 
Centers for Disease C, Prevention. Vital signs: carbapenem-resistant Enterobacteriaceae. 
MMWR Morb Mortal Wkly Rep. 2013;62(9):165-70. 
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