Clinical trial NCT03485950
Conditions: Other Infectious Diseases
Keywords: Other infectious diseases Febrile neutropenic adults with cancer Ceftolozane-Tazobactam Cefepime Meropenem Piperacillin/Tazobactam
Sponsor: M.D. Anderson Cancer Center
Start date: 2018-05-16; Completion date: 2022-02-16
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical research study is to learn if the study drug ceftolozane-tazobactam is more effective in controlling febrile neutropenia (fever and low white blood cell counts) than using approved antibiotics in patients with cancer. The safety of ceftolozane-tazobactam will also be studied.

This is an investigational study. Ceftolozane-tazobactam is FDA approved and commercially available to treat certain types of infections. It is not approved for the treatment of febrile neutropenia, either by itself or in combination with other antibiotics. Its use to treat febrile neutropenia is investigational.

All other antibiotics given on this study are FDA approved and commercially available for the treatment of infections. However, only cefepime is specifically FDA approved to treat febrile neutropenia. The study doctor can explain how the study drugs are designed to work.

Up to 100 participants will take part in this study. All will be enrolled at MD Anderson.

Detailed description:
Study Groups and Study Drug Administration:

If participant is found to be eligible to take part in this study and participant agrees, participant will be randomly assigned (as in the flip of a coin) to either receive either the study drug (Group 1) or a standard treatment antibiotic (Group 2). This is done because no one knows if one study group is better, the same, or worse than the other group. Both participant and the study doctor will know what participant is receiving.

If participant is in Group 1, participant will receive ceftolozane-tazobactam by vein over 1 hour every 8 hours.

If participant is in Group 2, participant will receive a standard treatment antibiotic. This may include one of the following 3 options:

cefepime by vein over about 30 minutes every 8 hours. meropenem by vein over about 30 minutes every 8 hours. piperacillin/tazobactam by vein over about 1 hour every 6 hours.

Participant will receive the study drugs by vein for at least 3 days. After 3 days, if the study doctor thinks it is in participant's best interest and participant is eligible, participant may switch to receiving a different antibiotic either by mouth or by vein. The study doctor will tell participant more about what antibiotic participant may begin to receive, how it is administered, and its possible risks. If participant begins taking the study drugs by mouth, the study doctor or study staff will tell participant how and when to take each drug.

If the doctor thinks it is needed, participant will be given additional standard drugs to help control the infection. Participant may ask the study staff for information about how the drugs are given and their risks.

Length of Study:

Participant may receive the study drugs for up to 14 days. Participant will no longer be able to receive the study drugs if the disease gets worse, if intolerable side effects occur, if participant needs treatment that is not allowed on this study, or if participant is unable to follow study directions.

Participation on this study will be over after the late follow-up visit.

Study Visits:

Participant will have the following tests/procedures while participant is in the hospital. If participant begins to take the study drugs by mouth, participant will no longer have these study visits.

Each day for up to 2 weeks, if the doctor thinks it is needed, blood (about 1 tablespoon) or urine will be collected for routine tests.

Every 2 days for up to 2 weeks, blood (about 1 tablespoon) will be drawn to check for infection. Participant will stop having these blood draws when there is no longer a sign of infection and participant does not have a fever.

Twice each week for up to 2 weeks, participant will have a physical exam.

Follow-Up:

Within 72 hours (3 days) after participant's last dose of participant's assigned study treatment and before starting the second antibiotic therapy (if applicable):

Participant will have a physical exam. Blood (about 1 tablespoon) and urine will be collected for routine tests. If participant tested positive for infection at the beginning of the study, blood (about 1 tablespoon) will be drawn to check for infection. The study doctor will tell participant if participant will have this blood draw.

About 21-28 days (3-4 weeks) after participant's first dose of study drug, participant will return to MD Anderson for the following tests/procedures:

Participant will have a physical exam. If participant tested positive for infection at the beginning of the study, blood (about 1 tablespoon) will be drawn to check for infection. The study doctor will tell participant if participant will have this blood draw.

If participant can become pregnant, blood (about 1 teaspoon) will be drawn for a pregnancy test.

About 35-42 days (5-6 weeks) after participant's first dose of study drug, a member of the study staff will call participant to ask about any new drugs participant may have started and if participant is having any side effects. If participant is called, it should last about 10 minutes. If the doctor or study staff thinks it is needed, participant will be asked to come back to the clinic for the following tests/procedures:

Participant will have a physical exam. If the doctor thinks it is needed, blood (about 1 tablespoon) will be drawn to check for infection.

At any of these follow-up visits, if participant's doctor thinks it is needed, participant will have a chest x-ray or CT scan to check participant's lungs.

Arms: arm 1: Participants receive ceftolozane-tazobactam IV over 1 hour every 8 hours for up to 14 days in the absence of disease progression or unacceptable toxicity. After at least 3 days, participants may switch to different PO or IV antibiotics at the discretion of the study doctor. arm 2: Participants receive standard of care antibiotic treatment consisting of either cefepime IV over 30 minutes every 8 hours, meropenem IV over 30 minutes every 8 hours, or piperacillin-tazobactam IV over 1 hour every 6 hours for up to 14 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Cefepime intervention 2: Ceftolozane intervention 3: Laboratory Biomarker Analysis intervention 4: Meropenem intervention 5: Piperacillin-Tazobactam intervention 6: Tazobactam
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Correlative studies intervention 4: Given IV intervention 5: Given IV intervention 6: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
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MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2017‐0729 
Protocol Title 
AN INVESTIGATOR INITIATED, PHASE II SINGLE‐CENTER, RANDOMIZED, 
OPEN‐LABEL, PROSPECTIVE, COMPARATIVE STUDY TO DETERMINE THE 
EFFICACY, SAFETY, AND TOLERABILITY OF CEFTOLOZANE‐TAZOBACTAM 
PLUS VANCOMYCIN, LINEZOLID VERSUS STANDARD OF CARE PLUS 
VANCOMYCIN, LINEZOLID AS EMPIRIC THERAPY IN FEBRILE 
NEUTROPENIC ADULTS WITH CANCER 
Protocol Version 
11 
Version Date 
11/16/2020 
 
Protocol PI 
Issam Raad, MD, FACP, FIDSA, FSHEA 
Department 
Infectious Disease 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
138618 
 
 
 
 


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IND Sponsor:  UT MD Anderson Cancer Center 
IND Number:  138618 
AN INVESTIGATOR INITIATED, PHASE II SINGLE-CENTER, 
RANDOMIZED, OPEN-LABEL, PROSPECTIVE, COMPARATIVE STUDY 
TO DETERMINE THE EFFICACY, SAFETY, AND TOLERABILITY OF 
CEFTOLOZANE-TAZOBACTAM PLUS VANCOMYCIN, LINEZOLID 
VERSUS STANDARD OF CARE PLUS VANCOMYCIN, LINEZOLID AS 
EMPIRIC THERAPY IN FEBRILE NEUTROPENIC ADULTS WITH 
CANCER  
 
 
Ceftolozane-Tazobactam   


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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 ...................................................................................................... 18 
7.2.1 
Summary Of Efficacy In Completed Clinical Studies ................................................ 18 
7.2.2 
Activity against Pseudomonas Aeruginosa ................................................................ 19 
7.3    
Summary of Safety ...................................................................................................... 19 
8.0 
STUDY OBJECTIVES ............................................................................................................ 20 
9.0 
INVESTIGATIONAL PLAN ................................................................................................. 21 
9.1 
Overall Study Design and Plan: Description ............................................................ 21 
9.3 
Selection of Study Population .................................................................................... 21 
9.3.1 
Inclusion Criteria ....................................................................................................... 21 
9.3.2 
Exclusion Criteria ...................................................................................................... 22 
9.3.3 
Removal of Patients from Therapy or Study Assessment ........................................... 23 


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9.3.3.1 
Premature Discontinuation from Inpatient IV Study Drug Due To Safety ................ 23 
9.3.3.2 
Premature Discontinuation from Inpatient IV Study Drug Due To Insufficient 
Therapeutic Effect ...................................................................................................................... 23 
9.3.3.3 
Premature Discontinuation from Oral or IV Therapy ............................................... 24 
9.3.3.4 
Withdrawal from Study .............................................................................................. 24 
9.3.4  
Patient Replacement Procedures ............................................................................... 26 
9.4.1 
TREATMENTS ...................................................................................................................... 26 
9.4.1 
Treatment Group ........................................................................................................ 26 
9.4.1.3 
Standard of Care Treatment Group ........................................................................... 26 
9.4.1.3 
Other Additional Antibacterial Therapy .................................................................... 27 
9.4.1.4 
Optional Oral or IV Therapy Switch ......................................................................... 29 
9.4.1.4.1  Criteria for Switching to Oral or IV Therapy ......................................................... 29 
9.4.4.4.2 Oral and IV Switch Therapy Options ....................................................................... 31 
9.4.1.5 
Duration of Treatment ............................................................................................... 32 
9.4.2 
Identity of Investigational Products ........................................................................... 32 
9.4.3 
Method of Assigning Patients to Treatment Groups .................................................. 32 
9.4.4  
Selection of Dosages in the Study .............................................................................. 33 
9.4.5 
Selection and Timing of Dose for Each Patient ......................................................... 33 
9.4.5.1 
Dose Adjustments for Ceftolozane/Tazobactam ........................................................ 33 
9.4.5.2 
Dose Adjustments - Other Investigational Products .................................................. 34 
9.4.6 
Blinding ...................................................................................................................... 34 
9.4.7 
Unblinding ................................................................................................................. 34 
9.4.8 
Prior and Concomitant Therapy ................................................................................ 34 
9.4.9 
Monitoring Treatment Compliance ............................................................................ 34 


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9.5 
EFFICACY AND SAFETY VARIABLES ............................................................................ 34 
9.5.1 
Primary and Secondary Efficacy Assessments .......................................................... 34 
9.5.1.2 
Microbiological Assessments ..................................................................................... 35 
9.5.1.3 
Clinical Outcome of The Infection ............................................................................. 36 
9.5.2 
Safety Assessments ..................................................................................................... 36 
9.5.2.1 
Adverse Events ........................................................................................................... 36 
9.5.2.2 
Causality Assessment ................................................................................................. 37 
9.5.2.3 
Serious Adverse Events (SAE) Reporting ................................................................... 38 
9.5.2.5 
Clinical Laboratory Determinations.......................................................................... 39 
9.5.2.6 
Vital Signs, Body Weight, and Height ........................................................................ 40 
9.5.2.7 
Chest Radiography ..................................................................................................... 40 
9.5.2.8 
Physical Examination ................................................................................................ 41 
9.5.3 
Schedule of Assessments ............................................................................................ 41 
9.5.3.1 
Baseline ...................................................................................................................... 41 
9.5.3.2 
Study Days 1 To ≤ 14 ................................................................................................. 43 
9.5.3.3 
End of Inpatient Intravenous Therapy ....................................................................... 44 
9.5.3.4 
Test-Of-Cure (Toc) ..................................................................................................... 44 
9.5.3.5 
Late Follow-Up .......................................................................................................... 45 
Record Infection Symptoms, Including Recurring Or Worsening Symptoms Indicative Of 
Clinical Failure .......................................................................................................................... 45 
9.6 
DATA QUALITY ASSURANCE ........................................................................................... 47 
9.6.1 
Data Recording, Documentation and Monitoring ..................................................... 47 
9.6.2 
Data Recording And Documentation ......................................................................... 47 
9.7 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ................... 48 


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9.7.1 
Analysis Sets ............................................................................................................... 48 
9.7.1.1 
Screened Analysis Set ................................................................................................ 50 
9.7.1.2 
Intent-To-Treat Analysis Set ...................................................................................... 50 
9.7.1.3 
Safety Analysis Set ..................................................................................................... 50 
9.7.1.4 
Modified Intent-To-Treat Analysis Set ....................................................................... 50 
9.7.1.5 
Microbiological Modified Intent-To-Treat Analysis Set ............................................ 50 
9.7.1.6 
Clinically Evaluable Analysis Set .............................................................................. 50 
9.7.1.7 
Microbiologically Evaluable Analysis Set ................................................................. 50 
9.7.2 
Patient Disposition ..................................................................................................... 51 
9.7.3 
Demographics And Other Baseline Characteristics .................................................. 51 
9.7.4 
Extent of Exposure and Treatment Compliance ........................................................ 51 
9.7.4.1 
Extent of Exposure ..................................................................................................... 51 
9.7.4.2 
Measurement Of Treatment Compliance ................................................................... 52 
9.7.5 
Efficacy Analyses ....................................................................................................... 53 
9.7.5.1 
Primary Efficacy Parameter ...................................................................................... 53 
9.7.5.2 
Secondary Efficacy Parameters ................................................................................. 53 
9.7.5.3 
Clinical Outcome Definitions ..................................................................................... 53 
9.7.5.4 
Microbiological Response Definitions ....................................................................... 55 
9.7.5.5 
Emergent Infections ................................................................................................... 56 
9.7.6 
Safety Analyses ........................................................................................................... 57 
9.7.6.1 
Adverse Events ........................................................................................................... 57 
9.7.6.2 
Clinical Laboratory Parameters ................................................................................ 58 
9.7.6.3 
Vital Signs .................................................................................................................. 58 


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9.7.6.4 
Chest Radiography ..................................................................................................... 58 
9.7.6.5 
Stopping Rule ............................................................................................................. 58 
9.7.7 
Health Economics and Outcomes Research Analyses ............................................... 59 
9.7.8 
Interim Analysis ......................................................................................................... 59 
9.7.9 
Determination of Sample Size .................................................................................... 59 
9.7.10 
Computer Methods ..................................................................................................... 59 
9.8 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES ........... 60 
9.9 
PROTOCOL DEVIATIONS .................................................................................................. 60 
10.0 
STUDY SPONSORSHIP ......................................................................................................... 60 
10.1 
STUDY TERMINATION ....................................................................................................... 60 
10.2 
REPORTING AND PUBLICATION .................................................................................... 60 
11.0 
INVESTIGATOR OBLIGATIONS ....................................................................................... 60 
11.1 
DOCUMENTATION ............................................................................................................... 60 
11.2 
USE OF INVESTIGATIONAL MATERIALS ..................................................................... 61 
11.3 
CASE REPORT FORMS ........................................................................................................ 61 
11.4 
RETENTION AND REVIEW OF RECORDS ..................................................................... 61 
11.5 
PATIENT CONFIDENTIALITY ........................................................................................... 61 
12.0 
APPENDICES .......................................................................................................................... 61 
APPENDIX I. ELEMENTS OF INFORMED CONSENT ........................................................... 62 
APPENDIX II. MD ANDERSON NEUTROPENIC FEVER INPATIENT ADULT 
TREATMENT GUIDELINES ........................................................................................................... 64 
APPENDIX III. MD ANDERSON PNEUMONIA IN ADULT PATIENTS WITH CANCER 
TREATMENT GUIDELINES ........................................................................................................... 73 
APPENDIX IV. POTENTIAL DRUG-INDUCED LIVER INJURY/HY’S LAW ..................... 83 


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PHL ....................................................................................................................................................... 83 
FOLLOW-UP AND REPORTING ................................................................................................... 83 
REFERENCE ...................................................................................................................................... 84 
13.0 
LITERATURE CITED ........................................................................................................... 85 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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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 
X 
Urine or Serum pregnancy testr 
X 
 
CrCl calculations 
X 
Xj 
if clinically 
indicated 
Blood sample and urine culture/urine  analysis (when 
clinically needed) t 
X 
X 
Xu 
if clinically indicated 
Other samples for culture from possible suspected 
infected site if clinically indicated 
if clinically indicated 
Randomization 
X 
Study drug administration 
Xv 
X 
a 
Perform baseline assessments within 24 hours beforefirst dose of  IV study drug. 
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 5 to 14 days with a minimum of 3 days (ie, 72 
hours and a minimum of 9 doses for Ceftolozane-Tazobactam and SOC therapies, except 
piperacillin/tazobactam, which is a minimum of 12 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 IV therapy after at least 72 hours of  IV gram negative 
antimicrobial coverage  (Section 9.4.1.4). 
d 
Perform TOC assessments in person between Study Days 21 and 28. 


 
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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 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 obtainable (eg, patient is immobilized), 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 72 hours. 
s 
The estimated CrCl should be calculated with the Cockcroft-Gault formula using the actual weight. If weight is 
not obtainable (eg, patient is immobilized), use the last known or stated weight. 
t 
Obtain 2 sets of blood samples from an existing CVC, if present, and from a peripheral vein site, 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 ≤ 101°F (38.3°C) and 
cultures are negative. 
u 
If baseline cultures were positive, repeat blood cultures at EOIV to determine microbiological response. 
v 
Administer 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. Ceftolozane-Tazobactam  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 
 
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 
 
q6h 
every 6 hours 
 
RSM 
Regional Site Manager 


 
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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, Sponsor, 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 
 
 
The steady rise of antibiotic-resistant bacteria is an imminent and urgent threat to individual patients 
and public health. Yet the treatment of infection is an area where there have been few major 
advances in recent years and the number of new antibiotics in this area of research has dropped off 
steadily. Despite the current hopeful efforts of the antibiotics stewardship programs, new resistances 
continue to emerge. There consequently remains an unmet medical need for new antibiotics, 
particularly those directed against multidrug-resistant (MDR) Gram-negative bacteria in hospitals. 
Already, some nonfermenters of the genera Acinetobacter and Pseudomonas are resistant to all well-
tolerated antibiotics, and many Enterobacteriaceae are resistant to all except carbapenems. 
 
In a world of increasing resistance, standard empirical monotherapy for patients with cancer and 
febrile neutropenia with piperacillin-tazobactam, cefepime, or carbapenems would be 
‘inappropriate’ against an increasing proportion of Gram-negative pathogens. Infections in onco-
hematologic patients produced by extended-spectrum β-lactamase (ESBL), or Ambler Class C 
(AmpC)-β-lactamase-producing Enterobacteriaceae, MDR Pseudomonas aeruginosa, 
Acinetobacter spp., or Stenotrophomonas spp. are significantly more likely to be treated using an 
inadequate initial empirical antibiotic therapy. As a consequence, failure to cover Gram-negative 
pathogens, particularly ESBL producers and MDR P. aeruginosa, significantly and independently 
impairs outcomes in onco-hematology patients, increasing mortality and prolonging hospitalization 
(Giamarellou, 2010; Gudiol et al, 2011; Ortega et al, 2009; Trecarichi et al, 2009; Tumbarello et al, 
2006). 
 
Infections caused by ESBL-producing Enterobacteriaceae (ESBL-ENT), particularly Escherichia 
coli and Klebsiella pneumoniae, are on the increase. Resistance among ESBL producers extends not 
only to β-lactams (BL) including penicillin and third-generation cephalosporins but also to 
aminoglycosides and fluoroquinolones. Carbapenems remain the preferred treatment for severe 
infections caused by ESBL producers. New antibiotics, such as BL/β-lactamase inhibitor (BLI) 
combinations, may be useful carbapenem-sparing options against ESBL-ENT. Furthermore, there is 
a paucity of novel classes of antimicrobials to target resistant Gram-negatives. 
 
7.2 
Clinical Overview 
 
Ceftolozane/tazobactam consists of a novel cephalosporin and an established β-lactamase inhibitor 
that is being developed to address antimicrobial resistance in serious infections caused by gram-
negative pathogens.  Ceftolozane/tazobactam is approved in the United States as Zerbaxa™ 
(ceftolozane and tazobactam) for the treatment of complicated intra-abdominal infections  
(administered with metronidazole) (cIAI) and complicated urinary tract infections (cUTI), including 
pyelonephritis, in adults (1-3).  Additionally, ceftolozane/tazobactam is being  developed for the 
treatment of ventilated nosocomial pneumonia in adults. In vitro activity of ceftolozane/tazobactam 
has been confirmed against a wide range of pathogens, including MDR/XDR drug-resistant 
Pseudomonas aeruginosa and  ESBL-producing Enterobacteriaceae (4-7).  
 
7.2.1 
Summary Of Efficacy In Completed Clinical Studies 
Ceftolozane/tazobactam was studied in a large Phase 3 clinical programme [Assessment of the 
Safety Profile and Efficacy of Ceftolozane/Tazobactam (ASPECT)] in patients with cIAI or cUTI. 
In ASPECT-cIAI, ceftolozane/tazobactam plus metronidazole was non-inferior to meropenem, and 
in ASPECT-cUTI, ceftolozane/tazobactam demonstrated efficacy superior to that of high-dose 
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In ASPECT-cIAI, for the primary endpoint, clinical cure rates were 83.0% (323/389) with 
ceftolozane/tazobactam plus metronidazole and 87.3% (364/417) with meropenem in the MITT 
population at the TOC visit, which occurred at a median of 27 days (interquartile range, 26–28 
days) after the TOC visit. The weighted difference in clinical cure rates (ceftolozane/tazobactam 
plus metronidazole minus meropenem) was −4.2% with a 2-sided 95% CI of −8.91% to .54%, thus 
meeting the statistical criteria for noninferiority. Statistical noninferiority was also demonstrated for 
the ME population, where clinical cure rates were 94.2% and 94.7% (weighted difference, −1.0; 
95% CI, −4.52 to 2.59) at the TOC visit.  
 
Clinical cure rates in the ITT population at TOC were 83.6% for ceftolozane/tazobactam plus 
metronidazole and 86.2% for meropenem (difference, −2.6; 95% CI, −7.08 to 1.87), similar to those 
observed in the MITT population. In the CE population, cure rates were 94.1% and 94.0%, 
respectively (difference, 0.1; 95% CI, −3.30 to 3.55). At the end of therapy, clinical cure rates in the 
MITT population were higher in both treatment groups: 89.2% for ceftolozane/tazobactam plus 
metronidazole and 92.3% for meropenem (difference, −3.1; 95% CI, −7.23 to .89). 
 
In the Trial with  cUTI for  the mMITT population, there were 212 patients (26.5%) with at least 
one baseline uropathogen that was resistant to levofloxacin. The majority of uropathogens in this 
subgroup were Enterobacteriaceae (n = 186) that were susceptible to ceftolozane/tazobactam [MIC 
≤2 mg/L, 88.7% (165/186)]. Among patients with levofloxacin-resistant pathogens, 
ceftolozane/tazobactam demonstrated significantly higher composite cure rates than levofloxacin in 
both the mMITT [60.0% (60/100) versus 39.3% (44/112); 95% CI for the treatment difference, 
7.2%-33.2%] and ME [64.0% (57/89) versus 43.4% (43/99); 95% CI for the treatment difference, 
6.3%-33.7%] populations, respectively. In conclusion, seven day treatment with 
ceftolozane/tazobactam was more effective than high-dose levofloxacin treatment in patients with 
cUTI caused by levofloxacin-resistant bacteria, and it may be an alternative treatment in settings of 
increased fluoroquinolone resistance. 
 
7.2.2 
Activity against Pseudomonas Aeruginosa 
 
Multidrug-resistant P. aeruginosa often requires complex antimicrobial regimens and, when treated 
inadequately, infections caused by this pathogen are associated with particularly poor outcomes 
including postoperative complications, longer hospital stays, and increased mortality [8-10]. In vitro 
studies have shown that ceftolozane/tazobactam is the most potent antipseudomonal agent, 
maintaining activity against many multidrug-resistant strains [4]. Ceftolozane/tazobactam 
demonstrated efficacy against P. aeruginosa, even though experience with multidrug-resistant P. 
aeruginosa was limited. 
 
These results suggest that ceftolozane/tazobactam is a potential alternative to the currently 
recommended antimicrobials for the treatment of cIAIs and cUTIs, especially when resistant 
Enterobacteriaceae or P. aeruginosa are suspected, such as in healthcare-associated infections. 
 
7.3    
Summary of Safety  
 
The incidence of AEs that developed during the phase 3 treatment of cIAI trial was similar between 
the ceftolozane/tazobactam plus metronidazole group and the meropenem group (44.0% and 42.7%, 
respectively), and most events were mild to moderate in severity. The most common laboratory AEs 
were increased alanine aminotransferase and aspartate aminotransferase, which occurred in 2.5% 
and 1.6% of all patients, respectively. Drug-related AEs leading to discontinuation were few, 


 
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occurring in 3 patients (0.6%) in the ceftolozane/tazobactam plus metronidazole group and 4 
patients (0.8%) in the meropenem group. Serious AEs occurred in 39 of 482 (8.1%) and 36 of 497 
(7.2%) patients in the ceftolozane/tazobactam plus metronidazole and meropenem groups, 
respectively. Drug-related serious AEs occurred in 1 patient in each treatment group (both 
Clostridium difficile infection). 
 
There were 11 deaths (2.3%) in the ceftolozane/tazobactam plus metronidazole group and 8 deaths 
(1.6%) in the meropenem group; no death was considered by the investigators to be related to study 
treatment. 
 
In conclusion, these results suggest that ceftolozane/tazobactam plus metronidazole is a potential 
alternative to the currently recommended antimicrobials for the treatment of cIAIs, especially when 
resistant Enterobacteriaceae or P. aeruginosa are suspected, such as in healthcare-associated 
infections. 
 
8.0 
STUDY OBJECTIVES 
 
Primary: 
• To evaluate the efficacy of  ceftolozane/tazobactam plus vancomycin, daptomycin or linezolid vs  
standard of care (SOC) plus 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 ceftolozane/tazobactam plus vancomycin, daptomycin, or  
linezolid compared with SOC plus vancomycin, daptomycin or linezolid as empiric therapy in 
febrile neutropenic adults with cancer 
 
 
Secondary: 
• To evaluate the efficacy of ceftolozane/tazobactam plus vancomycin, daptomycin  or linezolid 
compared with SOC plus 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  and 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 


 
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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 
ceftolozane/tazobactam plus vancomycin, daptomycin or linezolid with SOC plus vancomycin, 
daptomycin or linezolid as empiric therapy in febrile neutropenic adults with cancer. The total 
duration of study therapy will be 5 to 14 days; a minimum of 3 days (ie, 72 hours of IV 
antimicrobial gram negative coverage is required; 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 72 hours  IV gram negative antimicrobial coverage per Section 
9.4.1. Doses 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.  
 
 
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 ≥ 101°F (38.3°C) or a temperature of ≥ 100.4°F (38.0°C) sustained over a 1-hour 
period 
 
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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Is surgically sterile or at least 2-years postmenopausal, or if of childbearing potential, has negative 
screening serum or urine pregnancy test within 72 hours 
 
○ 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 cephalosporin antibiotic or tazobactam, 
 
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 
 
○ Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level 
> 5 times the upper limit of normal (× ULN). Patients with values > 3 × ULN and 
< 5 × ULN are eligible if the value is acute and directly related to the infectious process being treated. 
 
○ 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 > 24 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. Requirement for any non-study potentially effective concomitant systemic antibacterial therapy 
 
 
11. Past or current history of epilepsy or seizure disorder; exception: well-documented febrile seizure of 
childhood 
 


 
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12. 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) 
 
13. Unable or unwilling to adhere to the study-specified procedures and restrictions 
 
14. 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   
 
15. Participation in any other ongoing ceftolozane/tazobactam 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 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 


 
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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 72 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 
 
AE 
 
Protocol violation 
 
Lost to follow-up 
 
Study terminated by Sponsor 
 
Site terminated by Sponsor 
 
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 


 
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Other 
 
During treatment period: 
 
Withdrawal of consent 
 
Lost to follow-up 
 
Study terminated by Sponsor 
 
Site terminated by Sponsor 
 
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 
 
Other 
 
During follow-up period (ie, no longer receiving study therapy): 
 
Withdrawal of consent 
 
Lost to follow-up 
 
Study terminated by Sponsor 
 
Site terminated by Sponsor 
 
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 
 
Other 
 
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 Sponsor. 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). 
 


 
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9.3.4  
Patient Replacement Procedures 
 
Randomized patients who are withdrawn will not be replaced. 
 
9.4.1 TREATMENTS 
 
Treatments Administered 
 
 9.4.1 
Treatment Group 
 
As shown in Table 9.4.1.3-1, patients randomized to the Ceftolozane-Tazobactam   treatment group 
will receive: 
 
IV Ceftolozane/tazobactam (minimum of 9 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 9 doses) 
 
Meropenem (minimum of 9 doses) 
 
Piperacillin/tazobactam (minimum of 12 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 72 Hours As Described In Table 9.4.1.3–1 
 
 
Empirical Treatment Of C. Difficile With Oral Vancomycin Or Metronidazole (IV or oral) May Be 
Added at any time For Patients With Symptoms Of Abdominal Cramping And Diarrhea Until 
Diagnostic Results Are Available Or If C. Difficile Infection Is Strongly Suspected Clinically. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table 9.4.1.3–1. Investigational Products 
 
Investigational 
Product 
Dosagea and Route 
Form and Strength 
Supplier 
 Treatment Group: 
Ceftolozane-
Tazobactam 
1.0 g CEF and  0 .5 g of 
Tazo  IV over 1 hour 
q8h  
Investigational 
FRI 
PLUS one of the following adjunctive Gram-positive therapies: 
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 
Standard of Care (Comparator) Treatment Group: 
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 one of the following adjunctive Gram-positive therapies: 
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 72 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). 
  
Ceftolozane-Tazobactam; 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 72 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 
 
Patient received at least 72 hours  of IV gram negative antimicrobial coverage. 
 


 
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EOIV clinical signs and symptoms have been assessed 
 
Patient has the ability to maintain oral intake 


 
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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) 
 
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.  
 
9.4.4.4.2 Oral and IV Switch Therapy Options 
 
After completion of at least 72 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) 
 
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. 
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. 


 
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9.4.1.5 Duration of Treatment 
 
The total duration of study therapy will be 5 to 14 days; a minimum of 3 days 
(ie, 72 hours) of IV gram negative antimicrobial coverage is required. After at least 3 days (ie, 72 
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 120 hours (ie, 5 days, typically on or after Study Day 5) 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 Ceftolozane-Tazobactam contains both Ceftolozane and Tazobactam, 
which will be administered together in a single infusion bag. A single vial filled with the sterile 
crystalline form of Ceftolozane (1 g) and the sterile crystalline form of Tazobactam (0.5 g) for IV 
administration. The crystalline powders are reconstituted using Sterile Water 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. 
 
 
With the exception of ceftolozane/tazobactam 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 sponsor 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 


 
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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 ceftolozane-tazobactam that was selected for this study was based on phase I     
pharmacokinetic and safety studies in healthy adults and the probability of target attainment   
(30%T>MIC) against pathogens with an MIC of up to 8 μg/ml (≥90%). It is the FDA-approved dose 
for the treatment of cIAI and cUTI.  
 
Clinical efficacy data from the Phase 3 cIAI and cUTI studies demonstrated that administered at a 
dose of 1.5 g (1 g Ceftolozane and 0.5 g of Tazobactam) IV q8h is effective for the treatment of 
cIAI and cUTI caused by common gram-negative pathogens and is a beneficial adjunct to the 
current armamentarium of parenteral antimicrobial therapy for serious and severe infections. 
 
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 
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 Ceftolozane/Tazobactam 
 
In the case of renal impairment, at any time, the dose of ceftolozane/tazobactam  (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 ceftolozane/tazobactam   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 
 
 
Recommended dosages of Ceftolozane- Tazobactam by renal function 
Estimated CL Cr (ml/min) 
Dose 


 
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>50 
1.5 g IV every 8 hours 
30-50 
750 mg IV every 8 hours 
15-29 
375 mg IV every 8 hours 
ESRD on HD 
750 mg IV loading dose, followed by 150 mg 
every 8 hours: administer at earliest time 
possible after completion of dialysis 
 
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 
 
 
9.5.1 
Primary and Secondary Efficacy Assessments 
 


 
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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.  
 
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 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 ≤ 101°F (38.3°C) and blood cultures are 
negative 
 
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 
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, 2 sets of blood samples should be obtained from an existing 
central venous catheter, if present, and from a peripheral vein site. If no central venous catheter is 
present, collect 2 blood cultures from separate venipuncture sites. 
 


 
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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). 
 
 
 
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 sponsor 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 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. 
 
Adverse event for this protocol will be documented into the medical record and entered into 
RedCap according to the Recommended Adverse Event Guidelines for Phase II Protocols (please 
refer to chart on page 37). 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. Version 4.03 of the Common Toxicity Criteria for adverse 
events will be used to assess AEs and SAE (please refer to Section 9.5.2.1) 
 
Study subjects should be instructed to report all adverse events to the Investigator.  In addition, the Investigator should 


 
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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 will be noted, and whether intermittent or 
continuous also documentation of the outcomes and what was done with study drug is needed.  
 
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. 
 
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 
“sponsor correspondence”. 
 
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, or 
 
○ The patient did not take the investigational product, or 


 
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○ 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 Events (SAE) Reporting 
 
9.5.2.3. Serious Adverse Event (SAE) Reporting 
 
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 drug experience – any adverse experience that places the patient, 
in the view of the initial reporter, at immediate risk of death from the adverse experience as it 
occurred. It does not include an adverse experience that, had it occurred in a more severe form, 
might have caused death. 
• 
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 for 
Investigators on Reporting Serious Unanticipated Adverse Events for Drugs and Devices”.  Unless 
stated otherwise in the protocol, all SAEs, expected or unexpected, must be reported to the IND 
Office, regardless of attribution (within 5 working days of knowledge of the event). 
• 
All life-threatening or fatal events, that are unexpected, and related to the study drug, must 
have a written report submitted within 24 hours (next working day) of knowledge of the event to the 
Safety Project Manager in the IND Office.   
• 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB.  
• 
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 
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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. 
 
   Reporting to FDA: 
• 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) 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. 
 
 
 
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). 
 
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 72 hours). The test must be 


 
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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  
 
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 
 
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 obtainable (eg, 
patient is immobilized), 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 


 
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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 
 
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 
 
Obtain height and weight (if height or weight is not obtainable [eg, patient is immobilized], 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 
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Evaluate and record infection signs and symptoms per Section 9.5.1.3 
 
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 72 hours, 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 obtainable [eg, patient is immobilized], 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) 


 
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Microbiological assessments: 
 
 
Collect blood sample for culture per Section 9.5.1.2 (See pages 33-34). 
 
 
If clinically indicated, collect other samples for culture per Section 9.5.1.2 
 
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 per Section 9.5.1.3 
 
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 ≤ 101°F 
(38.3°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 performd ≥ 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 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). 
 
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 
 


 
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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 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 


 
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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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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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 summaries will be presented by treatment group. Summaries 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 72 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 > 24 hours of any potentially effective, systemic antibacterial therapy within 72 
hours before randomization for treatment of suspected infection. Any amount of prophylactic (in 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 
 


 
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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. 
 
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 


 
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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). 
 
 
9.7.4.2 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 
 
Efficacy analyses will be based on the MITT and mMITT analysis sets. Baseline for efficacy is 
defined as the last measurement collected just before the first dose of inpatient IV study drug. The 
primary objective of the study is show that efficacy of Ceftolozane-Tazobactam plus vancomycin, 
daptomycin or linezolid is non-inferior to standard of care (SOC) plus vancomycin, daptomycin or 
linezolid as empiric therapy in febrile neutropenic adults with cancer with respect to favorable 
clinical response. Non-inferiority test will be performed with the margin of 10%, that is, if the 
favorable clinical response of Ceftolozane-Tazobactam is not 10% worse than the SOC, it is deemed 
non-inferior to the SOC. The one-sided chi-square test will be used for this non-inferiority test at the 
significance level of 0.05. 
 
For each efficacy parameter listed below, the 2-sided 95% confidence intervals for the percentage of 
patients with favorable response will be obtained using the Clopper-Pearson method for each 
treatment group (Clopper and Pearson, 1934).  
 
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 
  
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. 
             


 
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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 
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 antibacterial therapy is required 
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 as 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. Another episode of 
neutropenic fever during the follow-up period will not be 
considered as a failure unless the patient present for a relapse of 
the same documented infection that was present at baseline. 
EOIVa 
TOCa 
LFUa 
Clinical failure 
Patients who meet any of the following: 
• 
Has persistent fever (ie, a single oral temperature measurement 
of≥> 38.3°C [101°F] or a temperature of ≥ 38.0°C [100.4°F] 
sustained over a 1-hour period) 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 while on 
study drug of new bacteremia with gram negative pathogen 
not present at baseline) 
• 
Has a documented gram negative 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 with gram negative organism that 
requires alternative nonstudy antimicrobial  
therapy (Investigator is encouraged to continue study 
therapy[ies] for at least 72 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 
• 
Patients who require more than 1 switch in therapy after 
discontinuing their original randomized IV treatment will be 
assessed as a clinical failure at TOC and LFU 
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) 
• 
Patient has an infection with documented gram positive 
organisms 
• 
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. 
 
 
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 
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9.7.6 
Safety Analyses 
 
Incidences of TEAEs, SAEs, deaths, and discontinuations due to AEs in the Safety Analysis Set 
 
Changes in clinical laboratory parameters and vital sign parameters in the Safety Analysis Set at 
each study visit that assessments are performed 
 
Safety summaries will be presented using the Safety 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. 
 
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, relationship to study therapy, and severity. 
 
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. 
 
 
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. 


 
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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 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 
Stopping Rule 
 
Toxicity will be monitored for each arm independently. Toxicities used for this monitoring consist 
of severe drug related adverse events leading to the discontinuation of the study drug. For this trial, 


 
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the upper limit of the toxicity rate is 20%. The trial will be discontinued if the observed data 
indicates that there is a 90% chance that the true toxicity rate is higher than 20% in any treatment 
arm. Statistically, this means that if the posterior probability of toxicity greater than 0.2 is greater 
than 0.9 (ie, Pr (toxicity > 0.2|data) > 0.9), the trial will be discontinued for toxicity. Toxicity will be 
monitored when the accrual is approximately 10, 20, 30, and 40. Accrual will be temporarily 
suspended for analysis after each of the following interim accrual goals. The parameters of the beta 
prior Beta (a, b) were chosen based on the following two considerations: (1) we wanted the prior to 
be vague and equivalent to an effective size of 
0.5 patient such that the estimates are essentially determined by the data. This requirement is 
equivalent to a+b=0.5; (2) the prior mean of the toxicity rate is 20%, which is equivalent to 
a/(a+b)=0.2. Solving these two equations, we obtained a=0.1 and b=0.4, that is, the beta prior Beta 
(0.1, 0.4). Assuming the prior beta distribution Beta (0.1, 0.4) for the toxicity, the above stopping 
rule translates into the following stopping boundary: the study will be terminated if the observed 
toxicity is >= 4/10, 7/20, 10/30, 12/40 (# of patients experienced toxicities/# of patients treated). The 
table below shows the operating characteristics of the stopping rule based on 1,000 simulated trials 
(Thall et al, 1995). 
 
Operating characteristics of the proposed stopping rule 
 
True toxicity probability 
0.1 
0.2 
0.3 
0.4 
Stopping Probability 
1.4% 
20.0% 
65.9% 
94.9% 
Average number of patients treated 
49.5 
44.0 
29.5 
17.7 
 
 
 
9.7.7 
Health Economics and Outcomes Research Analyses 
 
Not applicable. 
 
9.7.8 
Interim Analysis 
 
No interim analysis is planned for this study. 
 
 
9.7.9 
Determination of Sample Size 
 
The primary objective of the study is show that efficacy of Ceftolozane-Tazobactam plus 
vancomycin, daptomycin or linezolid is non-inferior to standard of care (SOC) plus vancomycin, 
daptomycin or linezolid as empiric therapy in febrile neutropenic adults with cancer with respect to 
favorable clinical response. Based on historical data, the estimate of favorable clinical response for 
the SOC is approximately 65%. We expect that the favorable clinical response of Ceftolozane-
Tazobactam plus vancomycin, daptomycin or linezolid is 80%. Given the non-inferiority margin of 
10% (i.e., if the favorable clinical response of Ceftolozane-Tazobactam 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 is performed using nQuery Advisor 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 SPONSORSHIP 
 
MD Anderson Cancer Center IND office (Study Sponsor); 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: 
 
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 
 
 


 
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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 eCRFs. The Investigator is responsible for 
verifying that all data entries in the eCRFs 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 
Sponsor 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 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX I. 
ELEMENTS OF INFORMED CONSENT 
 
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. 


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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. 
 
 
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 
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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 Sponsor 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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13.0 
LITERATURE CITED 
 
 
1. Solomkin J, Hershberger E, Miller B et al. Ceftolozane/tazobactam plus 
metronidazole for complicated intra-abdominal infections in an era of multidrug 
resistance: results from a randomized, double-blind, phase 3 trial (ASPECT-cIAI). Clin Infect Dis 
2015; 60: 1462–71.   
2. Wagenlehner FM, Umeh O, Steenbergen J et al. Ceftolozane-tazobactam compared with 
levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a 
randomised, double-blind, phase 3 trial (ASPECT-cUTI). Lancet 2015; 385: 1949–56. 
3. Merck Sharp & Dohme Corp. Safety and efficacy of ceftolozane/tazobactam to treat ventilated 
nosocomial pneumonia (ASPECT-NP). 
https://clinicaltrials.gov/ct2/show/NCT02070757?term=nct02070757. 
4. Farrell DJ, Flamm RK, Sader HS, Jones RN. Antimicrobial activity of ceftolozane-tazobactam 
tested against Enterobacteriaceae and Pseudomonas aeruginosa with various resistance patterns 
isolated in U.S. hospitals (2011–2012). Antimicrob Agents Chemother 2013; 57:6305–10.   
5. Sader HS, Farrell DJ, Flamm RK, Jones RN. Ceftolozane/tazobactam activity tested against aerobic 
gram-negative organisms isolated from intra-abdominal and urinary tract infections in European 
and United States hospitals (2012). J Infect 2014; 69:266–77. 
6. Sader HS, Farrell DJ, Castanheira M, Flamm RK, Jones RN. Antimicrobial activity of 
ceftolozane/tazobactam tested against Pseudomonas aeruginosa and Enterobacteriaceae with 
various resistance patterns isolated in European hospitals (2011–12). J Antimicrob Chemother 
2014; 69:2913–722.  
7. Walkty A, Karlowsky JA, Adam H, et al. In vitro activity of ceftolozane-tazobactam against 
Pseudomonas aeruginosa isolates obtained from patients in Canadian hospitals in the CANWARD 
study, 2007 to 2012. Antimicrob Agents Chemother 2013; 57:5707–9.  
8. Augustin P, Dinh AT, Valin N, et al. Pseudomonas aeruginosa post-operative peritonitis: clinical 
features, risk factors, and prognosis. Surg Infect (Larchmt) 2013; 14:297–303 
9. Hoban DJ, Bouchillon SK, Hawser SP, Badal RE, Labombardi VJ, DiPersio J. Susceptibility of 
gram-negative pathogens isolated from patients with complicated intra-abdominal infections in the 
United States, 2007–2008: results of the Study for Monitoring Antimicrobial Resistance Trends 
(SMART). Antimicrob Agents Chemother 2010; 54:3031–4.  
10. Micek ST, Lloyd AE, Ritchie DJ, Reichley RM, Fraser VJ, Kollef MH. Pseudomonas aeruginosa 
bloodstream infection: importance of appropriate initial antimicrobial treatment. Antimicrob Agents 
Chemother 2005; 49:1306–11.  
11. Lucasti C, Hershberger E, Miller B, et al. A multicenter, double-blind, randomized, phase II trial to 
assess the safety and efficacy of ceftolozane/tazobactam plus metronidazole compared with 
meropenem in adult patients with complicated intra-abdominal infections. Antimicrob Agents 
Chemother 2014; 58:5350–7.  
12. Boucher HW, Talbot GH, Benjamin DK, Jr, et al. 10×'20 progress—development of new drugs 
active against gram-negative bacilli: an update from the Infectious Diseases Society of America. 
Clin Infect Dis 2013; 56:1685–94.