Clinical trial NCT02070757
Conditions: Healthcare-Associated Pneumonia Ventilator-Associated Pneumonia Lung Diseases
Sponsor: Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Start date: 2014-09-02; Completion date: 2018-06-06
Enrollment: 726 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 3, multicenter, prospective, randomized study of intravenous (IV) ceftolozane/tazobactam versus IV meropenem in the treatment of adult participants with either ventilator-associated bacterial pneumonia (VABP) or ventilated hospital-acquired bacterial pneumonia (HABP). The primary objective is to demonstrate the non-inferiority of ceftolozane/tazobactam versus meropenem in adult participants with ventilated nosocomial pneumonia (VNP) based on the difference in Day 28 all-cause mortality rates in the Intent-to-treat (ITT) population using a non-inferiority margin of 10%.

Detailed description:

Arms: arm 1: Participants receive 3000 mg ceftolozane/tazobactam intravenous IV (comprising 2000 mg ceftolozane and 1000 mg tazobactam) every 8 hours for 8-14 days. arm 2: Participants receive 1000 mg meropenem IV every 8 hours for 8-14 days.
Interventions: intervention 1: Ceftolozane/tazobactam intervention 2: Meropenem
Intervention descriptions: intervention 1: Ceftolozane/tazobactam is an antibacterial consisting of a co-formulation of ceftolozane, a novel antipseudomonal cephalosporin and tazobactam, a well-established beta (β)-lactamase inhibitor (BLI) being developed for the treatment of serious bacterial infections. intervention 2: Meropenem is a broad spectrum injectable antibiotic widely used to treat serious infections such as ventilator-associated bacterial pneumonia and hospital-acquired bacterial pneumonia.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT02070757
Document Date: 
28-Jun-2018
A Prospective, Randomized, Double-Blind, Multicenter, Phase 3 
Study To Assess The Safety And Efficacy Of Intravenous 
Ceftolozane/Tazobactam Compared With Meropenem In Adult 
Patients With Ventilated Nosocomial Pneumonia


Ceftolozane/tazobactam 
 
 
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A PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, MULTICENTER, PHASE 3 
STUDY TO ASSESS THE SAFETY AND EFFICACY OF INTRAVENOUS 
CEFTOLOZANE/TAZOBACTAM COMPARED WITH MEROPENEM IN ADULT 
PATIENTS WITH VENTILATED NOSOCOMIAL PNEUMONIA 
 
IND Number: 
EudraCT Number: 
104,490 
2012-002862-11 
Protocol Number: 
CXA-NP-11-04 (MK-7625A PN008) 
Phase: 
3 
Investigational Drug: 
Ceftolozane/tazobactam 
Investigational Site(s): 
Multicenter 
Dose Forms: 
Intravenous 
Sponsor: 
Cubist Pharmaceuticals, LLC (formerly known as Cubist 
Pharmaceuticals, Inc.), an indirect wholly-owned subsidiary of 
Merck & Co., Inc. and with a principal place of business 
address of:  
Weystrasse 20 
6000 Lucerne 6  
Switzerland  
Sponsor Medical Director: 
 
Version: 
7.0 – SS2 JAPAN 
Date: 
28-Jun-2018 
Supersedes: 
Version 7.0 – SS1 JAPAN; 19 September 2017 
Version 6.0 – SS1 JAPAN; 15 March 2016 
Version 5.0; 22 October 2014 
Version 4.0; 14 March 2014 
Version 3.0; 27 November 2013 
Version 2.0; 06 February 2013 
Version 1.0; 11 May 2012 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) as set forth in the International 
Conference on Harmonisation (ICH) guidelines on GCP (ICH E6), and applicable local regulatory requirements. 
STATEMENT OF CONFIDENTIALITY 
The confidential information in the following document is provided to you as an Investigator, potential Investigator, or 
consultant, for review by you, your staff, and applicable Institutional Review Board(s).  It is understood that the information 
will not be disclosed to others without written authorization from Cubist Pharmaceuticals, LLC, except to the extent 
necessary to obtain informed consent from those persons to whom the drug may be administered. 
 
 
 
 
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PROTOCOL APPROVAL 
 
Protocol Title: 
 
A Prospective, Randomized, Double-blind, Multicenter, 
Phase 3 Study to Assess the Safety and Efficacy of 
Intravenous Ceftolozane/tazobactam Compared with 
Meropenem in Adult Patients with Ventilated 
Nosocomial Pneumonia 
Protocol Number 
CXA-NP-11-04 
Version: 
7.0 – SS2 JAPAN 
 
 
 
28-JUN-2018 
Merck & Co., Inc. 
 
Date 
 
 
 
 
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INVESTIGATOR’S AGREEMENT 
I have read the foregoing protocol (CXA-NP-11-04) Version 7.0 – SS2 JAPAN and agree 
that it contains all necessary details for carrying out this study.  I will conduct the study as 
outlined herein and will complete the study within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this study.  I will discuss this material with 
them to ensure they are fully informed regarding the drug and the conduct of the study. 
I will use only the informed consent form approved by the Sponsor or their designee and the 
Ethics Committee (EC) or Institutional Review Board (IRB) and will fulfill all 
responsibilities for submitting pertinent information to the IRB or EC responsible for this 
study. 
I further agree that the Sponsor or their designee shall have access to any source documents 
from which case report form information may have been generated. 
I agree to maintain the confidentiality of all information received or developed in connection 
with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 
 
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1. 
SUMMARY OF CHANGES 
1.1. 
Primary Reasons for this Amendment 
Section Number(s)  
and Title(s) 
Description of Change 
Rationale for Change 
2 Synopsis 
6 Trial Objectives and 
Purpose 
Added text explaining that the efficacy 
and safety of ceftolozane/tazobactam 
in the population of patients with 
sepsis will be evaluated under a Japan-
specific amendment.  
To evaluate the efficacy and 
safety of ceftolozane/tazobactam 
in population of patients with 
sepsis. 
Appendix F. 
Added the assessment plan of sepsis.  
To clarify the assessment plan of 
sepsis. 
 
 
 
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2. 
SYNOPSIS  
Name of Sponsor/Company: Cubist Pharmaceuticals, LLC 
Name of Investigational Product: Ceftolozane/tazobactam 
Name of Active Ingredient: Ceftolozane/tazobactam 
Title of Study: A Prospective, Randomized, Double-blind, Multicenter, Phase 3 Study to Assess the Safety 
and Efficacy of Intravenous Ceftolozane/tazobactam Compared with Meropenem in Adult Patients with 
Ventilated Nosocomial Pneumonia 
Study center(s): Global multi-center 
Study Duration: 38 to 50 months  
Phase of development: 3 
Objectives: To accommodate the unique requirements of different regulatory jurisdictions, the study objectives 
have been separated out in this section. In addition, the efficacy and safety of ceftolozane/tazobactam in the 
population of patients with sepsis will be evaluated under a Japan-specific amendment. Further details are 
provided in Appendix F. 
Study Objectives per the United States (US) Food and Drug Administration (FDA): 
Primary objective: 
 
To demonstrate the non-inferiority of ceftolozane/tazobactam versus meropenem in adult subjects 
with ventilated nosocomial pneumonia (VNP) based on the difference in Day 28 all-cause 
mortality rates in the Intent-to-treat (ITT) population using a non-inferiority margin of 10%. 
Key Secondary objective: 
 
To compare the clinical response rates of ceftolozane/tazobactam versus meropenem in adult 
subjects with VNP in the ITT population at the Test-of-cure (TOC) visit (7 to 14 days after the 
End-of-therapy [EOT] visit). 
Other Secondary objectives: 
 
To compare the Day 28 all-cause mortality rates of subjects in the ceftolozane/tazobactam versus 
meropenem arms in the microbiological ITT (mITT) population 
 
To compare the clinical response rates at the TOC visit (ceftolozane/tazobactam versus 
meropenem) in the subset of subjects who had P. aeruginosa isolated from the baseline lower 
respiratory tract (LRT) culture 
 
To compare the clinical response rates at the TOC visit (ceftolozane/tazobactam versus 
meropenem) in the subset of subjects who had Enterobacteriaceae isolated from the baseline LRT 
culture 
 
To compare the microbiological response rates of ceftolozane/tazobactam versus meropenem at the 
TOC visit 
 
To compare the per-pathogen microbiological response rates at the TOC visit 
(ceftolozane/tazobactam versus meropenem) 
 
To compare the Day 14 all-cause mortality rates of subjects in the ceftolozane/tazobactam versus 
meropenem arms 
 
To compare the clinical response rates at the EOT visit for ceftolozane/tazobactam versus 
meropenem 
 
To compare the clinical response rates at the Late Follow-up (LFU) visit for 
ceftolozane/tazobactam versus meropenem 
 
To compare the microbiological response rates of ceftolozane/tazobactam versus meropenem at the 
EOT visit 
 
 
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 
To compare the per-pathogen clinical response at TOC by baseline minimum inhibitory 
concentration (MIC) for ceftolozane/tazobactam versus meropenem 
 
To evaluate the safety and tolerability of ceftolozane/tazobactam 
Exploratory objectives: 
 
To compare the time to all-cause mortality in the ceftolozane/tazobactam versus meropenem arms 
 
To compare the clinical response rates at the EOT visit (ceftolozane/tazobactam versus 
meropenem) in the subset of subjects who had P. aeruginosa or Enterobacteriaceae isolated from 
the baseline LRT culture 
 
To compare the per-pathogen microbiological response at TOC by baseline minimum inhibitory 
concentration (MIC) for ceftolozane/tazobactam versus meropenem 
 
To compare the superinfection and new infection rate for ceftolozane/tazobactam versus 
meropenem 
 
To compare the emergence of nonsusceptibility to study drug for ceftolozane/tazobactam versus 
meropenem 
 
To compare the time to a ≥1-log reduction in bacterial burden of the causative gram-negative 
pathogen(s) identified from the baseline lower respiratory specimen 
 
To compare the incidence of 4-fold increases in MIC (ceftolozane/tazobactam versus meropenem) 
for subjects with P. aeruginosa or Enterobacteriaceae isolated from the baseline LRT culture (the 
elevated MIC must be ≥2 µg/mL) 
 
To evaluate the pharmacokinetics of ceftolozane/tazobactam 
 
To compare the health economics outcomes, including total number of days in hospital, proportion 
of patients discharged from the acute care hospital, number of days in intensive care unit (ICU), 
and number of days on a ventilator, of ceftolozane/tazobactam and meropenem in adults subjects 
with VNP within 28 days of randomization 
 
To evaluate the change in procalcitonin from baseline to Day 3 and to EOT 
Study Objectives per European Medicines Agency (EMA): 
Primary objective: 
 
To demonstrate the non-inferiority of ceftolozane/tazobactam versus meropenem in adult subjects 
with VNP based on the difference in clinical response rates in the ITT population at the TOC visit 
(7 to 14 days after the EOT visit), using a non-inferiority margin of 12.5% 
Key Secondary objective: 
 
To compare the Day 28 all-cause mortality rates of subjects in the ceftolozane/tazobactam versus 
meropenem arms in the ITT population 
Other Secondary objectives: 
 
To compare the clinical response rates of ceftolozane/tazobactam versus meropenem in adult 
subjects with VNP at the TOC visit in the CE population 
 
To compare the clinical response rates at the TOC visit (ceftolozane/tazobactam versus 
meropenem) in the subset of subjects who had P. aeruginosa isolated from the baseline LRT 
culture 
 
To compare the clinical response rates at the TOC visit (ceftolozane/tazobactam versus 
meropenem) in the subset of subjects who had Enterobacteriaceae isolated from the baseline LRT 
culture 
 
To compare the microbiological response rates of ceftolozane/tazobactam versus meropenem at the 
TOC visit 
 
To compare the per-pathogen microbiological response rates at the TOC visit 
(ceftolozane/tazobactam versus meropenem) 
 
 
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 
To compare the Day 28 all-cause mortality rates of subjects in the ceftolozane/tazobactam versus 
meropenem arms in the mITT population 
 
To compare the Day 14 all-cause mortality rates of subjects in the ceftolozane/tazobactam versus 
meropenem arms 
 
To compare the clinical response rates at the EOT visit for ceftolozane/tazobactam versus 
meropenem 
 
To compare the clinical response rates at the LFU visit for ceftolozane/tazobactam versus 
meropenem  
 
To compare the microbiological response rates of ceftolozane/tazobactam versus meropenem at the 
EOT visit 
 
To compare the per-pathogen clinical response at TOC by baseline MIC for 
ceftolozane/tazobactam versus meropenem 
 
To evaluate the safety and tolerability of ceftolozane/tazobactam 
Exploratory objectives: 
 
To compare the time to all-cause mortality in the ceftolozane/tazobactam versus meropenem arms 
 
To compare the clinical response rates at the EOT visit (ceftolozane/tazobactam versus 
meropenem) in the subset of subjects who had P. aeruginosa or Enterobacteriaceae isolated from 
the baseline LRT culture 
 
To compare the per-pathogen microbiological response at TOC by baseline MIC for 
ceftolozane/tazobactam versus meropenem 
 
To compare the superinfection and new infection rate for ceftolozane/tazobactam versus 
meropenem 
 
To compare the emergence of nonsusceptibility to study drug for ceftolozane/tazobactam versus 
meropenem 
 
To compare the time to a ≥1-log reduction in bacterial burden of the causative gram-negative 
pathogen(s) identified from the baseline lower respiratory specimen 
 
To compare the incidence of 4-fold increases in MIC (ceftolozane/tazobactam versus meropenem) 
for subjects with P. aeruginosa or Enterobacteriaceae isolated from the baseline LRT culture (the 
elevated MIC must be ≥2 µg/mL) 
 
To evaluate the pharmacokinetics of ceftolozane/tazobactam 
 
To compare the health economics outcomes, including total number of days in hospital, proportion 
of patients discharged from the acute care hospital, number of days in ICU, and number of days on 
a ventilator, of ceftolozane/tazobactam and meropenem in adults subjects with VNP within 28 days 
of randomization 
 
To evaluate the change in procalcitonin from baseline to Day 3 and to EOT 
Methodology: This is a prospective, randomized, double-blind, multicenter Phase 3 study to assess the safety 
and efficacy of ceftolozane/tazobactam 3000 mg (comprising 2000 mg ceftolozane and 1000 mg tazobactam) 
every 8 hours (q8h) administered as an intravenous (IV) infusion in the treatment of adult subjects with VNP 
(including ventilator-associated bacterial pneumonia [VABP] and ventilated hospital-acquired bacterial 
pneumonia [HABP] subjects), compared with meropenem 1000 mg q8h administered as an IV infusion. 
Subjects will be enrolled and randomized (1:1) to receive either ceftolozane/tazobactam or meropenem.  
Randomization will be stratified by diagnosis (VABP or ventilated HABP) and by age (≥65 or <65 years) to 
facilitate balanced distribution of high-risk subjects between the 2 treatment arms.  The number of subjects 
enrolled with VABP will be at least 50% of the randomized population. 
Patient participation will require a minimum commitment of 36 days and a maximum of 51 days. 
Number of patients (planned): Approximately 726 subjects will be randomized. 
 
 
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Diagnosis and main criteria for inclusion: 
To be eligible for enrollment, a subject must satisfy all of the following entry criteria before they will be allowed 
to participate in the study and prior to any study related procedures: 
1. Provide written informed consent prior to any study-related procedure not part of normal medical 
care.  If the subject is unable to do so, local country laws and institution-specific guidelines and 
requirements in place for obtaining informed consent should be met.  A legally acceptable 
representative may provide consent, provided this is approved by local country and 
institution-specific guidelines.  If a subject comes to consciousness while still in the study and per 
the Investigator’s judgment the subject is able to read, assess, understand, and make his/her own 
decision to participate in the trial, the subject can agree to continue study participation and the 
subject may be re-consented, if required by local country and institution-specific guidelines; 
2. Be males or females aged 18 years or older; 
If female, subject must not be pregnant or nursing, and is either: 
 
Not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile 
due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy; or 
 
Of childbearing potential and meets at least 1 of the following: 
 
Is practicing an effective method of contraception (eg, oral/parenteral contraceptives plus 
barrier method), or 
 
Has a vasectomized partner, or 
 
Is currently abstinent from sexual intercourse. 
Subjects must be willing to practice the chosen contraceptive method or remain abstinent 
during the conduct of the study and for at least 35 days after last dose of study medication. 
Non-vasectomized males are required to practice effective birth control methods (eg, 
abstinence, use of condom, or use of other barrier device) during the treatment period and for 
at least 75 days after last dose of study medication; 
3. Intubated (via endotracheal tube, including tracheostomy patients) and on mechanical ventilation at 
the time of randomization: 
For ventilated HABP: 
 
At least 1 of the following signs and/or symptoms must be present within the 24 hours prior to 
intubation OR within the 48 hours after intubation in a patient who has been either 
hospitalized for >48 hours or who has been discharged from a hospital within the prior 7 days 
(includes patients institutionalized in skilled nursing or other long-term care facility): 
 
A new onset of cough (or worsening of baseline cough) 
 
Dyspnea, tachypnea, or respiratory rate greater than 30 per minute, particularly if any or 
all of these signs or symptoms are progressive in nature 
 
Hypoxemia defined as an arterial blood gas partial pressure of oxygen less than 60 mmHg 
while the subject is breathing room air, OR a pulse oximetry oxygen saturation less than 
90% while the subject is breathing room air, OR worsening of the ratio of the partial 
pressure of oxygen to the fraction of inspired oxygen (PaO2/FiO2). 
For VABP: 
 
Receiving mechanical ventilation ≥48 hours and at least one of the following: 
 
Acute changes made in the ventilator support system to enhance oxygenation, as 
determined by worsening partial pressure of oxygen on arterial blood gas, or worsening 
PaO2/FiO2. 
 
Hypoxemia defined as an arterial blood gas partial pressure of oxygen less than 60 mmHg 
while the subject is breathing room air (or FiO2 equivalent), OR a pulse oximetry oxygen 
saturation less than 90% while the subject is breathing room air (or FiO2 equivalent), OR 
worsening PaO2/FiO2. 
 
 
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4. Chest radiograph obtained within the 24 hours prior to the first dose of study drug shows the 
presence of new or progressive infiltrate(s) suggestive of bacterial pneumonia (based on 
Investigator evaluation or report from a qualified medical professional who is not the investigator).  
A computed tomography (CT) scan may be used in place of a chest X-ray; 
5. Have the following clinical criteria within the 24 hours prior to the first dose of study drug: 
 
Purulent tracheal secretions 
 
And at least 1 of the following: 
 
Documented fever (body temperature  >38°C [100.4°F]) 
 
Hypothermia (body temperature <35°C [95.2°F]) 
 
White blood cell (WBC) count >10,000 cells/mm3  
 
WBC count <4,500 cells/mm3 
 
 >15% immature neutrophils. 
6. Have a baseline lower respiratory tract specimen obtained for Gram stain and quantitative culture 
within 36 hours prior to the first dose of study drug.  This specimen can be obtained by a 
bronchoalveolar lavage (BAL), nonbronchoscopic BAL (mini-BAL), protected brush specimen 
(PBS), or an endotracheal aspirate (ETA); 
Note:  ETA specimens with an average of ≥10 squamous epithelial cells or ≤25 polymorphonuclear 
cells per low power field will be considered inadequate, and a repeat specimen that is adequate will 
need to be obtained for Gram stain and subsequent quantitative culture. 
Note:  If BAL, mini-BAL, or PBS is available at the site, these modalities are strongly 
recommended rather than an ETA for obtaining the baseline LRT specimen. 
7. Willing and able to comply with all study procedures and restrictions. 
Investigational product, dosage and mode of administration: 
Ceftolozane/tazobactam 3000 mg q8h, IV infusion. 
Duration of treatment:  The duration of study drug administration will be a minimum of 8 days (24 doses) and 
up to a maximum of 14 days (42 doses).  The total number of infusions may increase if a dose adjustment is 
required based on renal function due to the addition of dummy infusions.  In subjects with P. aeruginosa isolated 
from the baseline LRT culture, a treatment duration of 14 days is strongly recommended for study drug 
administration. 
Reference therapy, dosage and mode of administration: 
Meropenem 1000 mg q8h, IV infusion. 
Study Endpoints per the US FDA: 
Primary Endpoint: 
 
Day 28 all-cause mortality in the ITT population 
Key Secondary Endpoint: 
 
Clinical response at the TOC visit in the ITT population 
Secondary Endpoints: 
 
Day 28 all-cause mortality in the mITT population 
 
Clinical response at the TOC visit in the CE population 
 
Clinical response for subjects at the TOC visit in the subset of subjects who had P. aeruginosa 
isolated from the baseline LRT culture in the mITT population 
 
Clinical response for subjects at the TOC visit in the subset of subjects who had Enterobacteriaceae 
isolated from the baseline LRT culture in the mITT population 
 
 
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 
Per-subject microbiological response at TOC in the Microbiologically Evaluable (ME) population 
 
Per-pathogen microbiological response for P. aeruginosa at TOC in the ME population 
 
Per-pathogen microbiological response for Enterobacteriaceae at TOC in the ME population 
 
Per-pathogen microbiological response at TOC in the ME population 
 
Day 14 all-cause mortality in the ITT population 
 
Clinical response at EOT in the ITT and CE populations 
 
Clinical response at the LFU visit in the CE population 
 
Per-subject microbiological response at EOT in the ME population 
 
Per-pathogen microbiological response at EOT in the ME population 
 
Per-pathogen clinical response at TOC by baseline MIC in the mITT and ME populations 
Exploratory Endpoints: 
 
Time to all-cause mortality in the ITT population 
 
Clinical response for subjects at TOC in the subset of subjects who had P. aeruginosa isolated 
from the baseline LRT culture in the ME population 
 
Clinical response for subjects at TOC in the subset of subjects who had Enterobacteriaceae isolated 
from the baseline LRT culture in the ME population 
 
Per-subject microbiological response at TOC in the mITT population 
 
Per-pathogen microbiological response at TOC in the mITT population 
 
Per-subject microbiological response at EOT in the mITT population 
 
Per-pathogen microbiological response at EOT in the mITT population 
 
Per-pathogen microbiological response by baseline MIC in the mITT and ME populations 
 
Superinfection and new infection rates in the mITT population 
 
Emergence of nonsusceptibility to study drug in the mITT population 
 
Time to a ≥1-log reduction in bacterial burden of the causative gram-negative pathogen(s) 
identified from the baseline lower respiratory specimen in the mITT and ME populations 
 
Emergence of a 4-fold increase in MIC to study drug for treated subjects with P. aeruginosa or 
Enterobacteriaceae isolated from the baseline LRT culture (the elevated MIC must be ≥2 µg/mL) 
in the mITT population 
 
Pharmacokinetics 
 
Total number of days in hospital within 28 days after randomization for the ITT population 
 
Proportion of patients discharged from the acute care hospital within 28 days  after randomization 
for the ITT population 
 
Number of days in ICU through 28 days after randomization for the ITT population 
 
Number of days on a ventilator through 28 days after randomization for the ITT population 
 
Change in procalcitonin from baseline to Day 3 and to EOT in the ITT population. 
 
Safety: Safety will be evaluated in the Safety population through review of summaries of deaths, serious adverse 
events (SAEs), adverse events (AEs), laboratory evaluations, vital signs, and physical examinations. 
 
Study Endpoints per the EMA: 
Primary Endpoint: 
 
Clinical response at the TOC visit in the ITT population 
Key Secondary Endpoint: 
 
Day 28 all-cause mortality in the ITT population 
 
 
 
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Secondary Endpoints: 
 
Clinical response at the TOC visit in the CE population 
 
Clinical response for subjects at the TOC visit in the subset of subjects who had P. aeruginosa 
isolated from the baseline LRT culture in the mITT population 
 
Clinical response for subjects at the TOC visit in the subset of subjects who had Enterobacteriaceae 
isolated from the baseline LRT culture in the mITT population 
 
Per-subject microbiological response at TOC in the ME population 
 
Per-pathogen microbiological response for P. aeruginosa at TOC in the ME population 
 
Per-pathogen microbiological response for Enterobacteriaceae at TOC in the ME population 
 
Per-pathogen microbiological response at TOC in the ME population 
 
Day 28 all-cause mortality in the mITT population 
 
Day 14 all-cause mortality in the ITT population 
 
Clinical response at EOT in the ITT and CE populations 
 
Clinical response at the LFU visit in the CE population 
 
Per-subject microbiological response at EOT in ME population 
 
Per-pathogen microbiological response at EOT in the ME population 
 
Per-pathogen clinical response at TOC by baseline MIC in the mITT and ME populations 
Exploratory Endpoints: 
 
Time to all-cause mortality in the ITT population 
 
Clinical response for subjects at TOC in the subset of subjects who had P. aeruginosa isolated 
from the baseline LRT culture in the ME population 
 
Clinical response for subjects at TOC in the subset of subjects who had Enterobacteriaceae isolated 
from the baseline LRT culture in the ME population 
 
Per-subject microbiological response at TOC in the mITT population 
 
Per-pathogen microbiological response at TOC in the mITT population 
 
Per-subject microbiological response at EOT in mITT population 
 
Per-pathogen microbiological response at EOT in the mITT population 
 
Per-pathogen microbiological response by baseline MIC in the mITT and ME populations 
 
Superinfection and new infection rates in the mITT population 
 
Emergence of nonsusceptibility to study drug in the mITT population 
 
Time to a ≥1-log reduction in bacterial burden of the causative gram-negative pathogen(s) 
identified from the baseline lower respiratory specimen in the mITT and ME populations 
 
Emergence of a 4-fold increase in MIC to study drug for treated subjects with P. aeruginosa or 
Enterobacteriaceae isolated from the baseline LRT culture (the elevated MIC must be ≥2 µg/mL) 
in the mITT population  
 
Pharmacokinetics 
 
Total number of days in hospital within 28 days after randomization for the ITT population 
 
Proportion of patients discharged from the acute care hospital within 28 days  after randomization 
for the ITT population 
 
Number of days in ICU through 28 days after randomization for the ITT population 
 
Number of days on a ventilator through 28 days after randomization for the ITT population 
 
To evaluate the change in procalcitonin from baseline to Day 3 and to EOT visit in the ITT 
population 
 
Safety: Safety will be evaluated in the Safety population through review of summaries of deaths, SAEs, AEs, 
laboratory evaluations, vital signs, and physical examinations. 
 
 
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Statistical methods: 
Primary Efficacy Analysis per US FDA: 
For analyses of dichotomous endpoints, 2-sided 95% confidence intervals (CI) for the difference in proportions 
between ceftolozane/tazobactam and meropenem will be calculated, with adjustment for the study stratification 
factors (diagnosis [VABP or ventilated HABP] and by age [≥65 or <65 years]).  The estimated overall 
proportion will be calculated as a weighted average across all strata, constructed using Mehrotra-Railkar 
continuity-corrected minimum-risk [MRc] stratum weights [22].  The 2-sided 95% confidence interval (CI) for 
the treatment group proportions and the treatment difference will be calculated as stratified Newcombe CIs, 
constructed using the MRc weights with the methods presented by Yan and Su [23]. 
 
Primary Efficacy Analysis per EMA: 
Similar general methodologies detailed in the preceding US FDA Analysis section will be employed; however, a 
2-sided 97.5% CI will be constructed instead of 95% CIs. 
 
Sample Size and Power Considerations for the US FDA Analysis: 
To demonstrate the non-inferiority of ceftolozane/tazobactam to meropenem with respect to the difference in 
Day 28 all-cause mortality rates, using a non-inferiority margin of 10%, a sample size of 726 subjects (363 per 
arm) in the ITT population will have 90% power at a 1-sided significance level of 0.025, assuming a Day 28 
all-cause mortality rate of 20% in both ceftolozane/tazobactam and meropenem arms. 
 
Sample Size and Power Considerations per the EMA Analysis: 
To demonstrate the non-inferiority of ceftolozane/tazobactam to meropenem with respect to the difference in 
clinical cure rates of VNP at the TOC visit in the ITT population, using a non-inferiority margin of 12.5%, at a 
1-sided significance level of 0.0125, a sample size of 726 subjects (363 per arm) will have 85.3% power 
assuming a cure rate of 58.4% in both ceftolozane/tazobactam and meropenem arms. 
 
 
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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
1. 
SUMMARY OF CHANGES ........................................................................................4 
1.1. 
Primary Reasons for this Amendment ..........................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............13 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................22 
5. 
INTRODUCTION ......................................................................................................25 
5.1. 
Nosocomial Pneumonia ..............................................................................................25 
5.2. 
Ceftolozane/tazobactam for Injection .........................................................................26 
5.3. 
Nonclinical Experience ...............................................................................................27 
5.4. 
Clinical Experience .....................................................................................................27 
5.4.1. 
Pharmacokinetics ........................................................................................................28 
5.4.2. 
Safety ..........................................................................................................................28 
5.5. 
Summary of Risks and Benefits .................................................................................30 
5.5.1. 
Ceftolozane/tazobactam ..............................................................................................30 
5.5.2. 
Meropenem .................................................................................................................30 
5.6. 
Rationale .....................................................................................................................31 
5.6.1. 
Study Rationale ...........................................................................................................31 
5.6.2. 
Dose Rationale ............................................................................................................32 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................37 
6.1. 
Study Objectives per the US FDA ..............................................................................37 
6.2. 
Study Objectives per the European Medicines Agency (EMA) .................................38 
7. 
INVESTIGATIONAL PLAN .....................................................................................41 
7.1. 
Overall Study Design ..................................................................................................41 
7.2. 
Study Visits .................................................................................................................46 
7.2.1. 
Screening (Baseline) ...................................................................................................46 
7.2.2. 
Treatment Period ........................................................................................................46 
7.2.3. 
End-of-therapy Visit ...................................................................................................46 
7.2.4. 
Test-of-cure Visit ........................................................................................................46 
 
 
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7.2.5. 
Late Follow-up Visit ...................................................................................................46 
7.3. 
Number of Subjects ....................................................................................................47 
7.4. 
Treatment Assignment ................................................................................................47 
7.5. 
Dose Adjustment Criteria ...........................................................................................47 
7.6. 
Criteria for Study Termination ...................................................................................49 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................50 
8.1. 
Subject Inclusion Criteria ...........................................................................................50 
8.2. 
Subject Exclusion Criteria ..........................................................................................52 
8.3. 
Subject Withdrawal Criteria .......................................................................................54 
8.3.1. 
Early Termination .......................................................................................................54 
8.3.2. 
Criteria for Premature Discontinuation of Study Drug or Subject 
Withdrawal from Study ..............................................................................................54 
8.3.3. 
Procedures for Premature Discontinuation of Study Drug .........................................55 
8.3.4. 
Replacement Policy ....................................................................................................55 
9. 
TREATMENT OF SUBJECTS ..................................................................................56 
9.1. 
Description of Study Drug ..........................................................................................56 
9.1.1. 
Investigational Product: Ceftolozane/tazobactam ......................................................56 
9.1.2. 
Active Comparator:  Meropenem ...............................................................................56 
9.2. 
Prior, Concomitant, and Adjunctive Medications and Procedures .............................56 
9.2.1. 
Prohibited Medications ...............................................................................................56 
9.2.2. 
Nonstudy Antibiotic Use ............................................................................................57 
9.2.3. 
Guidance on Empiric Adjunctive Therapy .................................................................57 
9.2.3.1. 
Gram-positive Adjunctive Therapy ............................................................................57 
9.2.3.2. 
Gram-negative Adjunctive Therapy ...........................................................................58 
9.2.3.3. 
Guidance on Study Drug Therapy following Baseline Culture Results .....................58 
9.3. 
Screening, Randomization, and Blinding ...................................................................59 
9.3.1. 
Screening Procedure ...................................................................................................59 
9.3.2. 
Subject Identification and Numbering ........................................................................59 
9.3.3. 
Randomization ............................................................................................................59 
9.3.4. 
Blinding ......................................................................................................................60 
9.3.5. 
Unblinding of Subjects ...............................................................................................60 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................61 
10.1. 
Study Drug ..................................................................................................................61 
 
 
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10.2. 
Study Drug Packaging and Labeling ..........................................................................61 
10.3. 
Study Drug Storage .....................................................................................................61 
10.4. 
Study Drug Preparation ..............................................................................................61 
10.4.1. 
Ceftolozane/tazobactam ..............................................................................................61 
10.4.2. 
Meropenem .................................................................................................................61 
10.5. 
Administration ............................................................................................................61 
10.6. 
Study Drug Accountability .........................................................................................61 
11. 
ASSESSMENT OF EFFICACY ................................................................................62 
11.1. 
Clinical Assessments ..................................................................................................62 
11.1.1. 
Medical/Surgical History ............................................................................................62 
11.1.2. 
Physical Examination and Clinical Symptom Assessment ........................................62 
11.1.3. 
APACHE II Score .......................................................................................................62 
11.1.4. 
Assessment of Need for Adjunctive Gram-negative Therapy at Baseline .................62 
11.1.5. 
PaO2/FiO2 ...................................................................................................................63 
11.1.6. 
Clinical Pulmonary Infection Score ............................................................................63 
11.1.7. 
Sepsis Organ Failure Assessment Score .....................................................................63 
11.1.8. 
Evaluation of the Baseline Lower Respiratory Tract Culture ....................................63 
11.1.9. 
Assessment of Clinical Response ...............................................................................63 
11.2. 
Chest X-ray .................................................................................................................63 
11.3. 
Microbiological Assessments .....................................................................................63 
11.3.1. 
Specimens for Quantitative Lower Respiratory Tract Culture ...................................63 
11.3.2. 
Gram Stains ................................................................................................................64 
11.3.3. 
Specimens for Blood Culture ......................................................................................64 
12. 
ASSESSMENT OF SAFETY .....................................................................................65 
12.1. 
Safety Parameters .......................................................................................................65 
12.1.1. 
Laboratory Assessments .............................................................................................65 
12.1.1.1. 
Hematology and Coagulation .....................................................................................65 
12.1.1.2. 
Blood Chemistry .........................................................................................................65 
12.1.1.3. 
Creatinine Clearance ...................................................................................................65 
12.1.2. 
Other Blood Sampling ................................................................................................66 
12.1.2.1. 
Pharmacokinetic Sample Collection ...........................................................................66 
12.1.2.2. 
Pregnancy Screen ........................................................................................................66 
12.2. 
Adverse and Serious Adverse Events .........................................................................66 
 
 
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12.2.1. 
Definition of Adverse Events .....................................................................................67 
12.2.1.1. 
Adverse Event .............................................................................................................67 
12.2.1.2. 
Serious Adverse Event ................................................................................................67 
12.2.2. 
Overdose .....................................................................................................................68 
12.2.3. 
Planned Hospitalization ..............................................................................................68 
12.2.4. 
Monitoring of Adverse Events ....................................................................................68 
12.2.5. 
Monitoring of Laboratory Assessments ......................................................................68 
12.3. 
Relationship to Study Drug ........................................................................................69 
12.4. 
Recording Adverse Events .........................................................................................69 
12.4.1. 
Assessment of Severity ...............................................................................................69 
12.4.2. 
Reference Safety Information for the Assessment of Expectedness of 
AEs .............................................................................................................................70 
12.5. 
Reporting Adverse Events ..........................................................................................70 
12.5.1. 
Reporting of Nonserious Adverse Events ...................................................................70 
12.5.2. 
Reporting of Drug Exposure During Pregnancy ........................................................70 
12.5.3. 
Reporting of Expedited Safety Observations by the Investigator ..............................71 
12.5.4. 
Expedited Reporting by the Sponsor to Applicable Health Authorities .....................71 
12.5.5. 
Safety Notifications by the Sponsor to Investigators .................................................71 
12.5.6. 
Unblinding Treatment for a Subject During the Trial ................................................71 
13. 
STATISTICS ..............................................................................................................72 
13.1. 
Data Collection, Processing and Reporting ................................................................72 
13.2. 
Statistical Considerations ............................................................................................72 
13.2.1. 
Analysis per the US FDA ...........................................................................................72 
13.2.1.1. 
General Methodology .................................................................................................72 
13.2.1.2. 
Multiple Comparisons and Multiplicity Adjustments ................................................73 
13.2.2. 
Analysis per the EMA ................................................................................................73 
13.2.2.1. 
General Methodology .................................................................................................73 
13.2.2.2. 
Multiple Comparisons and Multiplicity Adjustments ................................................74 
13.2.3. 
Handling of Missing Data ...........................................................................................74 
13.2.4. 
Populations for Analysis .............................................................................................75 
13.2.4.1. 
Intent-to-treat Population ............................................................................................75 
13.2.4.2. 
Safety Population ........................................................................................................75 
13.2.4.3. 
Microbiological Intent-to-treat Population .................................................................75 
 
 
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13.2.4.4. 
Clinically Evaluable Population .................................................................................75 
13.2.4.5. 
Microbiologically Evaluable Population ....................................................................75 
13.2.5. 
Study Endpoints ..........................................................................................................76 
13.2.6. 
Subject Disposition .....................................................................................................77 
13.2.7. 
Demographics and Baseline Data ...............................................................................77 
13.2.8. 
Primary Endpoint Analysis .........................................................................................78 
13.2.8.1. 
Primary Efficacy Analysis per the US FDA ...............................................................78 
13.2.8.2. 
Primary Efficacy Analysis per the EMA ....................................................................78 
13.2.9. 
Secondary and Exploratory Endpoint Analyses .........................................................79 
13.2.9.1. 
Key Secondary Endpoints per US FDA Analyses ......................................................79 
13.2.9.2. 
Key Secondary Endpoints per EMA Analyses ...........................................................79 
13.2.9.3. 
Other Secondary and Exploratory Endpoints (Per the USA FDA and 
EMA Analyses) ..........................................................................................................79 
13.2.10. 
Safety Analyses ..........................................................................................................80 
13.2.10.1. Adverse Events ...........................................................................................................80 
13.2.10.2. Vital Signs ..................................................................................................................80 
13.2.10.3. PaO2/FiO2 ...................................................................................................................80 
13.2.10.4. Clinical Pulmonary Infection Score ............................................................................80 
13.2.10.5. Sepsis Organ Failure Assessment Score .....................................................................80 
13.2.10.6. Safety Laboratory Tests ..............................................................................................80 
13.2.10.7. Prior and Concomitant Medications ...........................................................................80 
13.2.11. 
Sample Size and Power Considerations .....................................................................80 
13.2.11.1. Sample Size and Power Considerations per the US FDA Analysis ...........................80 
13.2.11.2. Sample Size and Power Considerations per the EMA Analysis .................................81 
13.2.12. 
Statistical Analysis Plans ............................................................................................81 
13.2.13. 
Pharmacokinetics ........................................................................................................81 
13.3. 
Evaluation Criteria ......................................................................................................81 
13.3.1. 
Clinical Response Definitions ....................................................................................81 
13.3.1.1. 
Clinical Outcomes at the EOT and TOC Visit ...........................................................82 
13.3.1.2. 
Clinical Outcomes at the LFU Visit ...........................................................................82 
13.3.2. 
Microbiological Response Definitions .......................................................................83 
13.3.2.1. 
Per-pathogen Microbiologic Outcomes at the EOT and TOC Visits .........................83 
13.3.2.2. 
Per-subject Microbiologic Outcomes at the EOT and TOC Visits .............................84 
 
 
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13.3.2.3. 
Emergent Infection .....................................................................................................84 
13.4. 
Data and Safety Monitoring Board .............................................................................85 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................86 
14.1. 
Study Monitoring ........................................................................................................86 
14.1.1. 
Protocol Deviations/Amendments ..............................................................................86 
14.1.2. 
Discontinuation of the Study ......................................................................................87 
14.2. 
Audits and Inspections ................................................................................................87 
14.3. 
Institutional Review Board .........................................................................................87 
14.3.1. 
Informed Consent and Screening Data .......................................................................87 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................89 
16. 
ETHICS ......................................................................................................................90 
16.1. 
Ethics Review .............................................................................................................90 
16.2. 
Ethical Conduct of the Study ......................................................................................90 
16.3. 
Written Informed Consent ..........................................................................................90 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................91 
17.1. 
Inspection of Records .................................................................................................91 
17.2. 
Retention of Records ..................................................................................................91 
18. 
PUBLICATION POLICY ..........................................................................................92 
19. 
LIST OF REFERENCES ............................................................................................93 
20. 
APPENDICES ............................................................................................................96 
APPENDIX A. SAFETY CONTACT INFORMATION ...........................................................97 
APPENDIX B. ACUTE PHYSIOLOGICAL ASSESSMENT AND CHRONIC 
HEALTH EVALUATION (APACHE) II SCORING SYSTEM ...............................98 
APPENDIX C. MODIFIED CLINICAL PULMONARY INFECTION SCORE ....................101 
APPENDIX D. SEPSIS-RELATED ORGAN FAILURE ASSESSMENT (SOFA) 
SCORE .....................................................................................................................102 
APPENDIX E. O2 SATURATION TO PAO2 CONVERSION TABLE..................................103 
APPENDIX F. THE ASSESSMENT PLAN OF SEPSIS ........................................................104 
1. 
DEFINITION OF SEPSIS ........................................................................................104 
2. 
RATIONALE OF SEPSIS ASSESSMENT .............................................................104 
3. 
TRIAL OBJECTIVES OF SEPSIS ASSESSMENT ................................................104 
3.1. 
Study Objectives .......................................................................................................104 
4. 
THE CRITERIA OF SEPSIS ...................................................................................104 
 
 
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5. 
STATISTICS OF SEPSIS ASSESSMENT ..............................................................105 
5.1. 
Handling of Missing Data .........................................................................................105 
5.2. 
Populations for Analysis ...........................................................................................105 
5.2.1. 
Sepsis Population ......................................................................................................105 
5.3. 
Study Endpoints ........................................................................................................105 
5.4. 
Efficacy Endpoint Analyses .....................................................................................105 
5.4.1. 
Primary Endpoint Analysis .......................................................................................105 
5.4.2. 
Secondary Endpoint Analysis ...................................................................................106 
5.5. 
Safety Analysis .........................................................................................................106 
5.5.1. 
Adverse Events .........................................................................................................106 
5.6. 
Evaluation Criteria of Sepsis ....................................................................................106 
5.6.1. 
Definition of Clinical Response for Sepsis ...............................................................106 
5.6.2. 
Definition of Microbiological Response for Sepsis ..................................................106 
5.6.2.1. 
Microbiologic Outcome for Sepsis ...........................................................................107 
6. 
LIST OF REFERENCES ..........................................................................................108 
 
 
 
 
 
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LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................22 
Table 2: 
Probability of Target Attainment for Dosing Regimen, MIC, and 
%T>MIC (Utilizing a Population PK Model) for Enterobacteriaceae and 
P. aeruginosa Strains ..................................................................................................33 
Table 3: 
Probability of Target Attainment for 2 Doses of Ceftolozane/tazobactam 
(q8h, 1-hour infusion) by MIC and %T>MIC Stratified by Creatinine 
Clearance ....................................................................................................................34 
Table 4: 
Probability of Target Attainment Versus Key Pathogens in Nosocomial 
Pneumonia Using the Simulated 3000-mg Dose of 
Ceftolozane/tazobactam ..............................................................................................35 
Table 5: 
Treatment-emergent Adverse Events Reported in Study CXA-MD-11-07 
(Safety Population) .....................................................................................................36 
Table 6: 
Schedule of Assessments ............................................................................................43 
Table 7: 
Dose Adjustments for Subjects Randomized to Ceftolozane/tazobactam 
Intravenous 60-minute Infusions ................................................................................48 
Table 8: 
Dose Adjustments for Subjects Randomized to Meropenem Intravenous 
60-minute Infusions ....................................................................................................48 
Table 9: 
Dosing Schedule for Subjects with CLCR ≤50 mL/min ..............................................49 
Table 10: Study Endpoints per Different Regulatory Jurisdictions ............................................76 
Table 11: Clinical Response Categories at the EOT and TOC Visit ..........................................82 
Table 12: Clinical Response Categories at the LFU Visit ..........................................................83 
Table 13: Per-pathogen Microbiologic Outcome Categories at the EOT and TOC 
Visits ...........................................................................................................................83 
Table 14: Per-subject Microbiologic Outcome Categories at the EOT and TOC 
Visits ...........................................................................................................................84 
Table 15: New Pathogens ...........................................................................................................84 
 
Table F-1: Clinical Response Categories for Sepsis at the TOC Visit .......................................106 
Table F-2: Microbiologic Outcome Categories for Sepsis at the TOC Visit .............................107 
  
 
 
 
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LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................42 
 
 
 
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms 
Abbreviation 
Definition 
AE 
Adverse event 
ALT (SGPT) 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
APACHE 
Acute Physiology and Chronic Health Evaluation 
AST (SGOT) 
Aspartate aminotransferase 
AUC 
Area under the curve 
BAL 
Bronchoalveolar lavage 
BLI 
β-lactamase inhibitor 
BUN 
Blood urea nitrogen 
CE 
Clinically Evaluable 
CFR 
Code of Federal Regulations 
CFU 
Colony forming unit 
CI 
Confidence interval 
cIAI 
Complicated intra-abdominal infections 
CLCR  
Creatinine clearance 
COPD 
Chronic obstructive pulmonary disease 
CPIS 
Clinical Pulmonary Infection Score 
CRP 
C-reactive protein 
CT 
Computed tomography 
cUTI 
Complicated urinary tract infections 
CYP450 
Cytochrome P450 
D 
Day 
DAO 
Data-as-Observed 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ELF 
Epithelial lining fluid 
 
 
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Abbreviation 
Definition 
EMA 
European Medicines Agency 
EOT 
End of therapy 
ESBL 
Extended spectrum β-lactamase 
ETA 
Endotracheal aspirate 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HABP 
Hospital-acquired bacterial pneumonia 
HIV 
Human immunodeficiency virus 
h 
Hour 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technologies 
ITT 
Intent-to-Treat 
Kg 
Kilogram 
IV 
Intravenous 
L 
Liter 
LAR 
Legally-authorized representative 
LFU 
Late follow-up 
LRT 
Lower respiratory tract 
M1 
Tazobactam metabolite 
MAOI 
Monoamine oxidase inhibitor (MAOI) 
MDR 
Multidrug resistant 
ME 
Microbiologically evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities 
µg 
Microgram 
mg 
Milligram 
MIC 
Minimum inhibitory concentration 
min 
Minute 
mini-BAL 
nonbronchoscopic bronchoalveolar lavage 
mITT 
Microbiological Intent-to-Treat 
 
 
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Abbreviation 
Definition 
mL 
Milliliter 
MRc 
Continuity-corrected minimum risk 
MRSA 
Methicillin-resistant Staphylococcus aureus 
MSSA 
Methicillin-susceptible Staphylococcus aureus 
NYHA 
New York Heart Association 
PaO2/FiO2 
Partial pressure of oxygen to the fraction of inspired oxygen 
PBP 
Penicillin-binding protein 
PBS 
Protected brush specimen 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PTA 
Probability of target attainment 
q8h 
Every eight hours 
q12h 
Every twelve hours 
RSI 
Reference Safety Information 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOFA 
Sepsis Organ Failure Assessment 
t½  
Terminal half-life 
%T>MIC 
Time above the minimum inhibitory concentration 
TEAE 
Treatment-emergent adverse event 
TFA 
Treatment Failure Approach 
TOC 
Test-of-cure 
US 
United States 
ULN 
Upper limit of normal 
VABP 
Ventilator-associated bacterial pneumonia 
VNP 
Ventilated nosocomial pneumonia 
Vss 
Volume of distribution at steady state 
WBC 
White blood cell 
 
 
 
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5. 
INTRODUCTION 
5.1. 
Nosocomial Pneumonia 
Nosocomial pneumonia is a prevalent hospital-acquired infection associated with increased 
morbidity, mortality, and prolongation of hospital stay [1].  As much as 50% of all deaths 
associated with nosocomial infection are due to nosocomial pneumonia.  A diagnosis of 
nosocomial pneumonia has been linked to prolongation of hospital stay by an excess of 
4 days at an additional cost of $40,000 or more per patient [2,3]. 
The term nosocomial pneumonia encompasses hospital-acquired bacterial pneumonia 
(HABP), ventilator-associated bacterial pneumonia (VABP), and healthcare-associated 
pneumonia.  According to the 2005 American Thoracic Society/Infectious Diseases Society 
of America guidelines, HABP is defined as pneumonia occurring 48 hours or more after 
hospital admission, which was not incubating at the time of admission [4].  It is typically 
characterized by the presence of new or progressive infiltrates on chest radiography 
associated with clinical symptoms suggestive of pneumonia (eg, fever, leukocytosis, and 
production of purulent sputum) [4].  Ventilator-associated bacterial pneumonia is a subset of 
HABP, and develops in mechanically ventilated patients 48 to 72 hours after endotracheal 
intubation [4].  Healthcare-associated pneumonia includes any patient with recent health-care 
exposure, including those hospitalized in an acute care hospital, nursing home, long-term 
care, or skilled nursing facility [4]. 
Gram-negative bacilli account for greater than 50% of commonly isolated pathogens in 
nosocomial pneumonia.  Notable among these are Pseudomonas aeruginosa, Enterobacter 
spp., Klebsiella pneumoniae, and Acinetobacter spp. [4,5,6].  Other commonly isolated lower 
respiratory tract (LRT) pathogens include Streptococcus pneumoniae, Haemophilus 
influenzae, Escherichia coli, Klebsiella spp., Proteus spp., Staphylococcus aureus, and 
Serratia marcescens.  Recent trends show an increase in the prevalence of nosocomial 
pneumonia caused by multidrug resistant (MDR) bacteria, most commonly P. aeruginosa 
with documented resistance to β-lactams, carbapenems, aminoglycosides, and 
fluoroquinolones [6,7].  The therapeutic effectiveness of current therapies for nosocomial 
pneumonia (especially ventilated nosocomial pneumonia [VNP]) are limited by the 
increasing prevalence of pathogens that express extended spectrum β-lactamases (ESBLs), 
AmpC β-lactamases, or methicillin resistance, emphasizing the need for development of new 
and effective antimicrobials [8]. 
Initial empiric antibiotic treatment may include the use of cephalosporins, aminoglycosides, 
fluoroquinolones, penicillins, or carbapenems alone or in combination.  Antibiotic selection 
is typically individualized based on a given patient’s risk factors for MDR pathogens (eg, 
prior hospitalization, admission from a long term care or skilled nursing facility, recent 
antibiotic exposure) and local susceptibility patterns [4,8].  Prompt and adequate 
antimicrobial therapy has been shown to reduce mortality and improve morbidity associated 
with nosocomial pneumonia [9]. 
 
 
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5.2. 
Ceftolozane/tazobactam for Injection 
Ceftolozane/tazobactam, an antibacterial consisting of ceftolozane, a novel antipseudomonal 
cephalosporin, with tazobactam, a well-established β-lactamase inhibitor (BLI), is being 
developed for the treatment of serious bacterial infections.  Ceftolozane/tazobactam is 
currently approved for use in adult patients with complicated urinary tract infections (cUTI) 
and complicated intraabdominal infections (cIAI) at a dose of 1500 milligrams (mg; 
compromising 1000 mg ceftolozane and 500 mg tazobactam) every 8 hours (q8h). 
Like other members of the cephalosporin class, ceftolozane exerts its bactericidal activity by 
inhibiting essential penicillin-binding proteins (PBPs), resulting in inhibition of bacterial cell 
wall synthesis and subsequent cell death.  Tazobactam is an inhibitor of most Class A and 
some Class C β-lactamases, with well-established in vitro and in vivo activity in combination 
with active β-lactams. 
Ceftolozane displays potent antibacterial activity against common gram-negative and 
selected gram-positive organisms, including pathogens involved in respiratory infections, 
such as P. aeruginosa, E. coli, K. pneumoniae, Enterobacter spp., Streptococcus spp., H. 
influenzae, Moraxella catarrhalis, and the majority of pathogenic enteric bacilli.  
Ceftolozane exhibits limited activity against Staphylococcus spp. and Enterococcus spp., 
insufficient for reliable treatment of this pathogen.  In general, the gram-positive and gram-
negative spectrum of activity of ceftolozane is similar to ceftazidime, but the 
antipseudomonal activity of ceftolozane is the most potent among all currently available 
β-lactams, including carbapenems.  Most importantly, ceftolozane has been shown to be 
active against strains of P. aeruginosa that are resistant to carbapenems, cephalosporins, 
fluoroquinolones, and aminoglycosides, including many MDR isolates. 
Ceftolozane is a potent PBP3 inhibitor, and shows affinities at least 2-fold higher than those 
of ceftazidime for all the essential PBPs (1b, 1c, and 3) in P. aeruginosa.  Like most 
cephalosporins, ceftolozane alone does not have activity against ESBL-producing 
Enterobacteriaceae and gram-negative anaerobes. 
Tazobactam increases the in vitro activity of ceftolozane against the majority of ESBL-
producing gram-negative bacilli and some AmpC over-expressing Enterobacteriaceae.  The 
addition of tazobactam has no significant impact on the antipseudomonal activity of 
ceftolozane, since P. aeruginosa rarely produces ESBLs.  Both ceftolozane and 
ceftolozane/tazobactam show time-dependent bactericidal activity against various gram-
negative organisms, with ceftolozane/tazobactam being more potent than 
piperacillin/tazobactam against Enterobacteriaceae (both ESBL-negative and ESBL-positive 
isolates) and P. aeruginosa. 
In summary, ceftolozane is a novel cephalosporin antibiotic which, in combination with the 
potent BLI, tazobactam, has broad-spectrum antibacterial coverage against β-lactam-resistant 
Enterobacteriaceae and MDR P. aeruginosa.  Both in vitro and in vivo efficacy data support 
its clinical development in nosocomial pneumonia as a potential human therapeutic agent for 
the treatment of severe bacterial infections caused by susceptible organisms, including 
Enterobacteriaceae and P. aeruginosa. 
 
 
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5.3. 
Nonclinical Experience 
When tested individually or in combination, ceftolozane and tazobactam (from historical data 
in combination with piperacillin) each displays an acceptable safety profile in animals.  In 
studies of ceftolozane alone, the no-observed-adverse-effect level for both rats and dogs was 
300 mg/kilogram (kg)/day.  Intravenous toxicity studies of up to 6 months duration have 
been performed with tazobactam alone and in combination with piperacillin in rats and dogs.  
Tazobactam appears to be very well tolerated, with no drug-related mortalities or serious 
clinical abnormalities.  The potential target organs identified in these studies were the 
hematological, hepatic, and gastrointestinal systems; however, only relatively minor changes 
were observed in each of these organ systems. 
The combination of ceftolozane and tazobactam did not increase the toxicity of the individual 
compounds in rats after 4 weeks of repeated dosing, and did not significantly alter the 
pharmacokinetic (PK) profile of the individual compounds in a dog study.  The combination 
of ceftolozane and tazobactam had similar PK characteristics, including a short plasma half-
life (t½), renal elimination, rapid distribution into the extracellular fluid compartment, and 
low plasma protein binding.  Because both of these compounds are primarily excreted by the 
kidney via glomerular filtration, the potential for drug-drug interactions is likely limited to 
drugs excreted by tubular secretion (eg, probenecid), as this is an alternate mechanism of 
tazobactam excretion. 
The efficacy of ceftolozane has been demonstrated in various animal models, including 
sepsis, pneumonia, urinary tract infection, burn wound, and thigh infection models.  In 
general, the in vivo efficacy of ceftolozane against P. aeruginosa, including MDR isolates, 
was better than, or comparable to that of ceftazidime, imipenem, and ciprofloxacin.  
Specifically, in a neutropenic mouse pneumonia model, ceftolozane demonstrated potent 
activity against K. pneumoniae and drug-resistant P. aeruginosa. 
In conclusion, ceftolozane/tazobactam has broad-spectrum antibacterial activity that includes 
cephalosporin- and carbapenem-resistant P. aeruginosa.  In vitro and in vivo efficacy, safety, 
and PK data support its clinical development as a potential human therapeutic agent for the 
treatment of severe bacterial infections. 
Refer to the Investigator’s Brochure/approved label for additional information on the 
nonclinical experience with ceftolozane/tazobactam. 
5.4. 
Clinical Experience 
Ceftolozane alone or ceftolozane/tazobactam has been evaluated in adults in ten completed 
Phase 1 studies, a Phase 2 study in cUTI, a Phase 2 study in cIAI, and two Phase 3 clinical 
studies (one in cUTI and one in cIAI). 
Doses as high as 9000 mg of ceftolozane/tazobactam per day (3000 mg q8h intravenously 
[IV]) have been given, and have generally been well tolerated by all subjects. 
Refer to the Investigator’s Brochure/approved label for additional information on the clinical 
experience with ceftolozane/tazobactam. 
 
 
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5.4.1. 
Pharmacokinetics 
The results from the adult Phase 1 and Phase 2 studies demonstrated ceftolozane/tazobactam 
PK characteristics are generally consistent with those of other renally-excreted β-lactam 
antibiotics.  Ceftolozane/tazobactam had linear PK across a wide range of doses (250 to 3000 
mg for ceftolozane and 100 to 1500 mg for tazobactam); and its volume of distribution at 
steady state (Vss), approximately 11 to 18 liters (L), was roughly equivalent to the 
extracellular fluid volume.  The plasma protein binding was low; approximately 16 to 21% 
and 30% for ceftolozane and tazobactam, respectively.  The t½ for ceftolozane and 
tazobactam was 2 to 3 hours and approximately 1 hour, respectively, independent of dose and 
with little or no accumulation after multiple dosing q8h or every 12 hours (q12h).  
Ceftolozane/tazobactam was primarily cleared from the systemic circulation into the urine by 
glomerular filtration, but tazobactam was also partly cleared by tubular secretion.  About 
20% of the tazobactam dose is converted to a single inactive metabolite (M1) via hydrolysis 
of the β-lactam ring while >95% for ceftolozane was eliminated as unchanged parent drug, 
suggesting minimal potential for cytochrome P450 (CYP450) mediated metabolism.  Co-
administration of ceftolozane/tazobactam given as 1-hour IV infusions in a fixed 2:1 ratio of 
ceftolozane to tazobactam did not change the PK profiles of either drug, nor of the 
tazobactam M1 metabolite. 
Systemic clearance was linearly related to creatinine clearance (CLCR), but no other 
significant intrinsic factors affecting the PK of ceftolozane/tazobactam were identified.  An 
ethno-bridging study that was conducted suggested that the PK of ceftolozane/tazobactam is 
dose-independent and comparable between Japanese, Chinese and Caucasian healthy 
subjects.  In addition, a drug-drug interaction study suggested a low potential for any 
CYP450 or transporter-mediated PK interaction, and there is a low potential for PK 
interaction with other drugs eliminated primarily by glomerular filtration, such as tobramycin 
and vancomycin. 
5.4.2. 
Safety 
Phase 1 studies suggested ceftolozane/tazobactam was safe and well tolerated.  The most 
common adverse events (AEs) in Phase 1 studies were mainly gastrointestinal in origin 
(nausea, vomiting, constipation and diarrhea), as well as headache and infusion site reactions.  
Multiple dose studies (CXA-101-01, CXA-201-01, and CXA-MD-11-07) demonstrated that 
doses of ceftolozane/tazobactam up to 9000 mg daily (3000 q8h) were well tolerated in 
adults for durations of up to 10 days.  The thorough QT study (CXA-QT-10-02) 
demonstrated that therapeutic and 3-fold supra-therapeutic dose of ceftolozane/tazobactam 
did not increase QTc, QTcF, and QTcB intervals, and no findings indicated an effect of 
ceftolozane/tazobactam on cardiac repolarization.  Only one serious adverse event (SAE) was 
reported in the ten Phase 1 studies for ceftolozane or ceftolozane/tazobactam.  One patient in 
study CXA-REN-11-01 reported an unrelated SAE of thrombosis of arteriovenous fistula on 
study day 44, 
.  Adverse 
events leading to discontinuation of ceftolozane/tazobactam in the Phase 1 studies were rare.  
One subject in study CXA-QT-10-02 discontinued due to an unrelated AE of fever, one 
subject in study CXA-MD-11-07 discontinued due to an AE of vomiting assessed by the 
Investigator as related, and one subject in study CXA-EB-13-05 discontinued due to an AE 
of acute drug eruption assessed by the Investigator as related. 
 
 
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In Phase 2 studies of ceftolozane in cUTI (CXA-101-03) and ceftolozane/tazobactam in cIAI 
(CXA-IAI-10-01), the most common AEs across both studies were pyrexia, nausea, 
constipation, sleep disorder, anemia, headache, vomiting, diarrhea and insomnia.  In study 
CXA-101-03, there was an imbalance in the incidence of hyperglycemia severity grade shifts 
which was neither associated with ongoing abnormalities in serum glucose nor reported as 
AEs.  In study CXA-IAI-10-01, there was an imbalance in the incidence of hemoglobin 
severity grade shifts in the ceftolozane/tazobactam group; however the decreases in 
hemoglobin appeared to be related to complicated surgical procedures in high-risk subjects or 
the subject’s underlying condition.  Collectively, three subjects experienced a shift from 
negative direct Coombs’ test at baseline to positive at the test of cure (TOC) visit, but none 
were associated with a report of hemolytic anemia. 
No deaths were reported in the ceftolozane/tazobactam treatment arm, and no subjects met 
laboratory criteria for Hy’s rule in study CXA-101-03.  However, in study CXA-IAI-10-01, 
three subjects died in the ceftolozane/tazobactam arm; all were unrelated to study drug and 
occurred following study drug discontinuation.  In the same study, one 
ceftolozane/tazobactam subject met the laboratory criteria for Hy’s rule on therapy.  These 
liver enzyme elevations were likely related to the underlying condition and surgical 
procedure as all levels declined during continued treatment. 
In the integrated Phase 3 studies of ceftolozane/tazobactam for cUTI and cIAI 
(CXA-cUTI-10-04, CXA-cUTI-10-05, CXA-cIAI-10-08, and CXA-cIAI-10-09), 1015 adult 
patients received treatment with ceftolozane/tazobactam.  The most common AEs from these 
trials were nausea, headache, diarrhea, pyrexia, constipation, hypertension, insomnia, and, 
vomiting.  Overall SAE rates were 5.3% and 5.2% in the ceftolozane/tazobactam and 
comparator arms, respectively.  Drug discontinuation rates due to AEs were similar, with 2% 
of patients who discontinued ceftolozane/tazobactam and 1.9% of patients who discontinued 
comparator drug.  Drug-related SAEs with ceftolozane/tazobactam were limited to only three 
cases (two cases of Clostridium difficile colitis and one of pseudomembranous colitis) 
compared to one drug-related SAE with comparator drug.  In cUTI, there was one death in 
the ceftolozane/tazobactam treatment arm and none in the comparator arm.  In cIAI, there 
were 11 deaths in the ceftolozane/tazobactam arm and eight deaths in the comparator arm.  
All of the deaths reported in these Phase 3 studies were deemed unrelated to study therapy by 
the Investigator.  Collectively, two subjects in Phase 3 experienced a shift from negative 
direct Coombs’ test at baseline to positive at the end of therapy visit, but none were 
associated with a report of hemolytic anemia. 
An open-label Phase 3 study in nosocomial pneumonia was electively terminated by the 
Sponsor after enrollment of four patients, in order to devote all resources in initiating and 
completing this larger registration study being conducted as part of the clinical development 
program for nosocomial pneumonia.  Two patients experienced SAEs, one in each arm, and 
the one in the ceftolozane/tazobactam treatment arm resulted in death.  Neither event was 
deemed to be related to study drug. 
 
 
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5.5. 
Summary of Risks and Benefits 
5.5.1. 
Ceftolozane/tazobactam 
The potential human toxicity of ceftolozane/tazobactam should be evaluated in the context of 
the human experience in clinical studies.  Ceftolozane and tazobactam have been studied in 
humans, both individually and as a combination.  The clinical experience for the combination 
product is described in Section 5.4.  To date, no clinically important or unexpected safety 
signal has been observed.  In general, ceftolozane/tazobactam appears safe and well tolerated 
in the populations studied, and its safety profile consistent with the cephalosporin class of 
antibiotics. 
As both ceftolozane and tazobactam are primarily excreted by the kidney via glomerular 
filtration, the potential for drug-drug interactions is likely limited to drugs excreted by 
tubular secretion (eg, probenecid), as this is an alternate mechanism of tazobactam excretion.  
In addition, a drug-drug interaction study (Section 5.4) suggested a low potential for any 
CYP450 or transporter-mediated PK interaction, and there is a low potential for PK 
interaction with other drugs eliminated primarily by glomerular filtration, such as tobramycin 
and vancomycin. 
For more detailed information regarding the risks and benefits associated with 
ceftolozane/tazobactam, please refer to the Investigator’s Brochure/approved label. 
5.5.2. 
Meropenem 
Meropenem is widely used for the treatment of a variety of serious bacterial infections, 
including nosocomial pneumonia.  Clinical practice and published treatment guidelines [4] 
for nosocomial pneumonia recommend a dosing regimen of 1000 mg q8h administered by IV 
infusion for meropenem. 
Meropenem is approved in the European Union and several other countries for treatment of 
nosocomial pneumonia and is widely used in the United States (US) for nosocomial 
infections.  It is generally considered one of the best available antibiotics for this indication, 
and appears in evidence-based guidelines as a first-line treatment option for nosocomial 
pneumonia [4,10].  Meropenem is highly potent, has a broad spectrum of activity against a 
range of bacterial organisms including most of the expected pathogens for this indication, 
and is stable to various bacterial resistance mechanisms [11]. 
The recommended dose in this indication, which will be used in this study, is 1000 mg q8h 
administered by IV infusion.  To facilitate blinding, meropenem will be administered in this 
study as a 1-hour infusion (versus over 30 minutes [min]) to match the duration of infusion of 
ceftolozane/tazobactam.  The efficacy of meropenem is not affected by administration in this 
way, as it is a β-lactam antibiotic that’s efficacy is dependent on the percent of time the drug 
concentration exceeds the minimum-inhibitory concentration (%T>MIC) of the pathogens 
being treated.  Improved efficacy of β-lactam antibiotics often requires either prolonged 
duration of infusion or more frequent dosing [4].  Prolonged infusions of meropenem, of 
longer than 1-hour, have been administered to nosocomial pneumonia patients with excellent 
results and without additional safety or tolerability risks [12,13]. In addition, meropenem, at 
 
 
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a dose of 1000 mg every 8 hours, has also been administrated as a 1-hour infusion in the 
completed Phase 3 cIAI study (Study CXA-cIAI-10-08/09) versus ceftolozane/tazobactam. 
The clinical safety of meropenem is well described in the clinical studies used to support its 
marketing authorization by the US Food and Drug Administration (FDA) [14].  In clinical 
studies of 2904 immunocompetent subjects treated with meropenem, the most frequently 
reported AEs were (>1% incidence): diarrhea (4.8%), nausea/vomiting (3.6%), inflammation 
at the injection site (2.4%), headache (2.3%), rash (1.9%), sepsis (1.6%), constipation (1.4%), 
apnea (1.3%), shock (1.2%), and pruritus (1.2%).  Premature discontinuation of meropenem 
due to AE was reported in 1.2% of subjects in these trials.  Other rare, but important AEs 
reported with meropenem include: hypersensitivity reactions, seizures, and 
C. difficile-associated diarrhea. Case reports have shown that co-administration of 
carbapenems, including meropenem, to patients receiving divalproex or valproic acid, may 
result in a reduction in valproic acid concentrations, increasing the risk for breakthrough 
seizures [14]. Due to the rapid onset and the extent of the decrease, co-administration of 
valproic acid/sodium valproate/valpromide with carbapenem agents should be avoided. 
5.6. 
Rationale 
5.6.1. 
Study Rationale 
Nosocomial pneumonia is often associated with high morbidity and mortality.  Current 
literature suggests that the pathogens in patients with nosocomial pneumonia often include 
MDR gram-negative pathogens as well as S. aureus [15,16].  Prompt therapy with effective 
antibiotics has been shown to significantly improve survival for subjects with nosocomial 
pneumonia.  There are limited clinical data correlating epithelial lining fluid (ELF) 
concentrations and clinical outcome; hence, the clinical significance of differences in 
pulmonary penetration of antibiotics is unknown.  However, adequate antibiotic 
concentrations at the site of bacterial infection are required for efficacy and there are some 
data that demonstrate that ELF concentrations predict effective concentrations in pneumonia. 
The intrapulmonary penetration of the 1500 mg q8h dose of ceftolozane/tazobactam was 
studied in a comparative ELF healthy volunteer study, using piperacillin/tazobactam as a 
comparator.  The results showed that the ceftolozane component of ceftolozane/tazobactam 
had an ELF/Plasma area under the curve (AUC) ratio of 0.48, compared to 0.26 for the 
piperacillin component of piperacillin/tazobactam.  In addition, the concentration of 
ceftolozane in the ELF exceeded 8 µg/mL for more than 60% of its 8-hour dosing interval.  
These results confirm that ceftolozane penetrates well into the ELF and that its penetration 
was comparable to piperacillin/tazobactam (a β-lactam approved for treatment of lower 
respiratory infections), supporting ceftolozane’s potential utility as an effective therapeutic 
agent in nosocomial pneumonia.  Ceftolozane/tazobactam is well suited for study as a 
potential therapeutic agent in VNP because of its good intrapulmonary penetration and broad 
spectrum activity against gram-negative pathogens, including MDR P. aeruginosa and most 
ESBL-producing Enterobacteriaceae. 
This study is designed to assess the safety and efficacy of ceftolozane/tazobactam in subjects 
with VNP, comprising VABP and ventilated HABP compared with meropenem, a 
 
 
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well-characterized β-lactam antibiotic widely used for the treatment of nosocomial 
pneumonia. 
5.6.2. 
Dose Rationale 
Ceftolozane/tazobactam was studied in Phase 3 trials of adult subjects with either cUTI or 
cIAI at a dose of 1500 mg (ie, 1000 mg of ceftolozane with 500 mg tazobactam).  The 
1500-mg dose selected for the cUTI and cIAI indications was supported by the safety and 
efficacy results of 2 successful randomized, controlled Phase 2 studies (CXA-101-03 and 
CXA-IAI-10-01).  However, due to the increased variability in PK seen in subjects with 
nosocomial pneumonia and the increasing prevalence of MDR bacteria in this subject 
population, a higher (3000 mg) dose was selected for this study.  This is consistent with 
current clinical practice as other β-lactam antibiotics, such as meropenem, have been used at 
higher doses for more serious and difficult-to-treat infections, such as VNP. 
The infusion duration selected for the 3000 mg dose is 1 hour.  The 1-hour infusion duration 
was based on the pharmacokinetic/pharmacodynamics (PK/PD) driver for 
ceftolozane/tazobactam.  Similar to other β-lactam antibiotics (including the cephalosporins) 
efficacy is dependent on the %T>MIC of the pathogens being treated.  Therefore, the 1-hour 
infusion was selected to ensure optimum activity based on the %T>MIC parameter. 
A robust and comprehensive dose evaluation process was used to select the dose for the 
treatment of subjects with nosocomial pneumonia caused by gram-negative pathogens.  A 
summary of this dose selection approach is as follows: 
PK/PD analyses of nonclinical data: 
 Dose-fractionation studies in animal models of infection determined that the potency 
of ceftolozane was dependent on the %T>MIC for the infecting pathogen. 
 Data from the mouse neutropenic thigh infection model demonstrated that for 
ceftolozane the %T>MIC required for in vivo stasis is 21.4 to 28.5 and for 1-log kill 
is 26.7 to 35.3.  The ceftolozane %T>MIC required for bactericidal activity were 
similar for both Enterobacteriaceae and P. aeruginosa. 
 Once the PD parameter correlating with efficacy was identified, PK/PD analyses of 
observed human PK data from Phase 1 and 2 studies were used to select the dose. 
PK/PD analyses of clinical data:  
 A stable, reliable, and interpretable population PK model was developed.  This 
population PK model characterized observed clinical PK data and allowed a 
calculation of %T>MIC for individual PK profiles.  To better understand the 
distribution and inherent increased variability in PK profiles that might result 
from a much larger sample size in the Phase 3 clinical trials, 1000 replicate Monte 
Carlo simulations were performed to derive the probability of target attainment 
(PTA; the probability of achieving the target of 40% or 50% time above minimum 
inhibitory concentration [MIC] values of pathogens).  PK/PD analysis was also 
performed to determine the PTA against various pathogens based on the MIC 
distributions of ceftolozane/tazobactam from a 2008 surveillance study. 
 
 
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Population PK combined with Monte Carlo simulations of observed clinical data is a 
well-established PK/PD approach in antibiotic clinical development that ensures a thorough 
exposure-response evaluation necessary for selecting the most optimal dose of antibiotics 
[17].  Based on the PTA from PK/PD analysis, and demonstrated safety/tolerability, a dose of 
3000 mg q8h ceftolozane/tazobactam administered by IV infusion was selected for the 
treatment of subjects with nosocomial pneumonia caused by gram-negative pathogens.  
Table 2 shows the PTA for 2 different doses of ceftolozane/tazobactam across a range of 
%T>MIC thresholds between 30 to 60%. 
Table 2: 
Probability of Target Attainment for Dosing Regimen, MIC, and 
%T>MIC (Utilizing a Population PK Model) for Enterobacteriaceae and 
P. aeruginosa Strains 
Ceftolozane/tazobactam 
MIC (µg/mL) 
%T>MIC 
30% 
35% 
40% 
45% 
50% 
60% 
1500 mg 
q8h 60-min infusion 
4 
100 
100 
100 
100 
99.7 
95.5 
8 
100 
99.7 
98.2 
96.1 
89.8 
74.6 
16 
96.1 
85.0 
74.9 
57.8 
44.9 
24.6 
3000 mg 
q8h 60-min infusion 
4 
100 
100 
100 
100 
100 
100 
8 
100 
100 
100 
100 
99.4 
97.0 
16 
100 
99.7 
98.8 
95.8 
90.7 
75.1 
Abbreviations:  MIC= minimum inhibitory concentration; %T>MIC= time above the minimum inhibitory 
concentration; q8h = every 8 hours; min = minute; PK = pharmacokinetic; µg/mL = microgram/milliliter. 
Source: Data on File. 
 
As expected, for both doses of ceftolozane/tazobactam, as the %T>MIC and MIC values 
increase, the PTA decreases.  However, the 3000 mg q8h dose of ceftolozane/tazobactam 
retains excellent PTA for pathogens with MIC values ≤8 microgram/milliliter (µg/mL) up to 
a %T>MIC threshold of 60.  Conversely, with the 1500 mg q8h dose of 
ceftolozane/tazobactam, the PTA for pathogens with MIC values ≤8 µg/mL declines to 
below 90% at a %T>MIC threshold of 50 and above.  In addition to achieving desirable PTA, 
it is very important during dose selection to account for the physiological changes frequently 
seen in subjects with nosocomial pneumonia.  Renal impairment is a well-recognized 
problem in critically ill subjects.  Renal hyperclearance is also an important concern, 
especially in hospitalized younger subjects (< 55 years of age) without co-morbidities upon 
admission to hospital.  Renal hyperclearance, defined as the increased renal elimination of 
solute, has been reported in certain subjects in the intensive care unit (ICU) particularly 
younger age groups and may compromise the activity of renally excreted antibiotics [18].  
Consideration of both renal impairment and renal hyperclearance is important when selecting 
an appropriate dosage regimen for a primarily renally excreted antibacterial agent for 
treatment of infections in the critically ill.  An analysis of CLCR from subjects enrolled in 
clinical trials of HABP (20.5 to 241.0 mL/min) and VABP (26.8 to 283.6 mL/min) confirms 
the wide variation in renal function in this subject population.  In this study, approximately 
15% of subjects with VABP and 10% of subjects with HABP subjects had a CLCR 
≥150 mL/min [19]. 
 
 
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In order to assess the impact of hyperclearance on the PK/PD of ceftolozane/tazobactam, a 
distribution of CLCR from critically ill subjects obtained from medical literature was 
incorporated in the population PK model to estimate antibacterial PTA in the critically ill.  
This initial PK/PD analysis was based on data collected in two Phase 1 studies (subjects with 
normal and impaired renal function) and one Phase 2 study of ceftolozane in subjects with 
cUTI.  This PK/PD analysis was used to predict the PTA with ceftolozane using thresholds of 
40% and 50% T>MIC.  The results are presented in Table 3. 
Table 3: 
Probability of Target Attainment for 2 Doses of Ceftolozane/tazobactam 
(q8h, 1-hour infusion) by MIC and %T>MIC Stratified by Creatinine 
Clearance 
CLCR (mL/min) 
MIC 
(μg/mL) 
1500 mg ceftolozane/tazobactam 
3000 mg ceftolozane/tazobactam 
40% T>MIC 
50% T>MIC 
40% T>MIC 
50% T>MIC 
180 
4 
100 
96 
100 
100 
8 
93 
64 
100 
99 
16 
40 
11 
97 
81 
200 
4 
100 
93 
100 
99 
8 
88 
52 
99 
93 
16 
27 
6 
88 
66 
220 
4 
99 
87 
100 
99 
8 
80 
42 
99 
88 
16 
20 
4 
81 
42 
250 
4 
97 
79 
100 
97 
8 
71 
32 
98 
81 
16 
12 
2 
73 
30 
Abbreviations:  CLCR=creatinine clearance; MIC=minimum inhibitory concentration; %T>MIC=percent time above the 
minimum inhibitory concentration; q8h=every 8 hours. 
Source:  Data on File. 
 
As shown in Table 3, by increasing the dose of ceftolozane/tazobactam to 3000 mg, the PTA 
was improved in subjects with renal hyperclearance for pathogens with an MIC up to 
8 µg/mL. 
When PK data from a Phase 2 study in subjects with cIAI became available, the population 
PK analysis was again conducted including this data.  Estimates of clearance and volume of 
distribution along with the associated inter-individual variability were obtained from these 
analyses.  To further account for the concentration at the site of action for a comprehensive 
exposure-response assessment, this analysis also incorporated mean ELF penetration data 
(ie, ELF/plasma AUC ratio of 0.48 (range: 0.25-0.65) from a completed ceftolozane ELF 
study (CXA-ELF-10-03).  Using the foregoing, the analysis estimated plasma and ELF 
concentrations versus time profiles in 1000 simulated subjects with nosocomial pneumonia.  
This analysis evaluated the PTA of the 3000 mg every 8 hours dose of 
 
 
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ceftolozane/tazobactam against 3 key pathogens frequently seen in nosocomial pneumonia 
(namely, P. aeruginosa, E. coli, and K. pneumoniae).  The MIC distribution for these 
pathogens was imputed from the 2008 United States surveillance data.  The PTA was defined 
as the achievement of an ELF or plasma concentration of ceftolozane higher than the MIC(s) 
of the lower respiratory pathogen(s) for a given subject (using a threshold %T>MIC of 50) 
on Day 7 of treatment.  Plasma and ELF concentrations were estimated at 15 time-points post 
administration on Day 7 when dosed q8h.  The results of these simulations are shown in 
Table 4. 
Table 4: 
Probability of Target Attainment Versus Key Pathogens in Nosocomial 
Pneumonia Using the Simulated 3000-mg Dose of 
Ceftolozane/tazobactam 
Organism 
Dosing Regimen 
50% T>MIC in 
Plasma  
50% T>MIC in 
ELF  
P. aeruginosa 
3000 mg q8h 
99.4 
98.5 
E. coli 
3000 mg q8h 
98.8 
95.5 
K. pneumoniae 
3000 mg q8h 
92.6 
89.3 
Abbreviations: ELF= epithelial lining fluid; T>MIC = Time above minimum inhibitory concentration; q8h=every 8 hours; 
mg = milligram. 
Source: Data on File. 
 
These results suggest that the 3000 mg dose of ceftolozane/tazobactam administered q8h is 
likely to provide adequate concentrations for treatment of the vast majority of lower 
respiratory infections caused by these pathogens. 
This clinical trial simulation was then repeated to predict concentration-time profiles in 
subjects with varying degree of renal impairment.  Creatinine clearance was previously 
identified as a covariate in a population PK model, which suggested increased plasma 
exposure (AUC) to ceftolozane/tazobactam in subjects with severe and moderate renal 
impairment.  Based on these simulations, the results showed that no dose adjustment is 
required in subjects with mild renal impairment (CLCR >50 to 89 mL/min) compared with 
that in subjects with normal renal function (CLCR ≥90 mL/min).  The dose in subjects with 
severe renal impairment (CLCR 15 to 30 mL/min) and moderate renal impairment (CLCR >30 
to 49 mL/min) should be reduced by 4-fold (ie, 750 mg ceftolozane/tazobactam every 
8 hours) and 2-fold (1500 mg ceftolozane/tazobactam every 8 hours), respectively. 
Since the PTA was optimized for a 3000 mg dose of ceftolozane/tazobactam, it was 
important to ascertain safety and tolerability of this dose.  In healthy volunteers, the safety 
and tolerability of a 10-day course of ceftolozane/tazobactam 3000 mg every 8 hours by IV 
infusion over 60 minutes was evaluated.  In this study (CXA-MD-11-07), subjects were 
randomized to receive either 3000 mg ceftolozane/tazobactam (n=8) or 1500 mg 
ceftolozane/tazobactam (n=4), or placebo (n=4) for 10 days.  The study results showed that 
ceftolozane/tazobactam was generally well tolerated in this study (Table 5). 
Fifteen of 16 randomized subjects completed the study as planned; one subject randomized to 
the 3000 mg ceftolozane/tazobactam arm prematurely discontinued treatment after the 
second dose due to a drug-related AE of vomiting.  Other drug-related AEs reported by this 
 
 
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subject included nausea, flushing, and bilateral leg aches.  There were no SAEs or deaths 
reported during the study.  The type, incidence, and distribution of AEs were generally 
similar in subjects randomized to either the 3000 mg or 1500 mg dose of ceftolozane and 
consistent with the side effect profile expected for β-lactams.  The most frequently reported 
group of AEs were non-treatment-limiting injection site reactions.  Remarkably, no AEs were 
reported during or after study drug therapy in subjects randomized to placebo.  Two subjects 
in the 3000 mg ceftolozane/tazobactam arm had a negative direct Coombs’ test at baseline 
with sero-conversion to a weekly positive test at follow-up.  None of these subjects had 
symptoms or laboratory values suggestive of hemolytic anemia or any AE suggestive of 
anemia.  When dosed at 3000 mg, the plasma concentrations of ceftolozane and tazobactam 
showed a dose-proportional increase compared to the 1500 mg dose, indicating that the PK 
of ceftolozane and tazobactam was linear.  No accumulation of either ceftolozane or 
tazobactam was observed following repeated dosing for 10 days. 
Table 5: 
Treatment-emergent Adverse Events Reported in Study CXA-MD-11-07 
(Safety Population) 
System Organ Class/Preferred 
Term 
Ceftolozane/tazobactam 
3000 mg (n=8)  
n (%) 
Ceftolozane/tazobactam 
1500 mg (n=4) 
n (%) 
Placebo 
(n=4) 
Subjects with at least 1 TEAE 
4 (50.0) 
3 (75.0) 
0  
Infusion site irritation 
2 (25.0) 
1 (25.0) 
0 
Nausea 
1 (12.5) 
0  
0 
Vomiting 
1 (12.5) 
0 
0 
Infusion site extravasation 
1 (12.5) 
0 
0 
Infusion site inflammation 
1 (12.5) 
0 
0 
Pain in extremity 
1 (12.5) 
0 
0 
Flushing 
1 (12.5) 
0 
0 
Sensation of heaviness 
0 
1 (25.0) 
0 
Headache 
0 
1 (25.0) 
0 
TEAE=Treatment emergent adverse event; mg = milligram. 
Source: CSR CXA-MD-11-07. 
 
Overall, these results demonstrate that the 3000 mg q8h IV dose of ceftolozane/tazobactam 
was well tolerated in this healthy volunteer population without any safety signals.  The data 
supports its use in this Phase 3 VNP clinical trial. 
In conclusion, a comprehensive exposure-response approach with high probability of target 
attainment, the favorable ELF data demonstrating good lung penetration, and the 
demonstrated safety and tolerability of the higher dose of ceftolozane/tazobactam in the 
Phase 1 study CXA-MD-11-07, support a dose of 3000 mg every 8 hours by IV infusion over 
60 minutes of ceftolozane/tazobactam for the treatment of subjects with VNP caused by 
gram-negative pathogens. 
 
 
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6. 
TRIAL OBJECTIVES AND PURPOSE 
To accommodate the unique requirements of different regulatory jurisdictions, the study 
objectives have been separated out in this section. In addition, the efficacy and safety of 
ceftolozane/tazobactam in the population of patients with sepsis will be evaluated under a   
Japan-specific amendment. Further details are provided in Appendix F. 
6.1. 
Study Objectives per the US FDA 
Primary objective: 
 To demonstrate the non-inferiority of ceftolozane/tazobactam versus meropenem 
in adult subjects with VNP based on the difference in Day 28 all-cause mortality 
rates in the Intent-to-treat (ITT) population using a non-inferiority margin of 10% 
Key Secondary objective: 
 To compare the clinical response rates in the ITT population of 
ceftolozane/tazobactam versus meropenem in adult subjects with VNP at the TOC 
visit (7 to 14 days after the End-of-therapy [EOT] visit) 
Other Secondary objectives: 
 To compare the Day 28 all-cause mortality rates of subjects in the 
ceftolozane/tazobactam versus meropenem arms in the microbiological ITT 
(mITT) population 
 To compare the clinical response rates at the TOC visit (ceftolozane/tazobactam 
versus meropenem) in the subset of subjects who had P. aeruginosa isolated from 
the baseline LRT culture 
 To compare the clinical response rates at the TOC visit (ceftolozane/tazobactam 
versus meropenem) in the subset of subjects who had Enterobacteriaceae isolated 
from the baseline LRT culture 
 To compare the microbiological response rates of ceftolozane/tazobactam versus 
meropenem at the TOC visit 
 To compare the per-pathogen microbiological response rates at the TOC visit 
(ceftolozane/tazobactam versus meropenem)  
 To compare the Day 14 all-cause mortality rates of subjects in the 
ceftolozane/tazobactam versus meropenem arms 
 To compare the clinical response rates at the EOT visit for 
ceftolozane/tazobactam versus meropenem 
 To compare the clinical response rates at the Late Follow-up (LFU) visit for 
ceftolozane/tazobactam versus meropenem 
 To compare the microbiological response rates of ceftolozane/tazobactam versus 
meropenem at the EOT visit 
 
 
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 To compare the per-pathogen clinical response at TOC by baseline MIC for 
ceftolozane/tazobactam versus meropenem 
 To evaluate the safety and tolerability of ceftolozane/tazobactam 
Exploratory objectives: 
 To compare the time to all-cause mortality in the ceftolozane/tazobactam versus 
meropenem arms 
 To compare the clinical response rates at the EOT visit (ceftolozane/tazobactam 
versus meropenem) in the subset of subjects who had P. aeruginosa or 
Enterobacteriaceae isolated from the baseline LRT culture 
 To compare the per-pathogen microbiological response at TOC by baseline MIC 
for ceftolozane/tazobactam versus meropenem 
 To compare the superinfection and new infection rate for ceftolozane/tazobactam 
versus meropenem 
 To compare the emergence of nonsusceptibility to study drug for 
ceftolozane/tazobactam versus meropenem 
 To compare the time to a ≥1-log reduction in bacterial burden of the causative 
gram-negative pathogen(s) identified from the baseline lower respiratory 
specimen 
 To compare the incidence of 4-fold increases in MIC (ceftolozane/tazobactam 
versus meropenem) for subjects with P. aeruginosa or Enterobacteriaceae isolated 
from the baseline LRT culture (the elevated MIC must be ≥2 µg/mL) 
 To evaluate the pharmacokinetics of ceftolozane/tazobactam 
 To compare the health economics outcomes, including total number of days in 
hospital, proportion of patients discharged from the acute care hospital, number of 
days in ICU, and number of days on a ventilator, of ceftolozane/tazobactam and 
meropenem in adults subjects with VNP within 28 days after randomization 
 To evaluate the change in procalcitonin from baseline to Day 3 and to EOT 
6.2. 
Study Objectives per the European Medicines Agency (EMA) 
Primary objective: 
 To demonstrate the non-inferiority of ceftolozane/tazobactam versus meropenem 
in adult subjects with VNP based on the difference in clinical response rates in the 
ITT population at the TOC visit (7 to 14 days after the EOT visit), using a non-
inferiority margin of 12.5% 
Key Secondary objective: 
 To compare the Day 28 all-cause mortality rates of subjects in the 
ceftolozane/tazobactam versus meropenem arms in the ITT population 
 
 
 
 
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Other Secondary objectives: 
 To compare the clinical response rates of ceftolozane/tazobactam versus 
meropenem in adult subjects with VNP at the TOC visit in the CE population 
 To compare the clinical response rates at the TOC visit (ceftolozane/tazobactam 
versus meropenem) in the subset of subjects who had P. aeruginosa isolated from 
the baseline LRT culture 
 To compare the clinical response rates at the TOC visit (ceftolozane/tazobactam 
versus meropenem) in the subset of subjects who had Enterobacteriaceae isolated 
from the baseline LRT culture 
 To compare the microbiological response rates of ceftolozane/tazobactam versus 
meropenem at the TOC visit 
 To compare the per-pathogen microbiological response rates at the TOC visit 
(ceftolozane/tazobactam versus meropenem) 
 To compare the Day 28 all-cause mortality rates of subjects in the 
ceftolozane/tazobactam versus meropenem arms in the mITT population 
 To compare the Day 14 all-cause mortality rates of subjects in the 
ceftolozane/tazobactam versus meropenem arms 
 To compare the clinical response rates at the EOT visit for 
ceftolozane/tazobactam versus meropenem 
 To compare the clinical response rates at the LFU visit for 
ceftolozane/tazobactam versus meropenem 
 To compare the microbiological response rates of ceftolozane/tazobactam versus 
meropenem at the EOT visit 
 To compare the per-pathogen clinical response at TOC by baseline MIC for 
ceftolozane/tazobactam versus meropenem 
 To evaluate the safety and tolerability of ceftolozane/tazobactam 
Exploratory objectives: 
 To compare the time to all-cause mortality in the ceftolozane/tazobactam versus 
meropenem arms 
 To compare the clinical response rates at the EOT visit (ceftolozane/tazobactam 
versus meropenem) in the subset of subjects who had P. aeruginosa or 
Enterobacteriaceae isolated from the baseline LRT culture 
 To compare the per-pathogen microbiological response at TOC by baseline MIC 
for ceftolozane/tazobactam versus meropenem 
 To compare the superinfection and new infection rate for ceftolozane/tazobactam 
versus meropenem 
 
 
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 To compare the emergence of nonsusceptibility to study drug for 
ceftolozane/tazobactam versus meropenem 
 To compare the time to a ≥1-log reduction in bacterial burden of the causative 
gram-negative pathogen(s) identified from the baseline lower respiratory 
specimen 
 To compare the incidence of 4-fold increases in MIC (ceftolozane/tazobactam 
versus meropenem) for subjects with P. aeruginosa or Enterobacteriaceae isolated 
from the baseline LRT culture (the elevated MIC must be ≥2 µg/mL) 
 To evaluate the pharmacokinetics of ceftolozane/tazobactam 
 To compare the health economics outcomes, including total number of days in 
hospital, proportion of patients discharged from the acute care hospital, number of 
days in ICU, and number of days on a ventilator, of ceftolozane/tazobactam and 
meropenem in adults subjects with VNP within 28 days after randomization 
 To evaluate the change in procalcitonin from baseline to Day 3 and to EOT 
 
 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a prospective, randomized, double-blind, multicenter, Phase 3 study to assess the 
safety and efficacy of ceftolozane/tazobactam 3000 mg (comprising 2000 mg ceftolozane 
and 1000 mg tazobactam) q8h administered as an IV infusion in the treatment of adult 
subjects with VNP (including VABP and ventilated HABP subjects), compared with 
meropenem 1000 mg q8h administered as an IV infusion. 
Approximately 726 subjects will be enrolled and randomized 1:1 to receive either 
ceftolozane/tazobactam or meropenem.  Randomization will be stratified by diagnosis 
(VABP or ventilated HABP) and by age (≥65 or <65 years) to facilitate balanced distribution 
of high-risk subjects between the 2 treatment arms.  The number of subjects enrolled with 
VABP will be at least 50% of the randomized population. 
Figure 1 presents a schematic of the study design.  Subject participation will require a 
minimum commitment of 36 days and a maximum of 51 days.  All screening assessments for 
study eligibility must occur within 24 hours before administration of the first dose of study 
drug.  However, baseline LRT specimens for quantitative culture, LRT specimens for Gram 
stain, and serum procalcitonin levels may be obtained up to 36 hours before receipt of first 
dose of study drug.  
The duration of study drug administration will be a minimum of 8 days (24 doses) and up to 
a maximum of 14 days (42 doses) [20].  The total number of infusions may increase if a dose 
adjustment is required based on renal function due to the addition of dummy infusions.  In 
subjects with P. aeruginosa isolated from the baseline LRT culture, a treatment duration of 
14 days is strongly recommended for study drug administration.  Subjects must remain 
hospitalized throughout the treatment period and complete all study treatment intravenously.  
No oral switch is permitted in this study. 
Table 6 presents a Schedule of Assessments. 
 
 
 
 
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Figure 1: 
Study Design 
Screening 
Treatment 
EOT 
D 14a 
TOC 
D 28a 
LFU 
Day -1 to 1 
Days 1 to 14 
Within 24 hours 
after last dose of 
study drug 
Day 14 
7-14 days after 
the EOT 
Day 28 
28 to 35 days 
after the 
EOT 
Assess 
eligibility 
Collect 
LRT 
specimen 
Randomize 
to 
treatment 
Infuse blinded IV study 
therapy 
(ceftolozane/tazobactam 
3000 mg q8h 
or 
meropenem 
1000 mg q8h) 
Total duration of study 
drug administration is a 
minimum of 8 days 
(24 doses) and a 
maximum of 14 days 
(42 doses)b 
Evaluation for 
assessment of 
microbiological 
response, clinical 
response, and 
safety 
Assess 
for All-
cause 
mortality 
Subjects return 
to study center 
for primary 
assessment of 
microbiological 
response, 
clinical 
response, and 
safety 
Assess 
for 
All-cause 
mortality 
Evaluation 
for final 
assessment 
of clinical 
response and 
safety 
EOT = end-of-therapy visit; IV=intravenous; LFU = Late Follow-up visit; LRT= lower respiratory tract; q8h=every 8 hours; TOC 
= Test-of-cure visit; D = day; mg = milligram. 
a If TOC visit and LFU visit are not on Day 14 and Day 28, respectively, an assessment of all-cause mortality must be conducted 
independently. 
b The total number of infusions may increase if a dose adjustment is required based on renal function due to the addition of dummy 
infusions. 
 
 
 
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Table 6: 
Schedule of Assessments 
 
Screening 
Treatment Period 
Post Treatment Period 
 
D-1 to 1a 
D1 
D2 
D3 
D4-7 
D8 
D9-14b 
EOT/ 
Early 
Term 
Day 14 
TOC 
(7-14 days 
after EOT) 
Day 28 
LFU 
(28-35 days 
after 
EOT)c 
General Procedures/Assessments 
Informed consentd 
x 
 
 
 
 
 
 
 
 
 
 
 
Assess Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
x 
 
 
 
 
 
 
 
 
 
 
 
Ceftolozane/tazobactam or meropenem 
administration 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
Clinical Procedures/Assessments 
Medical history (including height and 
weight and demographics) e 
x 
 
 
 
 
 
 
 
 
 
 
 
Calculate APACHE II score f 
x 
 
 
 
 
 
 
 
 
 
 
 
Assess need for adjunctive gram-
negative coverage 
x 
 
 
 
 
 
 
 
 
 
 
 
Empiric baseline linezolid 
administration g 
 
x 
x 
x 
xi 
xi 
xi 
 
 
 
 
 
Discontinue empiric gram-negative 
adjunctive therapy 
(if started at baseline) h  
 
 
 
x 
 
 
 
 
 
 
 
 
Capture clinical presentation of the 
subject in eCRF (ie, responding or not 
responding to treatment) 
 
 
 
x 
 
 
 
 
 
 
 
 
Complete physical examination  
x 
 
 
 
 
 
 
 
 
 
 
 
Focused pulmonary examination 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
xi 
 
 
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Screening 
Treatment Period 
Post Treatment Period 
 
D-1 to 1a 
D1 
D2 
D3 
D4-7 
D8 
D9-14b 
EOT/ 
Early 
Term 
Day 14 
TOC 
(7-14 days 
after EOT) 
Day 28 
LFU 
(28-35 days 
after 
EOT)c 
Assessment of clinical symptoms of 
pneumonia 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
Assessment of severity of lung injury 
(PaO2/FiO2) 
x 
xq 
xq 
xq 
xq 
xq 
xq 
xq 
 
xq 
 
xi,q 
Temperature and vital signs 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
xi 
Assess for prior/concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
Assess for concomitant pulmonary 
procedures 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Assess for adverse events 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
Radiology Procedures/Assessments 
Chest X-ray/CT scan 
x 
 
xi 
xi 
xi 
xi 
 
xi 
 
 
 
 
Microbiology Procedures/Assessments 
Blood sample for aerobic blood cultures 
x 
 
xi 
xi 
xi 
xi 
xi 
xi 
 
 
 
 
Respiratory sample Gram stain 
xj,r 
 
 
 
 
 
 
 
 
 
 
 
Obtain quantitative LRT culturek 
xj 
xl 
xl 
xl 
 
xl 
 
xi,l 
 
xi,l 
 
 
Laboratory Procedures/Assessments 
Blood samples for serum hematology 
and chemistry evaluations 
x 
 
 
x 
 
x 
 
x 
 
x 
 
xi 
Serum creatinine and calculated CLCRm 
x 
 
 
 
 
 
 
 
 
 
 
 
Serum procalcitonin 
xj 
x 
x 
x 
 
x 
 
x 
 
x 
 
 
C-reactive protein 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
 
Direct Coombs’ test 
x 
 
 
 
 
 
 
x 
 
 
 
 
Serum pregnancy test 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Screening 
Treatment Period 
Post Treatment Period 
 
D-1 to 1a 
D1 
D2 
D3 
D4-7 
D8 
D9-14b 
EOT/ 
Early 
Term 
Day 14 
TOC 
(7-14 days 
after EOT) 
Day 28 
LFU 
(28-35 days 
after 
EOT)c 
Blood samples for WBC count (with 
differential) 
xn 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
xi, 
Pharmacokinetic Sampling 
 
 
 
 
xo 
 
 
 
 
 
 
 
Assess components of the CPIS 
x 
 
 
 
 
 
 
 
 
 
 
 
Assess Components of the SOFA Score 
x 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Procedures/Assessments 
Assess clinical response 
 
 
 
 
 
 
 
x 
 
x 
 
x 
Assess for all-cause mortalityp 
 
 
 
 
 
 
 
 
X 
 
x 
 
APACHE=Acute Physiology and Chronic Health Evaluation; BAL=Bronchoalveolar lavage; CLCR = Creatinine clearance; CPIS=Clinical Pulmonary Infection Score; CT=computed tomography; 
eCRF=Electronic case report form; EOT=End-of-therapy; ETA=Endotracheal aspirate; D=Day; LFU=Late Follow-up; LRT=Lower respiratory tract; PBS=Protected brush specimen; SOFA=Sepsis 
Organ Failure Assessment; TOC=Test-of-cure; WBC=white blood cell; PaO2/FiO2 = partial pressure of oxygen to the fraction of inspired oxygen. 
a Prior to study drug administration.  Note, there is no Study Day 0. 
b Applies to subjects receiving greater than 8 days of study treatment. 
c LFU visit may be conducted by telephone if the subject does not have any known adverse events or laboratory abnormalities that require an in-person follow-up assessment. 
d Informed Consent Form may be signed up to 72 hours before receipt of first dose of study drug. 
e The medical history will also include reviews of the subject’s significant baseline comorbidities. 
f Modified APACHE II score can be used. See Section 11.1.3. 
g Alternatives to linezolid may be permitted following prior documented approval by the medical monitor. 
h Assess when results of the baseline LRT culture are available (within 72 hours of starting study drug). 
i If applicable and clinically indicated. 
j May be obtained up to 36 hours before receipt of first dose of study drug. 
k BAL (or mini-BAL) or PBS are strongly recommended for obtaining the LRT specimen, when these modalities are available at the site.  If ETA is used, refer to Section 11.3.2. Sputum specimens may 
be used for post baseline LRT specimens only in extubated subjects. 
l Only required in intubated subjects. 
m Serum CLCR may be performed locally as frequently as clinically indicated to guide appropriate drug therapy in subjects with renal impairment. 
n Blood sample for WBC count with differential must include a band count, for determining the CPIS. 
o If blood samples cannot be collected on Day 4, samples can be collected after Day 4 and within the treatment period, but preferably between Day 4 and Day 6. 
p If the TOC visit and the LFU visit are on Day 14 and Day 28, respectively, the assessment of all-cause mortality should be done at these visits. 
q O2 saturation may be substituted for PaO2 in subjects who do not have an arterial line or in whom drawing an arterial blood gas would not be considered standard of care.  See Appendix E. 
r Results of the baseline Gram stain are not required if the subject has a lower respiratory tract culture obtained within 72 hours prior to the first dose of study drug confirming the presence of a gram-
negative pathogen. For LRT samples collected by ETA, the adequacy of the sample (based on polymorphonuclear and squamous cell count) must still be assessed. 
 
 
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7.2. 
Study Visits 
7.2.1. 
Screening (Baseline) 
Baseline (screening) assessments are to be performed within 24 hours before the start of 
administration of the first dose of study drug.  However, baseline LRT specimen for 
quantitative culture and Gram stain, and baseline serum procalcitonin levels may be 
obtained up to 36 hours before receipt of the first dose of study drug. The Informed 
Consent Form may be signed up to 72 hours before receipt of first dose of study drug. 
All results of baseline study assessments required to fulfill the eligibility criteria (with the 
exception of the baseline LRT culture result) must be available before randomization and 
administration of the first dose of study drug.  For a complete list of assessments refer to 
the Schedule of Assessments (Table 6). 
NOTE:  Local (ie, site) or regional laboratory results will be used to determine subject 
eligibility for study enrollment as well as for the ongoing management of the subject 
during the treatment period. 
7.2.2. 
Treatment Period 
The duration of study drug administration will be a minimum of 8 days (24 doses) and up 
to a maximum of 14 days (42 doses).  The total number of infusions may increase if a 
dose adjustment is required based on renal function due to the addition of dummy 
infusions.  In subjects with P. aeruginosa isolated from the baseline LRT culture, a 
treatment duration of 14 days is strongly recommended for study drug administration. 
For study days occurring during the treatment period, all study assessments are to be 
performed when applicable.  For study assessments that are to be performed daily, the 
assessments are to be performed preferably at a consistent time, for each calendar day. 
For a complete list of assessments, refer to the Schedule of Assessments (Table 6). 
7.2.3. 
End-of-therapy Visit 
The EOT visit must occur within the 24 hours following the completion of the last dose of 
study drug. 
For a complete list of assessments, refer to the Schedule of Assessments (Table 6). 
7.2.4. 
Test-of-cure Visit 
The TOC visit should occur within 7 to 14 days after the EOT visit. 
For a complete list of assessments, refer to the Schedule of Assessments (Table 6). 
7.2.5. 
Late Follow-up Visit 
The LFU visit should occur within 28 to 35 days after the EOT visit.  The LFU visit may 
be conducted by telephone to assess the subject’s wellbeing if the subject does not have 
any known AEs or laboratory abnormalities that require an in-person follow-up 
assessment.  If subjects have symptoms suggestive of respiratory infection during the 
telephone interview, an in-person visit must be scheduled.  Subjects who are still 
hospitalized at the time of the LFU evaluation will have an in-person visit. 
For a complete list of assessments, refer to the Schedule of Assessments (Table 6). 
 
 
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7.3. 
Number of Subjects 
Approximately 726 subjects will be randomized. 
7.4. 
Treatment Assignment 
Subjects will be randomized 1:1 to receive either ceftolozane/tazobactam 3000 mg every 
8 hours by IV infusion or meropenem 1000 mg every 8 hours by IV infusion.  All IV 
infusions will be administered as a 60 (±10)-minute infusion, with a (±) 2-hour dosing 
window. 
Randomization will be stratified by diagnosis (VABP or ventilated HABP) and age (≥65 
or <65 years) to facilitate balanced distribution of high-risk subjects between the 2 
treatment arms. The number of subjects enrolled with VABP will be at least 50% of the 
randomized population. 
7.5. 
Dose Adjustment Criteria 
Dose adjustments will be made based on subject CLCR levels as shown in Table 7 and 
Table 8. 
A dummy infusion is not required in cases where dosing every 8 hours is used for both 
ceftolozane/tazobactam and meropenem. 
Conversely, to maintain blinding of the dosing regimens when meropenem is required to 
be dosed q12h, the treatment schedule must be adjusted to four infusions per day by 
adding dummy infusion(s).  These four infusions (active plus dummy) are to 
accommodate the three q8h infusions for ceftolozane/tazobactam and the two q12h 
infusions for meropenem.  Note: The first study drug infusion subjects receive following 
randomization must always be active study drug (ie, either ceftolozane/tazobactam or 
meropenem) and NOT a dummy infusion; see Table 9. 
Dose adjustments for renal insufficiency will be performed by the unblinded pharmacist 
following notification from the Investigator, including the subject’s CLCR value. 
Refer to the pharmacy manual for specific instructions regarding preparation of doses 
following adjustments. 
 
 
 
 
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Table 7: 
Dose Adjustments for Subjects Randomized to 
Ceftolozane/tazobactam Intravenous 60-minute Infusions  
Renal Function 
Dose 
Infusion Frequency 
CLCR >50 mL/min 
3000 mg IV 
(comprising 2000 mg ceftolozane and 
1000 mg tazobactam) 
q8(±2)h 
CLCR 30 - 50 mL/min 
1500 mg IV 
(comprising 1000 mg ceftolozane and 
500 mg tazobactam) 
q8(±2)h 
CLCR 26 - 29 mL/min  
750 mg IV 
(comprising 500 mg ceftolozane and 
250 mg tazobactam) 
q8(±2)h 
CLCR 15 -  25 mL/min 
750 mg IV 
(comprising 500 mg ceftolozane and 
250 mg tazobactam) 
q8(±2)h 
CLCR <15 mL/min 
Discontinue study drug 
CLCR=creatinine clearance; IV=intravenous; q8h=every 8 hours. 
 
Table 8: 
Dose Adjustments for Subjects Randomized to Meropenem 
Intravenous 60-minute Infusions 
Renal Function 
Dose 
Infusion Frequency 
CLCR >50 mL/min 
1000 mg IV 
q8(±2)h  
CLCR 30 - 50 mL/min 
1000 mg IV 
q12(±2)h 
CLCR 26 - 29 mL/min  
1000 mg IV 
q12(±2)h 
CLCR 15 - 25 mL/min 
500 mg IV 
q12(±2)h 
CLCR <15 mL/min 
Discontinue study drug 
CLCR=creatinine clearance; IV=intravenous; q8h=every 8 hours; q12h=every 12 hours. 
 
Subjects with CLCR ≤50 mL/min, based on the treatment randomized, should be dosed as 
shown in Table 9.  The first study drug infusion subjects receive following randomization 
must always be active study drug (ie, either ceftolozane/tazobactam or meropenem) and 
not a dummy (saline) infusion. 
 
 
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Table 9: 
Dosing Schedule for Subjects with CLCR ≤50 mL/min  
Elapsed Time (h) 
Randomized to 
ceftolozane/tazobactam 
Randomized to meropenem 
First dose* 
Active ceftolozane/tazobactam 
Active meropenem infusion 
01:00 
 
 
02:00 
 
 
03:00 
 
 
04:00 
 
 
05:00 
 
 
06:00 
 
 
07:00 
 
 
08:00 
Active ceftolozane/tazobactam 
 Dummy (saline) infusion 
09:00 
 
 
10:00 
 
 
11:00 
 
 
12:00 
Dummy (saline) infusion 
Active meropenem infusion 
13:00 
 
 
14:00 
 
 
15:00 
 
 
16:00 
Active ceftolozane/tazobactam 
Dummy (saline) infusion 
17:00 
 
 
18:00 
 
 
19:00 
 
 
20:00 
 
 
21:00 
 
 
22:00 
 
 
23:00 
 
 
CLCR = creatinine clearance; h = hours 
*The first study drug infusion subjects receive following randomization must always be active study drug (ie, either 
ceftolozane/tazobactam or meropenem) and not a dummy (saline) infusion 
Subjects who develop a CLCR <15 mL/minute or who are placed on dialysis or 
hemofiltration must be withdrawn from study drug because dose recommendations of 
ceftolozane/tazobactam for such subjects have not yet been determined.  These subjects 
will continue to be followed through the LFU visit.  For additional subject withdrawal 
criteria, please refer to Section 8.3. 
7.6. 
Criteria for Study Termination 
The Sponsor may stop the study at any time on the basis of new information regarding 
safety or efficacy.  Additionally, the Sponsor may terminate the study if progress is 
unsatisfactory. 
 
 
 
 
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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
To be eligible for enrollment, a subject must satisfy all of the following entry criteria 
before they will be allowed to participate in the study and prior to any study related 
procedures: 
1. Provide written informed consent prior to any study-related procedure not part 
of normal medical care.  If the subject is unable to do so, local country laws 
and institution-specific guidelines and requirements in place for obtaining 
informed consent should be met.  A legally acceptable representative may 
provide consent, provided this is approved by local country and 
institution-specific guidelines.  If a subject comes to consciousness while still 
in the study and per the Investigator’s judgment the subject is able to read, 
assess, understand, and make his/her own decision to participate in the trial, 
the subject can agree to continue study participation and the subject may be re-
consented, if required by local country and institution-specific guidelines; 
2. Be males or females aged 18 years or older; 
If female, subject must not be pregnant or nursing, and is either: 
 Not of childbearing potential, defined as postmenopausal for at least 1 year 
or surgically sterile due to bilateral tubal ligation, bilateral oophorectomy, 
or hysterectomy; or 
 Of childbearing potential and meets at least 1 of the following: 
 Is practicing an effective method of contraception (eg, oral/parenteral 
contraceptives plus barrier method), or 
 Has a vasectomized partner, or 
 Is currently abstinent from sexual intercourse. 
Subjects must be willing to practice the chosen contraceptive method or 
remain abstinent during the conduct of the study and for at least 35 days after 
last dose of study medication. 
Non-vasectomized males are required to practice effective birth control 
methods (eg, abstinence, use of condom, or use of other barrier device) during 
the treatment period and for at least 75 days after last dose of study 
medication; 
3. Intubated (via endotracheal tube, including tracheostomy patients) and on 
mechanical ventilation at the time of randomization: 
For ventilated HABP: 
 At least 1 of the following signs and/or symptoms must be present within 
the 24 hours prior to intubation OR within the 48 hours after intubation in 
a patient who has been either hospitalized for ≥48 hours or who has been 
discharged from a hospital within the prior 7 days (includes patients 
institutionalized in skilled nursing or other long-term care facility): 
o A new onset of cough (or worsening of baseline cough) 
 
 
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o Dyspnea, tachypnea, or respiratory rate greater than 30 per minute, 
particularly if any or all of these signs or symptoms are progressive 
in nature 
o Hypoxemia defined as an arterial blood gas partial pressure of 
oxygen less than 60 mmHg while the subject is breathing room air, 
OR a pulse oximetry oxygen saturation less than 90% while the 
subject is breathing room air, OR worsening of the ratio of the 
partial pressure of oxygen to the fraction of inspired oxygen 
(PaO2/FiO2) 
For VABP: 
 Receiving mechanical ventilation ≥48 hours and at least one of the 
following: 
o Acute changes made in the ventilator support system to enhance 
oxygenation, as determined by worsening partial pressure of 
oxygen on arterial blood gas, or worsening PaO2/FiO2 
o Hypoxemia defined as an arterial blood gas partial pressure of 
oxygen less than 60 mmHg while the subject is breathing room air 
(or FiO2 equivalent), OR a pulse oximetry oxygen saturation less 
than 90% while the subject is breathing room air (or FiO2 
equivalent), OR worsening PaO2/FiO2. 
4. Chest radiograph obtained within the 24 hours prior to the first dose of study 
drug shows the presence of new or progressive infiltrate(s) suggestive of 
bacterial pneumonia (based on Investigator evaluation or report from a 
qualified medical professional who is not the Investigator). A computed 
tomography (CT) scan may be used in place of a chest X-ray. 
5. Have the following clinical criteria within the 24 hours prior to the first dose 
of study drug:  
 Purulent tracheal secretions 
 And at least 1 of the following: 
 Documented fever (body temperature ≥38°C [100.4°F]) 
 Hypothermia (body temperature ≤35°C [95.2°F]) 
 White blood cell (WBC) count ≥10,000 cells/mm3  
 WBC count ≤4,500 cells/mm3 
 ≥15% immature neutrophils. 
6. Have a baseline lower respiratory tract specimen obtained for Gram stain and 
quantitative culture within 36 hours prior to the first dose of study drug.  This 
specimen can be obtained by a bronchoalveolar lavage (BAL), 
nonbronchoscopic BAL (mini-BAL), protected brush specimen (PBS), or an 
endotracheal aspirate (ETA); 
Note:  ETA specimens with an average of ≥10 squamous epithelial cells or 
≤25 polymorphonuclear cells per low power field will be considered 
 
 
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inadequate, and a repeat specimen that is adequate will need to be obtained for 
Gram stain and subsequent quantitative culture. 
Note:  If BAL, mini-BAL, or PBS is available at the site, these modalities are 
strongly recommended rather than an ETA for obtaining the baseline LRT 
specimen. 
7. Willing and able to comply with all study procedures and restrictions. 
8.2. 
Subject Exclusion Criteria 
A subject will not be enrolled if the subject meets any of the following criteria: 
1. Any of the following diagnoses or conditions that interfere with the 
assessment or interpretation of outcome: 
 Atypical, viral, or fungal (including Pneumocystis jiroveci), known or 
suspected community-acquired bacterial pneumonia 
 Tracheobronchitis (without documented pneumonia), chemical 
pneumonitis, or postobstructive pneumonia 
 Active primary or metastatic lung cancer 
 Pleural effusions (or empyema) requiring therapeutic drainage, lung 
abscess, or bronchiectasis 
 Cystic fibrosis, acute exacerbation of chronic bronchitis, or active 
pulmonary tuberculosis 
 New York Heart Association (NYHA) Stage IV Congestive Heart Failure 
or Cirrhotic Liver Disease 
 Full thickness burns (greater than 15% of total body surface area) 
 Severe confounding respiratory condition due to penetrating chest trauma 
(ie, chest trauma with paradoxical respiration) 
2. Has a documented history of any moderate or severe hypersensitivity (or 
allergic) reaction to any β-lactam antibacterial;  
Note: A history of a rash while on a β-lactam antibiotic does not automatically 
exclude a subject (eg, a subject with history of a mild rash followed by 
uneventful re-exposure may be considered for enrollment) 
3. Received systemic or inhaled antibiotic therapy effective against gram-
negative pathogens that cause VNP, for >24 hours (ie, >1 dose of a once daily 
antibiotic, >2 doses of a twice daily antibiotic, etc.) in the 72 hours prior to the 
first dose of study drug.  Drugs with only gram-positive activity [eg, 
daptomycin, vancomycin, linezolid] are allowed. 
Exceptions: 
 Persistent/worsening signs and/or symptoms of VNP are still present 
despite ≥48 hours of antibiotic therapy for the treatment of the current 
VNP, and (a) a LRT culture obtained while the subject is on the failing 
antibiotic therapy for this episode of VNP showed growth of a gram-
negative pathogen and (b) the isolated pathogen is not known to be 
resistant to one of the study drugs. 
 
 
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 Signs and/or symptoms of VNP develop after receiving ≥48 hours of 
antibacterial therapy for treatment of an infection other than the current 
VNP.  NOTE: Subjects on ≥48 hours of antibiotics for infection 
prophylaxis (rather than treatment of a documented or suspected 
infection) are not eligible for enrollment under this exception. 
 Treatment with a non-absorbed antibiotic used for gut decontamination 
(eg, low-dose erythromycin) or to eradicate C. difficile. 
4. Baseline Gram stain shows the presence of only gram-positive bacteria. 
Exception: If the subject has a lower respiratory tract culture growing a gram-
negative pathogen obtained within 72 hours prior to the first dose of study 
drug, these results will supersede baseline Gram stain results of only gram-
positive bacteria. 
5. Active immunosuppression, including human immunodeficiency virus (HIV) 
with a known CD4 count of <200 cells/mm3, active hematological malignancy, 
recipients of solid organ or bone marrow transplants,  subjects currently on 
immunosuppressive therapy including cancer chemotherapy, medications for 
prevention of transplant rejection, or chronic administration of corticosteroids 
(defined as >40 mg of prednisone per day administered continuously for more 
than 14 days prior to the first dose of study drug); 
6. Receipt of >24 hours of a carbapenem within 7 days prior to the first dose of 
study drug; 
7. Growth of a meropenem-resistant or ceftolozane/tazobactam-resistant, gram-
negative pathogen from a respiratory or blood culture, within 15 days prior to 
the first dose of study drug;   
8. Development of end-stage renal disease defined as a CLCR <15 mL/min, OR 
requirement for peritoneal or hemo-dialysis or hemofiltration, OR a urine 
output <20 mL/hour over a 24-hour period; 
9. The presence of any of the following: 
 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
>3 × upper limit of normal (ULN) 
 Total bilirubin >2 × ULN 
 Alkaline phosphatase >4 × ULN. 
Note: Subjects with an alkaline phosphatase value >4 × ULN and <5× ULN 
are eligible if this value is historically stable. 
10. Hematocrit <21% or hemoglobin <7 gm/dL; 
11. Neutropenia with absolute neutrophil count  <500/mm3; 
12. Platelet count <50,000/mm3; 
13. Expected survival <72 hours; 
14. Any condition or circumstance that, in the opinion of the Investigator, would 
compromise the safety of the subject or the quality of study data; 
 
 
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15. Participation in any clinical study of a therapeutic investigational product 
within 30 days prior to the first dose  of study drug; 
16. Previous participation in any study of ceftolozane or ceftolozane/tazobactam; 
17. Employees of the Investigator or study center, directly involved in the study or 
other studies conducted by the Investigator or study center, as well as family 
members of the employees or the Investigator. 
18. Anticipated concomitant use of any of the following medications during the 
course of study therapy (through the EOT visit): valproic acid or divalproex 
sodium. For subjects who will receive linezolid as gram-positive adjunctive 
therapy, anticipated concomitant use of serotonin re-uptake inhibitors, tricyclic 
antidepressants, or serotonin 5-HT1 receptor agonists (triptans), meperidine, 
or buspirone during the course of linezolid treatment. 
19. For subjects who will receive linezolid as gram-positive adjunctive therapy, 
receipt of a monoamine oxidase inhibitor within 14 days prior to the first dose 
of study drug or anticipated concomitant use during linezolid therapy. 
8.3. 
Subject Withdrawal Criteria 
8.3.1. 
Early Termination 
Subjects will be informed that they have the right to discontinue study participation at any 
time without prejudicing their medical care and are not obliged to state their reasons.  
Subjects that discontinue for any reason should be asked to provide the reason(s) for 
discontinuation and assessments should be performed as outlined in the Schedule of 
Assessments (Table 6).  Any discontinuations must be fully documented in the electronic 
case report form (eCRF). 
8.3.2. 
Criteria for Premature Discontinuation of Study Drug or Subject 
Withdrawal from Study 
Subjects should be encouraged to complete all study assessments.  However, subjects 
retain the right to withdraw consent to participate in this study at any time without penalty 
or loss of benefits to which they are otherwise entitled.  For all subjects who prematurely 
withdraw consent from participation in the study, the subject will be queried to 
investigate the root cause for withdrawal of participation. 
Subjects may be prematurely discontinued from study medication, at the discretion of the 
Investigator, should any untoward effect occur (including an AE or clinically significant 
laboratory abnormality that, in the opinion of the Investigator, warrants the subject’s 
permanent discontinuation from study drug administration). 
In addition, subjects may be prematurely discontinued from study medication, at the 
discretion of the Investigator, for insufficient therapeutic effect. An insufficient 
therapeutic effect may be determined any time before the scheduled completion of 
therapy. This determination will require an overall assessment of clinical status based on 
signs and symptoms and available laboratory data. 
The following reasons require premature discontinuation from study drug administration 
per protocol: 
 
 
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 Subjects in whom all baseline gram-negative LRT pathogens are resistant to 
both study drugs. 
 Investigator decides to continue (or add) gram-negative adjunctive therapy 
beyond 72 hours of treatment or if the Investigator decides to add to or change 
the study treatment post baseline. 
 Development of end stage renal disease defined as a CLCR less than 
15 mL/min or oliguria (less than 20 mL/h urine output over 24 hours), or if 
dialysis or hemofiltration is required while the subject is receiving study drug 
therapy. 
 Suspected or confirmed pregnancy or nursing during the study drug 
administration period.  Female subjects whose pregnancy test becomes 
positive during study therapy must stop study drug immediately and be 
followed through the immediate postnatal period or until termination of the 
pregnancy. 
All subjects who prematurely discontinue study drug, regardless of the reason, should be 
followed for safety through the LFU visit. 
8.3.3. 
Procedures for Premature Discontinuation of Study Drug 
Discontinuations must be fully documented in the subject’s medical record and in the 
eCRF.  All efforts must be made to complete and report the required observations as 
thoroughly as possible. 
Each subject who discontinues early from study drug therapy is to undergo EOT 
evaluations on the day of discontinuation.  In this case, only the assessments required for 
the EOT visit must be performed and recorded in the eCRF.  The subject should return 7 
to 14 days after EOT for a TOC evaluation, and should return to the study site or be 
contacted a minimum of 28 days and a maximum of 35 days after EOT for a LFU 
assessment.  See Table 6 for a complete list of assessments to be performed. 
8.3.4. 
Replacement Policy 
Randomized subjects will not be replaced. 
 
 
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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
9.1.1. 
Investigational Product: Ceftolozane/tazobactam 
Study medication will be supplied by the Sponsor for use in this protocol and is for 
investigational use only.  Please refer to the current Investigator’s Brochure or pharmacy 
manual for additional information. 
Product Name: 
Ceftolozane/tazobactam 
Dosage Form: 
IV infusion over 60 (±10) minutes 
Unit Dose: 
3000 mg (2000 mg ceftolozane and 1000 mg tazobactam) 
q8h 
Route of Administration: 
Intravenous 
9.1.2. 
Active Comparator:  Meropenem 
 
Product Name: 
 
Meropenem 
Dosage Form: 
IV infusion over 60 (±10) minutes 
Unit Dose: 
1000 mg q8h 
Route of Administration: 
Intravenous 
9.2. 
Prior, Concomitant, and Adjunctive Medications and 
Procedures 
All nonantibiotic medications given within 7 days prior to the first dose of study drug 
through the EOT visit must be recorded in the appropriate section of the eCRF.  After the 
EOT visit through the LFU visit, only nonantibiotic medications given for the treatment 
of pneumonia or sepsis should be recorded in the eCRF. 
All nonstudy antibiotics given up to 14 days prior to the first dose of study drug through 
the LFU visit should be recorded in the eCRF.   
All concomitant diagnostic and therapeutic pulmonary procedures after the administration 
of the first dose of study drug through the LFU visit should be collected in the eCRF. 
9.2.1. 
Prohibited Medications 
Concomitant use of valproic acid or divalproex sodium during the course of study therapy 
is prohibited. 
For subjects who will receive linezolid as gram-positive adjunctive therapy, the following 
are prohibited: 
 Prior use of a monoamine oxidase inhibitor within 14 days of the first dose of 
linezolid. 
 Concomitant use of any of the following medications during linezolid therapy: 
o serotonin re-uptake inhibitors, 
 
 
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o tricyclic antidepressants, 
o serotonin 5-HT1 receptor agonists (triptans), 
o meperidine, 
o buspirone, or 
o monoamine oxidase inhibitors. 
9.2.2. 
Nonstudy Antibiotic Use 
In the 72 hours preceding the first dose of study drug for treatment of the current VNP, 
subjects may not receive more than 24 hours (ie, >1 dose of a once daily antibiotic, 
>2 doses of a twice daily antibiotic, etc.) of antibiotic therapy active against gram-
negative pathogens known to cause VNP.  Exceptions to this prior antibiotic rule are 
noted in Section 8.2 under Exclusion criteria #3. 
After randomization, nonstudy antibiotics for the treatment of VNP are not permitted 
except in the following circumstances: 
 Allowed empiric adjunctive therapy (as described in Section 9.2.3) 
administered at baseline for potential resistant pathogens, OR 
 For treatment of documented clinical and/or microbiologic failure. 
If nonstudy antibiotics for the treatment of VNP are required after randomization, the 
subject must be discontinued from study treatment (see Section 8.3.2). 
9.2.3. 
Guidance on Empiric Adjunctive Therapy 
9.2.3.1. 
Gram-positive Adjunctive Therapy 
Because ceftolozane/tazobactam has limited activity against S. aureus and both 
ceftolozane/tazobactam and meropenem are inactive against methicillin-resistant S. 
aureus (MRSA), empiric therapy at baseline with linezolid 600 mg every 12 hours IV is 
required in all subjects pending baseline LRT culture results.  In this study, linezolid is 
the preferred agent for gram-positive adjunctive therapy because of its proven activity 
against both methicillin-susceptible S. aureus (MSSA) and MRSA and its convenience of 
administration compared to vancomycin [21]. 
Alternatives to linezolid may be permitted if these are standard of care at the site and are 
an effective treatment for gram-positive pneumonia (ie, daptomycin and tigecycline are 
not acceptable alternatives).  Approval of linezolid alternatives should be obtained from 
the Medical Monitor prior to first subject being enrolled at the site.  At sites with a low 
incidence of MRSA pneumonia (eg, MRSA prevalence <5% as determined by the local 
antibiogram), the Investigator may request, from the Medical Monitor, substitution of 
linezolid with a semisynthetic, anti-staphylococcal penicillin (eg, nafcillin).  
Semisynthetic penicillins with gram-negative activity (ie, ampicillin) are not acceptable 
alternatives for linezolid.  For subjects who do not tolerate linezolid, or in whom linezolid 
is contraindicated, alternatives are permitted.  In all cases, any substitution gram-positive 
adjunctive therapy must not have any activity against gram-negative bacteria.  Such cases 
should be discussed with the Medical Monitor prior to or within 24 hours following 
dosing. 
If S. aureus is isolated from the baseline LRT culture, gram-positive adjunctive therapy 
should be continued for a minimum of 8 days.  See Section 9.2.3.3 for further guidance 
 
 
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on the management of gram-positive adjunctive therapy following baseline LRT culture 
results. 
9.2.3.2. 
Gram-negative Adjunctive Therapy 
To protect subjects who may be at risk for LRT infections caused by gram-negative 
pathogens potentially resistant to 1 or both study therapies, empiric adjunctive gram-
negative therapy with IV amikacin will be permitted at baseline, at sites where the local 
prevalence of meropenem-resistant P. aeruginosa is at least 15% (eg, as determined by 
the local antibiogram). 
The recommended dose of IV amikacin is 15 mg/kg daily; the dose may be adjusted for 
creatinine clearance per standard of care at the site.  Alternative aminoglycosides may be 
permitted if these are standard of care at the site.  Approval of amikacin alternatives 
should be obtained from the Medical Monitor prior to first subject being enrolled at the 
site.  For subjects who do not tolerate amikacin, or in whom amikacin is contraindicated, 
alternatives are permitted. Such cases should be discussed with the Medical Monitor prior 
to or within 24 hours following dosing. 
The maximum duration of gram-negative adjunctive therapy started at baseline is 
72 hours, at which time the results of the baseline LRT culture should be available.  See 
Section 9.2.3.3 for further guidance on the management of gram-negative adjunctive 
therapy following baseline LRT culture results. 
9.2.3.3. 
Guidance on Study Drug Therapy following Baseline Culture Results 
Susceptibility testing to both study drugs (and adjunctive therapy, as appropriate) is 
required for all gram-negative pathogens isolated and will be conducted at the local 
microbiology laboratory. Susceptibility testing methods (eg, MIC gradient test strips) will 
be provided to all sites, however other standard and validated testing methods may be 
used if available. 
Upon availability of the baseline LRT culture and pathogen susceptibility results: 
Management of study drug and empiric gram-negative adjunctive therapy: 
 If all gram-negative isolates are resistant to both study drugs: study drug must be 
discontinued, appropriate nonstudy antibiotics started, and the subject followed 
for safety through the LFU visit. 
 If gram-negative isolate(s) with varying susceptibility results is/are present: the 
Investigator is strongly encouraged to base decisions regarding continuation or 
discontinuation of study therapy on the clinical presentation of the patient and the 
totality of the available clinical and laboratory data, including the baseline LRT 
culture susceptibility testing results.  Empiric gram-negative adjunctive therapy, if 
started at baseline, must be discontinued after 72 hours. 
 If no growth of any gram-negative organism: study drug should be continued 
based on the discretion of the Investigator and guided by the subject’s clinical 
response. Empiric gram-negative adjunctive therapy, if started at baseline, must be 
discontinued after 72 hours. 
 
 
 
 
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Management of empiric gram-positive adjunctive therapy: 
 If S. aureus (MSSA or MRSA) is present [with or without a gram-negative 
pathogen]:  linezolid should be continued for a minimum of 8 days.  If MSSA is 
the only LRT pathogen isolated, the Investigator may switch the gram-positive 
adjunctive therapy to an anti-staphylococcal semisynthetic penicillin (with gram-
positive coverage only) and complete treatment with the semisynthetic penicillin. 
 If S. aureus (MRSA or MSSA) does not grow: empiric gram-positive coverage 
should be discontinued, unless in the opinion of the Investigator, continuation 
provides expected benefit for the patient. If gram-positive adjunctive therapy is 
discontinued and then a subsequent, post-baseline LRT culture shows presence of 
S. aureus, the appropriate gram-positive adjunctive therapy may be reinitiated (ie, 
linezolid if MRSA or anti-staphylococcal semisynthetic penicillin for MSSA). 
In all instances above, Investigators must capture a description of the subject’s clinical 
condition in the eCRF at the time of availability of the results of baseline LRT culture. 
All subjects, regardless of discontinuation or continuation of study drug, should be 
followed for safety through the LFU visit. 
9.3. 
Screening, Randomization, and Blinding 
9.3.1. 
Screening Procedure 
All subjects who are screened (including screen failures) will be assigned a screening 
number by each site and will be documented.  This will be reviewed at monitoring visits 
and will be part of the study record.  Subjects meeting all eligibility criteria will be 
enrolled into the study once informed consent has been obtained. 
9.3.2. 
Subject Identification and Numbering 
Once eligibility has been determined by the inclusion and exclusion criteria, subjects will 
be randomized to study drug group or comparator control group and a subject 
identification number will be assigned based on a centralized computer-generated 
randomization schedule. 
9.3.3. 
Randomization 
An interactive response technologies (IRT), stratified by baseline diagnosis (VABP or 
ventilated HABP) and by age (≥65 or <65 years), will be used to randomize subjects (1:1) 
to either the ceftolozane/tazobactam or meropenem treatment group.  The number of 
subjects enrolled with VABP will be at least 50% of the randomized population. 
After informed consent has been obtained and study eligibility has been established, the 
study site’s unblinded pharmacist or designee will obtain, via the IRT, the subject number 
and the study drug assignment from a computer-generated randomization schedule.  
Subjects are considered randomized when the unblinded pharmacist or designee obtains 
the subject number and study drug assignment from the IRT. 
Once a subject number and treatment have been assigned to a subject, the subject 
identification number cannot be reused even if the subject discontinues the study early or 
withdraws prior to receiving any study medication.  Subjects who discontinue from the 
study will not be permitted to re-enroll. 
 
 
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9.3.4. 
Blinding 
This is a double-blinded study.  The subject, site personnel (with the exception of the 
unblinded pharmacist), Sponsor personnel (with the exception of the unblinded drug 
supply and quality assurance teams, as appropriate) and Sponsor designees (with the 
exception of the unblinded monitoring team) will have no knowledge of treatment 
assignment. 
Unblinded Sponsor and designee roles and responsibilities are described in the Unblinded 
Team Plan. 
A double dummy design will be used to maintain the study blind for certain categories of 
renal impairment (see Section 7.5). 
9.3.5. 
Unblinding of Subjects 
A treatment assignment should only be unblinded in a situation of urgent medical 
necessity when the identity of the study medication must be known in order to select 
appropriate continuing therapy for the disease under study or to manage an AE.  The 
decision should be made only after consultation with the Medical Monitor unless the 
urgency of a case requires immediate action. 
When the Investigator needs to identify the study drug used by a subject and the dosage 
administered in case of emergency (eg, the occurrence of serious adverse experiences), 
he/she will contact the emergency unblinding call center by telephone and make a request 
for emergency unblinding.  As requested by the Investigator, the emergency unblinding 
call center will provide the information to him/her promptly and report unblinding to the 
Sponsor.  Prior to contacting the emergency unblinding call center to request unblinding 
of a subject’s treatment assignment, the Investigator must enter the severity of the adverse 
experiences observed, the relation to study drug, the reason thereof, etc., in the source 
documentation. 
Treatment assignments can also be obtained through a controlled IRT transaction. 
If a treatment code is unblinded for any reason, the Investigator will promptly notify the 
Medical Monitor and document who unblinded the subject, the reason for doing so, and 
the date of unblinding in the eCRF. 
All subjects, regardless of the reason for unblinding, should be followed for safety 
through the LFU visit. 
 
 
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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
Study medication and linezolid will be supplied by the Sponsor for use in this protocol 
and is limited to investigational use only.  Please refer to the current Investigator’s 
Brochure for additional information. 
10.2. 
Study Drug Packaging and Labeling 
Labeling and packaging of ceftolozane/tazobactam will meet applicable regulatory 
requirements.  All drug shipment requests for ceftolozane/tazobactam will be processed 
and approved by the Sponsor or designee. 
10.3. 
Study Drug Storage 
Study medication must be stored in a secure, limited access area, and may be dispensed 
only by specifically authorized personnel (eg, pharmacist or delegate). 
10.4. 
Study Drug Preparation 
10.4.1. 
Ceftolozane/tazobactam 
Vials of study medication must be stored under secure conditions at ≥2°C to ≤8°C (36°F 
to 46°F).  Please refer to the Pharmacy Manual for additional storage and handling 
information and preparation instructions. 
10.4.2. 
Meropenem 
Meropenem should be stored as indicated in the Package Insert.  Please refer to the 
Pharmacy Manual and Package Insert [14] for specific instructions on preparation. 
10.5. 
Administration 
Subjects will be randomized 1:1 to either ceftolozane/tazobactam 3000 mg q8h or 
meropenem 1000 mg q8h.  All infusions will be administered intravenously as a 
60 ±10-minute infusion, with a ±2-hour dosing window. 
10.6. 
Study Drug Accountability 
Unused study medication must not be discarded nor used for any purpose other than the 
present study.  The study monitor will collect the drug accountability forms and check all 
study medication prior to arranging for return or destruction of all study medication. 
 
 
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11. 
ASSESSMENT OF EFFICACY 
This section describes all assessments to be performed from screening through the last 
study evaluation.  Subjects will be monitored from the first dose of study drug through the 
last study evaluation. 
For complete details and timing of procedures and assessments please refer to the 
Schedule of Assessments (Table 6). 
11.1. 
Clinical Assessments 
11.1.1. 
Medical/Surgical History 
A recent medical/surgical history (within 5 years) will be obtained and documented.  In 
addition, significant baseline co-morbidities will be recorded in the eCRF including 
diabetes, congestive heart failure, chronic obstructive pulmonary disease (COPD), 
empyema, and pleural effusion.  
11.1.2. 
Physical Examination and Clinical Symptom Assessment 
A complete physical examination (ie, skin, eyes, ears/nose/throat, head/neck, chest, 
heart/vascular, abdomen, neurological [sensory and motor], musculoskeletal and 
extremities) including a detailed pulmonary exam, temperature, vital signs (blood 
pressure and heart rate), height, and weight will be performed at baseline.  Core 
temperatures should be taken, but if a core temperature is not feasible, other standard 
methods are acceptable. 
A clinical symptom assessment (to evaluate the presence and severity of cough [if 
applicable], tachypnea [if applicable], dyspnea, rigors or shaking chills, and pleuritic 
chest pain), temperature, vital signs, and a focused physical examination of the 
pulmonary system will be performed as indicated (and if applicable) at time points 
specified in the Schedule of Assessments (Table 6). 
Whenever possible the same person should conduct the physical examination for any 
given subject throughout the study. 
11.1.3. 
APACHE II Score 
Record the subjects’ Acute Physiology and Chronic Health Evaluation (APACHE) II 
score (see Appendix B).  The APACHE II score used in this study is a modified version 
of the APACHE II score, as many subjects in this study will be sedated, making an 
accurate assessment of the Glasgow Coma Scale difficult.  The Glasgow Coma Scale 
should not be calculated on obtunded or otherwise sedated subjects.  In these subjects if a 
reliable pre-sedation Glasgow Coma Scale score is available, this should be used in 
calculating the APACHE II score.  If a reliable pre-sedation score is not available, a score 
of 15 should be given for the Glasgow Coma Scale component of the APACHE II score 
(resulting in 0 points on this APACHE II score component). 
11.1.4. 
Assessment of Need for Adjunctive Gram-negative Therapy at Baseline 
Assess the need for empiric gram-negative adjunctive therapy at baseline. 
 
 
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Empiric adjunctive therapy with amikacin to cover potential meropenem-resistance will 
be only permitted at baseline, at sites where the prevalence of meropenem-resistant 
P. aeruginosa (as determined by the local antibiogram) is at least 15%. 
11.1.5. 
PaO2/FiO2 
Record subjects’ PaO2/FiO2 to document severity of lung injury.  Post-screening, in 
subjects without arterial access or in whom arterial blood sampling would not be 
considered standard of care, measurement of O2 saturation may be substituted for the 
PaO2 measurement (Appendix E). 
11.1.6. 
Clinical Pulmonary Infection Score 
Record the components required to calculate a modified clinical pulmonary infection 
score (CPIS), including a qualitative examination of the tracheal secretions (Appendix C). 
11.1.7. 
Sepsis Organ Failure Assessment Score 
Record the components required to calculate a System Organ Failure Assessment (SOFA) 
score (Appendix D). 
11.1.8. 
Evaluation of the Baseline Lower Respiratory Tract Culture 
Results of the baseline LRT culture should be available and reviewed within 72 hours of 
starting study drug.  Guidance on the continuation or discontinuation of study drug and 
adjunctive therapy is provided in Section 9.2.3.3. 
11.1.9. 
Assessment of Clinical Response 
Determine clinical outcome as described in Section 13.3.1, based on an overall 
assessment of clinical status based on signs and symptoms and available laboratory data. 
Subjects concluded to have an insufficient therapeutic effect and who discontinue study 
drug therapy should be considered a “clinical failure” on the day they prematurely 
discontinue treatment (their effective EOT visit).  These subjects do not need efficacy and 
clinical response assessments at the TOC or LFU visits (as a clinical failure at an earlier 
visit is always carried forward to subsequent visits).  However, these subjects should 
complete all other scheduled procedures required at these visits. 
11.2. 
Chest X-ray 
Obtain a chest X-ray to document the presence of new or progressive infiltrates consistent 
with VNP.  A CT scan may be used in place of a chest X-ray.  The Investigator’s (or 
qualified designee’s at the site) interpretation of the chest X-ray will be used to make the 
enrollment decision. 
In addition to the local reading of chest X-rays, a centralized independent second 
evaluation of the baseline X-ray, will be conducted on all subjects enrolled in the study. 
11.3. 
Microbiological Assessments 
11.3.1. 
Specimens for Quantitative Lower Respiratory Tract Culture 
A quantitative LRT culture obtained at baseline is required in all subjects to establish a 
microbiologic diagnosis of VNP.  The LRT culture specimen may be obtained by any 1 of 
 
 
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the following techniques: BAL, mini-BAL, PBS, or an ETA.  However, at sites where 
BAL, mini-BAL, or PBS are available, these modalities are strongly recommended, 
instead of an ETA, for obtaining the baseline LRT specimen. 
All baseline ETA specimens should be assessed for adequacy prior to randomization. 
ETA specimens with an average of ≥10 squamous epithelial cells or ≤25 
polymorphonuclear cells per low power field will be considered inadequate, and a repeat 
specimen that is adequate will need to be obtained for Gram stain and subsequent 
quantitative culture. 
Whenever possible, it is recommended that the same method used to obtain the baseline 
LRT specimen be used consistently throughout the study for obtaining post-baseline LRT 
specimens. 
For post-baseline specimens only, sputum samples may be used for extubated subjects.  
Sputum specimens with an average of ≥10 squamous epithelial cell or ≤25 
polymorphonuclear cells per low power field on Gram stain will be considered inadequate 
and a repeat specimen that is adequate should be obtained. 
In addition to the local microbiology testing, all locally-identified pathogens will be sent 
to a central microbiology laboratory for re-identification and susceptibility testing. 
11.3.2. 
Gram Stains 
At baseline, perform a Gram stain on an acceptable baseline respiratory specimen (BAL, 
mini-BAL, PBS and ETA).  Gram stain results for the baseline respiratory specimen must 
be available prior to randomization   As per Exclusion Criterion #4, subjects whose 
baseline respiratory specimen shows only gram-positive bacteria on Gram stain are not 
eligible for the study unless the subject has a lower respiratory tract culture growing a 
gram-negative pathogen obtained within 72 hours prior to the first dose of study drug 
(these results will supersede baseline Gram stain results of only gram-positive bacteria, 
refer to Section 8.2). 
All ETA baseline specimens must be assessed for adequacy of the sample, regardless of 
the exception to Exclusion Criterion #4 noted above.  An ETA specimen with an average 
of ≥10 squamous epithelial cells or ≤25 polymorphonuclear cells per low power field will 
be considered inadequate, and a repeat ETA specimen that is adequate will need to be 
obtained for Gram stain and subsequent quantitative culture. 
11.3.3. 
Specimens for Blood Culture 
Obtain blood samples for blood culture (1 aerobic bottle from 2 separate sites for a total 
of 2 aerobic bottles). 
In addition to the local microbiology testing, all locally-identified pathogens will be sent 
to a central microbiology laboratory for re-identification and susceptibility testing. 
 
 
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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
12.1.1. 
Laboratory Assessments 
Laboratory samples should be drawn at time points specified in the Schedule of 
Assessments (Table 6).  Laboratory samples sent to the central laboratory will be used for 
analysis and will not be used for the subjects’ real-time clinical management. 
Laboratory samples necessary for the routine clinical management of the subject should 
be drawn and analyzed locally, as per the site’s standard of care. 
Note:  Local (ie, site) or regional laboratory results will be used to determine subject 
eligibility for study enrollment. 
The total volume to be drawn in the study may vary based on local/regional specific 
laboratory requirements. Approximately 150 – 175 mL of blood per subject will be 
required throughout the study period for study related assessments. 
12.1.1.1. Hematology and Coagulation 
Hemoglobin, hematocrit, red blood cell count, WBC count (total and differential), 
platelets, and prothrombin time. 
12.1.1.2. Blood Chemistry 
Total bilirubin, alkaline phosphatase, ALT, AST, blood urea nitrogen (BUN), creatinine, 
phosphorus, calcium, glucose, total protein, albumin, sodium, potassium, bicarbonate, 
chloride, and magnesium. 
12.1.1.3. Creatinine Clearance 
Estimate the subject’s CLCR using the subject’s serum creatinine value, body weight, and 
the appropriate Cockroft-Gault formula below.  For body weight, actual body weight 
should be used; use of ideal or adjusted body weight is not permitted. If actual body 
weight is not available, an estimation of actual body weight should be used. 
For serum creatinine reported in µmol/L: 
Males:  
CLCR (mL/min) = 
(140 – age in years) × weight (kg) 
 
 
 
0.814 × serum creatinine (µmol/L) 
Females:  
CLCR (mL/min) = 0.85x 
(140 – age in years) × weight (kg) 
 
 
0.814 × serum creatinine (µmol/L) 
 
 
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For serum creatinine reported in mg/dL: 
Males:  
CLCR (mL/min) = 
(140 – age in years) × weight (kg) 
 
 
72 × serum creatinine (mg/dL) 
 
 
 
Females:  
CLCR (mL/min) = 0.85 × (140 – age in years) × weight (kg) 
 
 
72 × serum creatinine (mg/dL) 
12.1.2. 
Other Blood Sampling 
Obtain a sample for evaluation of the direct Coombs’ test, serum procalcitonin and C-
reactive protein (CRP) according to the Schedule of Assessments (Table 6). 
A blood specimen for WBC count (with differential) should be obtained daily. 
In addition, an arterial blood gas sample should be obtained.  Post-screening, the 
measurement of O2 saturation may be substituted for the PaO2 measurement in subjects 
without arterial access or in whom arterial blood sampling would not be considered 
standard of care (see Appendix E). 
12.1.2.1. Pharmacokinetic Sample Collection 
All sites (except at sites where the absence of key equipment [eg, refrigerated centrifuge] 
does not permit the site from doing so) will collect blood samples from all patients over 
1 dosing interval to evaluate the PK of ceftolozane/tazobactam in adult subjects with 
VNP.  The blood samples for determination of plasma PK will be collected on Day 4 of 
the treatment period.  If Day 4 is not possible, PK samples can be collected after Day 4.  
Timing of blood samples and study drug administration will be recorded.  Blood samples 
will be obtained at the following times relative to 1 of the 3 daily infusions: 
 Immediately (within 15 minutes) before the start of a blinded study drug 
administration on or after Day 4; 
 At the end of blinded study drug infusion (within 10 minutes after end of 
infusion); 
 30 to 90 minutes after the end of blinded study drug administration; 
 2.5 to 3.5 hours after the end of blinded study drug administration; 
 5.0 to 6.0 hours after the end of blinded study drug administration. 
For subjects with renal impairment requiring 4 daily doses of blinded study drug, blood 
samples should be obtained following the first daily infusion. 
12.1.2.2. Pregnancy Screen 
Serum pregnancy tests will be performed for all females of child-bearing potential and for 
those who are less than 1 year postmenopausal. 
12.2. 
Adverse and Serious Adverse Events 
Adverse events and SAEs will be collected from administration of the first dose of study 
medication through the LFU visit, whether or not they are related to the study, and must 
be recorded on the AE and SAE eCRFs. 
 
 
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12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical 
product that does not necessarily have to have a causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not related to the medicinal product.  
 An AE may be a new event or a pre-existing condition that has become 
aggravated or has worsened in severity or frequency. 
 An AE may be a clinically significant change from baseline in physical 
examination, laboratory tests, or other diagnostic investigation (eg, laboratory 
result, X-ray finding). 
Pregnancy is not an AE; however, if a female subject or the female partner of a male 
subject who has received at least 1 dose of study medication becomes pregnant during the 
conduct of the study, the Investigator must notify the Sponsor according to the procedures 
in Section 12.5.2.  If a female subject becomes pregnant during study drug administration, 
study drug must be stopped immediately. 
Clinical failures, including the following, are NOT AEs: 
 progression, relapse, or recurrence of new symptoms or complications 
attributable to VNP 
 lack of resolution (persistence) or insufficient improvement in signs and 
symptoms of VNP which were present at baseline that required new or 
prolonged antibiotic therapy 
12.2.1.2. Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death; or 
 Is life-threatening. 
Note: “Life-threatening” refers to a situation in which the subject was at 
risk of death at the time of the event; it does not refer to an event which 
might have caused death if it were more severe; 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
Note:  Adverse events requiring hospital admission that are less than 
24 hours in duration do not meet this criterion.  However, hospitalizations 
of less than 24 hours that meet any other seriousness criteria must be 
reported as SAEs. A scheduled hospitalization for a pre-existing condition 
that has not worsened during participation in the study does not meet this 
criterion.  Pre-planned hospitalizations for an elective medical/surgical 
procedure or routine check-ups do not meet this criterion; 
 Results in persistent or significant disability or incapacity; 
 Is a congenital anomaly or birth defect; 
 
 
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 Is considered to be an important medical event. 
Note: Important medical events are those that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the subject or 
may require intervention to prevent one of the outcomes listed in the definition 
above. 
12.2.2. 
Overdose 
An overdose is defined as a deliberate or accidental administration of study drug at a dose 
that is 1.5 times higher than the protocol-specified dose for the subject’s renal function, 
with or without associated AEs.  Report signs and symptoms of an overdose, if any, as 
AEs as described in Section 12.5. 
12.2.3. 
Planned Hospitalization 
A hospitalization planned prior to first dose of study medication is considered a 
therapeutic intervention and not the results of a new AE.  If the planned hospitalization or 
procedure is executed as planned, it should be recorded in the subject’s medical history.  
However, if complications arise during the planned hospitalization or procedure or the 
subject experiences an AE during the planned hospitalization or procedure, it must be 
reported as an AE. 
12.2.4. 
Monitoring of Adverse Events 
Each subject will be monitored for the occurrence of AEs, including SAEs, beginning 
immediately after administration of the first dose of study medication.  Each subject will 
be followed for safety monitoring until the late follow-up visit in the trial as described in 
the Schedule of Assessments (Table 6). 
 Subjects will be questioned and/or examined by the Investigator or a qualified 
designee for evidence of AEs.  The questioning of subjects with regard to the 
possible occurrence of AEs will be generalized such as, “How have you been 
feeling since your last visit?”  The presence or absence of specific AEs should 
not be elicited from subjects. 
 Subjects having AEs will be monitored with relevant clinical assessments and 
laboratory tests, as determined by the Investigator. 
 An AE, actions taken as a result of the AE, and follow-up results must be 
recorded in the eCRF, as well as in the subject’s source documentation.  
Follow-up laboratory results should be filed with the subject’s source 
documentation. 
For all AEs and SAEs that require the subject to be discontinued from the trial, relevant 
clinical assessments and laboratory tests will be repeated as clinically appropriate, until 
final resolution or stabilization of the event(s). 
12.2.5. 
Monitoring of Laboratory Assessments 
The Investigator will review clinical laboratory values for significance and consideration 
as an AE. 
 
 
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12.3. 
Relationship to Study Drug 
A medically-qualified Investigator must assess the relationship of any AE (including any 
SAE) to the use of the investigational product, as related or not related, based on clinical 
judgment and using all available information, and may include consideration of the 
following factors: 
 Possible alternative causes of the AE, including the disease under treatment, 
pre-existing conditions, concomitant use of other drugs, and presence of 
environmental or genetic factors. 
 The temporal association between drug exposure and onset of the AE. 
 Whether the manifestations of the AE are consistent with known actions or 
toxicity of the investigational product. 
 Dechallenge: The AE resolved or improved with decreasing the dose or 
stopping use of the investigational product.  Judgment should be used if 
multiple products are discontinued at the same time. 
 Rechallenge: The AE recurred or worsened upon re-exposure to the 
investigational product. 
The causal relationship between the study medication and the AE will be assessed using 
one of the following categories: 
Not Related: An AE is not associated with study medication if: 
 Temporal relationship is lacking (ie, the event did not occur within a 
reasonable time frame following administration of the study medication); or 
 Other causative factors more likely explain the event (eg, a pre-existing 
condition, other concomitant treatments); or 
 Dechallenge was either not clinically indicated or did not result in clinical 
improvement; or 
 The AE did not reoccur upon rechallenge (if applicable). 
Related: An AE is attributed to the study medication if:  
 There is a positive temporal relationship (ie, the event occurred within a 
reasonable time frame following administration of study medication); or 
 The AE is more likely explained by the investigational product than by 
another cause (ie, the AE shows a pattern consistent with previous knowledge 
of the investigational product or the class of the investigational product), or 
 The event improved on dechallenge and/or re-occurred upon rechallenge (if 
applicable). 
12.4. 
Recording Adverse Events 
12.4.1. 
Assessment of Severity 
The term “severe” is often used to describe the intensity (severity) of a specific event (as 
in mild, moderate, or severe myocardial infarction).  The event itself, however, may be of 
relatively minor medical significance (such as severe nausea).  This is not the same as 
 
 
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“serious,” which is based on subject/event outcome or action criteria usually associated 
with events that pose a threat to a subject’s life or functioning. 
The severity of AEs will be assessed according to the following definitions: 
 Mild:  The AE is noticeable to the subject and/or the Investigator, but does not 
interfere with routine activity. 
 Moderate:  The AE interferes with routine activity, but responds to 
symptomatic therapy or rest. 
 Severe:  The AE significantly incapacitates the subject, limits the subject’s 
ability to perform routine activities, or significantly affects the subject’s 
clinical status despite symptomatic therapy. 
12.4.2. 
Reference Safety Information for the Assessment of Expectedness of AEs 
The Reference Safety Information (RSI) for assessing the expectedness of an AE for 
ceftolozane/tazobactam in this trial can be found in the most recent Investigator’s 
Brochure for ceftolozane/tazobactam. 
The RSI for assessing the expectedness of an AE for comparator (meropenem) in this trial 
can be found in the most recent clinically packaged product for the country of use. 
Known signs and symptoms of VABP and ventilated HABP and known complications of 
mechanical ventilation listed below are considered expected events for this protocol: 
pneumothorax, acute lung injury, acute respiratory distress syndrome, empyema, 
worsening lung function, reintubation, ongoing fever, pulmonary infiltrates, increasing 
PaO2/FiO2, ongoing positive LRT culture, or elevated WBC count. 
12.5. 
Reporting Adverse Events 
12.5.1. 
Reporting of Nonserious Adverse Events 
All AEs, regardless of seriousness, severity, or causal relationship to study medication, 
will be recorded on the AE page of the eCRF. 
12.5.2. 
Reporting of Drug Exposure During Pregnancy 
If a female subject or the female partner of a male subject who has received at least 1 
dose of study medication becomes pregnant during the course of study, the Investigator 
must report this using the Pregnancy Reporting Form within 24 hours of becoming aware 
of the event. 
If not all information on the Pregnancy Reporting Form is available at the time of the 
initial report, follow-up reports must be submitted.  The Investigator is required to follow 
up on the pregnancy until it has completed.  The outcome of the pregnancy and the status 
of the newborn (if applicable) will be reported on the Pregnancy Reporting Form within 
24 hours of the Investigator becoming aware. 
If the female partner of a male subject becomes pregnant, the Investigator must attempt to 
obtain consent to collect pregnancy information (including the status of the newborn, if 
applicable). 
 
 
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12.5.3. 
Reporting of Expedited Safety Observations by the Investigator 
Any occurrence of the following events or outcomes in a subject in the trial must be 
reported expeditiously by the Investigator or qualified designee to the Sponsor: 
 SAE; 
 Death of a subject; 
 Overdose (deliberate or accidental); 
 New onset of cancer. 
The Investigator is to report any Expedited Safety Observations from the list above within 
24 hours of becoming aware of the event.  If the observation above that is reported is also 
an AE, the Investigator must record the AE in the eCRF, as well as in the subject's source 
documentation.  If not all information on the Safety Reporting Form is available at the 
time of the initial report, follow-up SAE reports will be completed and submitted. 
The Investigator is required to follow SAEs until resolution, stabilization, or withdrawal 
of consent.  Resolution is defined as: 
 Resolved without residual effects; 
 Resolved with residual effects; 
 A return to baseline for a pre-existing condition; 
 Fatal; or 
 The Investigator does not expect any further improvement or worsening of the 
event. 
In the event the eCRF is not available, expedited safety observations can be reported by 
fax or email using hardcopy forms (Appendix A).  Events reported using hardcopy forms 
must be entered into the eCRF once it becomes available. 
12.5.4. 
Expedited Reporting by the Sponsor to Applicable Health Authorities 
The Sponsor will monitor the data for safety and manage the expedited reporting of 
relevant safety information to the applicable Health Authorities in accordance with 
applicable laws and regulations. 
12.5.5. 
Safety Notifications by the Sponsor to Investigators 
Investigators will receive prompt notification of any adverse experience associated with 
the use of the study medication that is both serious and unexpected, or any finding that 
suggests a significant risk for subjects.  The Investigator will promptly inform the 
IRB/EC of the notification and insert the notification in the Investigator’s Regulatory 
Binder in accordance with local regulations. 
12.5.6. 
Unblinding Treatment for a Subject During the Trial 
Requirements for emergency unblinding by the Investigator are detailed in Section 9.3.5.  
To assess an occurrence of a safety observation, the Sponsor may unblind the treatment of 
any subject. 
 
 
 
 
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13. 
STATISTICS 
13.1. 
Data Collection, Processing and Reporting 
The site will be supplied with the following data collection tool: a web browser address 
for an Electronic Data Capture (EDC) system database that has been fully validated and 
conforms to Title 21 Code of Federal Regulations (CFR) Part 11 and the Guidance for 
Industry on Computerized Systems Used in Clinical Trials requirements.  The EDC 
system database will be maintained by the Sponsor. 
The trained Investigational site staff will enter the data required by the protocol into the 
eCRFs from source documents (eg, medical records and study-specific data capture forms 
as needed) into the EDC system.  All information on the eCRFs must be traceable to these 
source documents.  Data recorded directly on the eCRFs will be defined before study 
start. 
The eCRFs will be completed for all subjects randomized to study treatment.  The eCRFs 
for subjects who are randomized but not treated will be completed with all data collected 
at the time of subject study discontinuation.  A Clinical Monitor will review the eCRFs 
entered by investigational staff for completeness and accuracy. 
Automatic validation programs or manual checks for data discrepancies in the eCRFs 
may result in electronic queries generated for resolution by the investigational site.  
Designated Investigative site staff is required to respond to these queries and make any 
necessary changes to the data.  After database lock, the Investigator will receive a CD-
ROM of the subject data for archiving at the investigational site. 
All TEAEs (events occurring from the first dose of study medication through the last 
study evaluation) will be recorded.  Adverse events will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA).  Concomitant medications will be coded 
using a standard dictionary (eg, WHODrug) and Medical History will be coded using 
MedDRA. 
An IRT will be used to allocate the randomized treatments to subjects as they are 
enrolled.  The randomized treatment assignments will be transferred electronically for 
integration with the clinical study data at the appropriate time. 
13.2. 
Statistical Considerations 
13.2.1. 
Analysis per the US FDA 
13.2.1.1. General Methodology 
For analyses of dichotomous endpoints, 2-sided 95% confidence intervals (CIs) for the 
difference in proportions between ceftolozane/tazobactam and meropenem will be 
calculated, with adjustment for the study stratification factors [diagnosis (VABP or 
ventilated HABP) and by age (≥65 or <65 years)].  For negative endpoints, eg, Day 28 
all-cause mortality, the difference will be calculated as meropenem minus 
ceftolozane/tazobactam; for positive endpoints, eg, clinical response at TOC, the 
difference will be calculated as ceftolozane/tazobactam minus meropenem.  The 
estimated overall proportion will be calculated as a weighted average across all strata, 
constructed using Mehrotra-Railkar continuity-corrected minimum-risk [MRc] stratum 
weights [22].  The 2-sided 95% CIs for the treatment group proportions and the treatment 
 
 
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difference will be calculated as stratified Newcombe CIs, constructed using the MRc 
weights with the methods presented by Yan and Su [23]. 
For analysis of other secondary and exploratory dichotomous endpoints with reduced 
sample sizes (eg, per-pathogen microbiological response and subgroup analyses), the 2-
sided 95% CIs for the treatment difference will be calculated as unstratified Newcombe 
CIs. 
For continuous outcomes, comparisons between treatment groups will be performed using 
analysis of covariance (ANCOVA) with a model that contains fixed-effect terms for 
treatment and strata. 
For time-to-event endpoints, Kaplan-Meier curves that are stratified by diagnosis (VABP 
or ventilated HABP) and by age (≥65 or <65 years) will be produced, along with an 
overall Kaplan-Meier curve.  Comparisons of the survival curves between treatment 
groups will be based on a stratum-adjusted log-rank test.  Subjects who do not have the 
event outcome recorded will not be excluded from these analyses, but will be right-
censored as of the subject’s last available evaluation, unless otherwise specified.  All tests 
will be 2-sided and will be conducted at the 0.05 significance level. 
For categorical data, descriptive statistics will consist of frequency and percentage for 
each category and 95% CIs will be constructed around the percentage, when appropriate.  
Descriptive statistics for continuous data will consist of sample size (n), mean, standard 
deviation, median, minimum, and maximum.  Summary tables will be presented by 
treatment groups. 
For time-to-event endpoints, summaries will include the number of subjects, the number 
of subjects who achieved the event of interest, the number of subjects censored and the 
quartiles, ie, the 25th, 50th (median) and 75th percentiles of the distribution of the event 
times (in days).  A 95% CI will also be provided for the median event times. 
13.2.1.2. Multiple Comparisons and Multiplicity Adjustments 
In order to maintain an overall 1-sided 0.025 type I error rate across the primary and key 
secondary efficacy endpoints in the ITT population, a sequential testing approach will be 
used.  Testing will be performed in the following sequence: 
Step 1: Non-inferiority for the primary efficacy endpoint (Day 28 all-cause mortality in 
the ITT population) will be evaluated.  If the primary efficacy endpoint demonstrates non-
inferiority of ceftolozane/tazobactam to meropenem at the 1-sided 0.025 significance 
level, then Step 2 will be performed. 
Step 2: Non-inferiority for the key secondary endpoint (favorable clinical response at the 
TOC visit in the ITT population) will be tested between ceftolozane/tazobactam and 
meropenem at the 1-sided 0.025 significance level. 
13.2.2. 
Analysis per the EMA 
13.2.2.1. General Methodology 
Similar general methodologies detailed in the preceding US FDA Analyses section will 
be employed (see Section 13.2.1).  However, a 2-sided 97.5% CI will be constructed 
instead of 95% CIs, regardless of the data and safety monitoring board (DSMB) review. 
 
 
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13.2.2.2. Multiple Comparisons and Multiplicity Adjustments 
In order to maintain a 1-sided 0.0125 overall type I error rate across the primary and key 
secondary efficacy endpoints in the ITT population, a sequential testing approach will be 
used.  Testing will be performed in the following sequence: 
Step 1: Non-inferiority for the primary efficacy endpoint (clinical response at TOC for the 
ITT population) will be evaluated.  If the primary efficacy endpoint demonstrates non-
inferiority of ceftolozane/tazobactam to meropenem at the 1-sided 0.0125 significance 
level, then Step 2 will be performed. 
Step 2: Non-inferiority for the key secondary efficacy endpoint (Day 28 all-cause 
mortality in the ITT population) will be tested between ceftolozane/tazobactam and 
meropenem at the 1-sided 0.0125 significance level. 
13.2.3. 
Handling of Missing Data  
Every effort should be made to collect all data at specified times, according to the 
schedule of study events.  For all data points other than all-cause mortality, clinical, and 
microbiological outcomes, missing data will be handled as follows: 
 Missing values for individual data points will remain missing.  Missing values 
will not be imputed and only observed values will be used in data analyses and 
presentations. 
 Where individual data points are missing, categorical data will be summarized 
based on reduced denominators (ie, only subjects with data available will be 
included in the denominators). 
For all-cause mortality, missing data will be handled as follows: 
 For the analysis of Day 14 and Day 28 all-cause mortality rates, subjects whose 
mortality outcome is missing or unknown will be analyzed as deceased on Day 14 
or Day 28. 
 For the analysis of time to all-cause mortality, subjects with a missing or unknown 
all-cause mortality status will be analyzed as follows:  
1) Assumed to have died at the time of last study contact, and  
2) Have their time to all-cause mortality censored at the time of last contact. 
For clinical response, missing data will be primarily handled with a Treatment Failure 
Approach (TFA) for the ITT and mITT populations and with Data-as-Observed (DAO) 
approach for the CE and ME populations defined as follows: 
 TFA:  All subjects with a missing clinical response at the EOT and TOC visits 
will be categorized as treatment failures in the ITT and mITT populations.  For the 
analysis of clinical response, all subjects with clinical response of missing or 
indeterminate who meet the population criteria (ITT or mITT, as appropriate) will 
be included in the denominator. 
 DAO:  All subjects with missing clinical response, including indeterminate, will 
be excluded from the CE and ME populations.  A missing clinical outcome at the 
TOC visit will be considered an indeterminate outcome unless the clinical 
outcome at EOT was failure.  A clinical response of failure at EOT will be carried 
forward to the TOC visit. 
 
 
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For per-pathogen microbiological outcome, missing data will be considered presumed 
eradication, presumed persistence or indeterminate as defined in Table 13. 
For per-subject microbiological outcome, missing data will be considered presumed cure, 
presumed failure or indeterminate as defined in Table 14. 
Handling of missing AE data and partial and missing dates is presented in detail in the 
SAP. 
13.2.4. 
Populations for Analysis 
The definitions of analysis populations are outlined below.  Further details are provided in 
the SAP. 
13.2.4.1. Intent-to-treat Population 
The Intent-to-treat (ITT) population will consist of all randomized subjects, regardless of 
whether or not they go on to receive study drug.  Subjects in the ITT population will be 
categorized based on the treatment arm that they are randomized to. 
13.2.4.2. Safety Population  
The Safety population is a subset of the ITT population who receive any amount (ie, full 
or partial dose) of study drug.  All safety analyses will be performed in this population.  
Subjects in the Safety population will be categorized based on the actual treatment that 
they receive, irrespective of the treatment arm they are randomized to. 
13.2.4.3. Microbiological Intent-to-treat Population 
The Microbiological Intent-to-treat (mITT) population is a subset of the ITT population 
who receive any amount of study drug and have at least 1 bacterial respiratory pathogen 
isolated from the baseline LRT culture that is susceptible to at least 1 of the study drugs.  
Subjects with S. aureus as their only baseline LRT pathogen are excluded from the mITT 
population. 
13.2.4.4. Clinically Evaluable Population 
The Clinically Evaluable (CE) population is a subset of the ITT population who have 
received study drug, adhere to the study protocol through the TOC visit, and have an 
evaluable clinical outcome (either Cure or Failure) at the TOC visit (or are classified as a 
clinical failure prior to the TOC visit). 
13.2.4.5. Microbiologically Evaluable Population 
The Microbiologically Evaluable (ME) population is a subset of mITT who adhere to the 
study protocol through the TOC visit, have an evaluable clinical outcome (either Cure or 
Failure) at the TOC visit (or are classified as clinical failure prior to the TOC visit), and 
have at least 1 bacterial respiratory pathogen (at the appropriate colony-forming unit 
(CFU)/mL threshold) isolated from the baseline LRT culture that is susceptible to at least 
1 of the study drugs.  To be eligible for the ME population, the following quantitative 
bacterial counts are required: ≥105 CFU/mL for ETA, ≥104 CFU/mL for BAL/mini-BAL, 
and ≥103 CFU/mL for PBS. 
 
 
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13.2.5. 
Study Endpoints 
Study endpoints to accommodate the unique requirements of different regulatory 
jurisdictions, have been outlined in Table 10. 
Table 10: 
Study Endpoints per Different Regulatory Jurisdictions 
 
Per the US FDA 
Per the EMA 
Primary Endpoint 
 Day 28 all-cause mortality in the 
ITT population. 
 Clinical response at the TOC 
visit in the ITT population. 
Key Secondary Endpoint 
 Clinical response at the TOC 
visit in the ITT population 
 Day 28 all-cause mortality in 
the ITT population 
Secondary Endpoints 
 Clinical response at the TOC visit in the CE population 
 Clinical response for subjects at the TOC visit in the subset of subjects 
who had P. aeruginosa isolated from the baseline LRT culture in the 
mITT population 
 Clinical response for subjects at the TOC visit in the subset of subjects 
who had Enterobacteriaceae isolated from the baseline LRT culture in 
the mITT population 
 Per-subject microbiological response at TOC in the ME population 
 Per-pathogen microbiological response for P. aeruginosa at TOC in the 
ME population 
 Per-pathogen microbiological response for Enterobacteriaceae at TOC 
in the ME population 
 Per-pathogen microbiological response at TOC in the ME population 
 Day 28 all-cause mortality in the mITT population 
 Day 14 all-cause mortality in the ITT population 
 Clinical response at EOT in the ITT and CE populations 
 Clinical response at the LFU visit in the CE population 
 Per-subject microbiological response at EOT in the ME population 
 Per-pathogen microbiological response at EOT in the ME population 
 Per-pathogen clinical response at TOC by baseline MIC in the mITT 
and ME  
Exploratory Endpoints 
 Time to all-cause mortality in the ITT population 
 Clinical response for subjects at TOC in the subset of subjects who had 
P. aeruginosa isolated from the baseline LRT culture in the ME 
population 
 Clinical response for subjects at TOC in the subset of subjects who had 
Enterobacteriaceae isolated from the baseline LRT culture in the ME 
population 
 Per-subject microbiological response at TOC in the mITT population 
 Per-pathogen microbiological response at TOC in the mITT population 
 Per-subject microbiological response at EOT in the mITT population 
 Per-pathogen microbiological response at EOT in the mITT population 
 Per-pathogen microbiological response by baseline MIC in the mITT 
and ME populations 
 Superinfection and new infection rates in the mITT population 
 
 
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Per the US FDA 
Per the EMA 
 Emergence of nonsusceptibility to study drug in the mITT population 
 Time to a ≥1-log reduction in bacterial burden of the causative gram-
negative pathogen(s) identified from the baseline lower respiratory 
specimen in the mITT and ME populations 
 Emergence of a 4-fold increase in MIC to study drug for treated 
subjects with P. aeruginosa or Enterobacteriaceae isolated from the 
baseline LRT culture (the elevated MIC must be ≥2 µg/mL) in the 
mITT population 
 Pharmacokinetics 
 Total number of days in hospital within 28 days after randomization 
for the ITT population 
 Proportion of patients discharged from the acute care hospital within 
28 days after randomization for the ITT population 
 Number of days in ICU through 28 days after randomization for the 
ITT population 
 Number of days on a ventilator through 28 days after randomization 
for the ITT population 
 Change in procalcitonin from baseline to Day 3 and to the EOT visit in 
the ITT population. 
Safety Endpoints 
Safety will be evaluated in the Safety population through review of 
summaries of: 
 
Deaths and other SAEs 
 
Adverse events 
 
Laboratory evaluations 
 
Vital signs 
 
Physical examinations. 
13.2.6. 
Subject Disposition 
Descriptive statistics of disposition information for all randomized subjects will be 
presented by treatment arm.  The number and percent of subjects included in the various 
analysis populations specified in Section 13.2.4 will be provided.  The number and 
percent of subjects who complete treatment, discontinue study medication prematurely, or 
discontinue the study prematurely, will be tabulated.  The primary reason for premature 
discontinuation of study medication and/or discontinuation from study participation will 
be tabulated. 
13.2.7. 
Demographics and Baseline Data 
Subject demographics and baseline characteristics will be presented by treatment group.  
Unless otherwise noted, baseline will be the assessment obtained closest and prior to the 
first dose of study drug. 
 
 
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13.2.8. 
Primary Endpoint Analysis  
13.2.8.1. Primary Efficacy Analysis per the US FDA 
The primary statistical goal of this study for the US FDA is to establish non-inferiority of 
ceftolozane/tazobactam to meropenem with respect to the difference in the Day 28 all-
cause mortality rates using a 10% non-inferiority margin in the ITT population [24]. 
The hypotheses for non-inferiority are as follows where p1 is the proportion of deceased 
subjects on Day 28 treated with meropenem and p2 is the proportion of deceased subjects 
on Day 28 treated with ceftolozane/tazobactam: 
 
Null Hypothesis, H0:   
p1 – p2 ≤-10% 
 
Alternative Hypothesis, H1:  p1 – p2 >-10%. 
A 2-sided 95% CI around the difference (meropenem minus ceftolozane/tazobactam) in 
the Day 28 all-cause mortality rates will be constructed, adjusting for the stratification 
factors (diagnosis [VABP or ventilated HABP] and age [≥65 or <65 years]).  The 
estimated overall difference in proportions between the 2 groups will be calculated as a 
weighted average across all strata, constructed using Mehrotra-Railkar MRc stratum 
weights [22].  The 2-sided 95% CI for the difference will be calculated as a stratified 
Newcombe CI, constructed using MRc weights with methods presented by Yan and Su 
[23]. 
Ceftolozane/tazobactam will be considered non-inferior to meropenem if the lower limit 
of the 2-sided 95% CI around the difference is greater than minus 10% [25]. 
As sensitivity analysis, a 95% CI for the difference in Day 28 all-cause mortality rates 
(meropenem minus ceftolozane/tazobactam) unadjusted for the stratification factors will 
be constructed. 
13.2.8.2. Primary Efficacy Analysis per the EMA 
The primary statistical goal of this study per the EMA analysis is to establish non-
inferiority of ceftolozane/tazobactam to meropenem with respect to the difference in 
clinical cure rates at TOC using a 12.5% non-inferiority margin in the ITT population.  
The hypotheses for non-inferiority are as follows, where p1 is the proportion of subjects 
treated with ceftolozane/tazobactam with a clinical response of cure at the TOC visit and 
p2 is the proportion of subjects treated with meropenem with a clinical response of cure at 
the TOC visit: 
 
Null Hypothesis, H0:   
p1 – p2 ≤-12.5% 
 
Alternative Hypothesis, H1:  p1 – p2 >-12.5%. 
A 2-sided, 97.5% CI around the difference (ceftolozane/tazobactam minus meropenem) in 
the clinical cure rates at TOC will be constructed, adjusting for the stratification factors 
(diagnosis [VABP or ventilated HABP] and age [≥65 or <65 years]).  When calculating 
the clinical cure rate for each treatment group, all subjects in the ITT population in each 
treatment group will be included in the denominator.  The estimated overall difference in 
proportions between the 2 groups will be calculated as a weighted average across all 
strata, constructed using Mehrotra-Railkar MRc stratum weights [22].  The 2-sided 97.5% 
CI for the difference will be calculated as a stratified Newcombe CI, constructed using 
MRc weights with methods presented by Yan and Su [23]. 
 
 
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Ceftolozane/tazobactam will be considered non-inferior to meropenem if the lower limit 
of the 2-sided 97.5% CI around the difference is greater than minus 12.5% [25]. 
As sensitivity analysis, a 97.5% CI for the difference in clinical cure rates at TOC 
(ceftolozane/tazobactam minus meropenem) unadjusted for the stratification factors will 
be constructed. 
13.2.9. 
Secondary and Exploratory Endpoint Analyses 
13.2.9.1. Key Secondary Endpoints per US FDA Analyses 
The key secondary efficacy endpoints listed in Table 10 will be compared between 
ceftolozane/tazobactam and meropenem using the methodology for dichotomous 
endpoints described in Section 13.2.1.1.  Clinical response at the TOC visit will be 
compared between ceftolozane/tazobactam and meropenem for the ITT populations using 
a 12.5% non-inferiority margin. 
13.2.9.2. Key Secondary Endpoints per EMA Analyses 
All key secondary efficacy endpoints listed in Table 10, will be compared between 
ceftolozane/tazobactam and meropenem using the methodology for dichotomous 
endpoints described in Section 13.2.2.1.  Day 28 all-cause mortality rates in the mITT 
population will be compared between ceftolozane/tazobactam and meropenem using a 
10% non-inferiority margin. 
13.2.9.3. Other Secondary and Exploratory Endpoints (Per the USA FDA and 
EMA Analyses) 
The proportions of subjects achieving the outcome of interest will be provided by 
treatment group for other dichotomous secondary efficacy and exploratory endpoints.  
The 2-sided, 95% (per US FDA) or 97.5% (per EMA) of the difference in proportions 
will be used to compare other dichotomous secondary efficacy and exploratory endpoints 
between ceftolozane/tazobactam and meropenem. 
Stratified Kaplan-Meier method will be used to analyze time to event endpoints, eg, time 
to all-cause mortality in the ITT population and time to a 1-log reduction in bacterial 
burden of the causative gram-negative baseline LRT pathogen(s) in the mITT and ME 
populations. 
The proportion of patients who are discharged from the acute care hospital within 28 days 
after randomization will be presented by treatment group for the ITT population.  
Descriptive statistics will also be provided for the total number of days in hospital within 
28 days after randomization, the number of days in the ICU through 28 days after 
randomization and the number of ventilator days through 28 days after randomization by 
treatment group in the ITT population.  Analyses will be conducted only in those patients 
who did not die prior to Study Day 28. 
Procalcitonin levels and change from baseline to Day 3 and to EOT will also be 
summarized by treatment group in the ITT population.  Change from baseline will be 
calculated for each patient at the specified time point as the value at the specified time 
point minus the baseline value. 
Further details of statistical methods will be described in the SAP for these other 
secondary and exploratory endpoints. 
 
 
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13.2.10. 
Safety Analyses 
13.2.10.1. Adverse Events 
The incidence (n and %) of TEAEs, SAEs, and early termination of study medication 
and/or study participation due to an AE will be presented for subjects in each treatment 
arm.  Additionally, AEs will be tabulated according to severity and relatedness categories 
as reported by the Investigator.  Adverse events will be presented in tables organized 
alphabetically by System Organ Class and Preferred Term.  Each subject will be counted 
only once for each AE reporting level. 
13.2.10.2. Vital Signs 
Vital sign data will be tabulated for actual values and change from baseline for all 
scheduled time points. 
13.2.10.3. PaO2/FiO2 
PaO2/FiO2 data will be tabulated for actual values and change from baseline for all 
scheduled time points. 
13.2.10.4. Clinical Pulmonary Infection Score  
Modified CPIS will be calculated and tabulated for actual values at baseline. 
13.2.10.5. Sepsis Organ Failure Assessment Score 
The SOFA score will be calculated and tabulated for actual values at baseline. 
13.2.10.6. Safety Laboratory Tests 
Change in laboratory assessments from baseline will be evaluated and presented by 
treatment group.  Baseline is defined as the closest value prior to the first dose of study 
drug.  Shifts from baseline to post-baseline grade in selected safety laboratory parameters 
will also be examined. 
13.2.10.7. Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the WHO Drug format medication 
dictionary. 
13.2.11. 
Sample Size and Power Considerations 
Approximately 726 subjects will be enrolled into this study, randomized 1:1 to receive 
ceftolozane/tazobactam or meropenem.  This study is designed to show non-inferiority in 
the primary outcome measure of Day 28 all-cause mortality in the ITT population for the 
US FDA analysis.  For the analysis per the EMA, this study is designed to show non-
inferiority in the primary outcome of clinical cure rate in the ITT population. 
13.2.11.1. Sample Size and Power Considerations per the US FDA Analysis 
To demonstrate the non-inferiority of ceftolozane/tazobactam to meropenem with respect 
to the difference in Day 28 all-cause mortality rates, using a non-inferiority margin of 
10%, a sample size of 726 subjects (363 per arm) in the ITT population will have 90% 
power at a 1-sided significance level of 0.025, assuming a Day 28 all-cause mortality rate 
of 20% in both ceftolozane/tazobactam and meropenem arms.  Note that due to the 
 
 
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planned futility look by the DSMB when approximately 30% of patients have been 
enrolled and completed the study, the power of the primary endpoint analysis was 
decreased from 92% to 90%. 
13.2.11.2. Sample Size and Power Considerations per the EMA Analysis 
To demonstrate the non-inferiority of ceftolozane/tazobactam to meropenem with respect 
to the difference in clinical cure rates of VNP at the TOC visit in the ITT population, 
using a non-inferiority margin of 12.5%, at a 1-sided significance level of 0.0125, a 
sample size of 726 subjects (363 per arm) will have 85.3% power assuming a cure rate of 
58.4% in both ceftolozane/tazobactam and meropenem arms.  Note that due to the 
planned futility look by the DSMB when approximately 30% of patients have been 
enrolled and completed the study, the power of the primary endpoint analysis was 
decreased from 88.0% to 85.3%. 
The cure rate assumption is based on data from a recent pivotal trial in VNP caused by 
predominantly gram-negative organisms [16].  
13.2.12. 
Statistical Analysis Plans 
A separate comprehensive SAP will be prepared and finalized before database lock and 
analysis of the data per the US FDA and EMA.  The SAPs will provide detailed 
descriptions of the statistical methods and expand on the details provided in this protocol. 
13.2.13. 
Pharmacokinetics 
Plasma samples will be analyzed to determine plasma concentration of ceftolozane, 
tazobactam, and M1-tazobactam using a validated tandem mass spectrometric assay. 
Detailed instructions on collecting and processing blood PK samples are provided in 
Table 6 and Section 12.1.2.1. 
Descriptive statistics of pharmacokinetic information for subjects will be presented by, 
and analyzed for, the following analytes: ceftolozane, tazobactam, and M-1-tazobactam.  
Noncompartmental analyses will be conducted to estimate standard PK parameters such 
as maximum concentration achieved (Cmax), total exposure during one dosing interval 
(AUC0-τ), steady-state volume of distribution (Vss), half-life (t½), and clearance (CLss), as 
allowed by the data. 
As data allow, the Sponsor may explore plasma exposure-response analyses based on 
noncompartmental analysis of plasma PK data.  In addition, the Sponsor may characterize 
plasma PK using population PK to predict individual exposure values for potential 
exposure-response analysis to determine influence of covariates, and to evaluate the 
probability of target attainment (plan and results, if applicable, will be documented 
separately). 
13.3. 
Evaluation Criteria 
13.3.1. 
Clinical Response Definitions 
Clinical outcome assessments will be made at the EOT, TOC, and LFU visits. 
 
 
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13.3.1.1. Clinical Outcomes at the EOT and TOC Visit 
Clinical response at the EOT and TOC visit will be classified as cure, failure, or 
indeterminate (Table 11).  A favorable clinical response is “clinical cure.” 
Table 11: 
Clinical Response Categories at the EOT and TOC Visit 
Outcome 
Definition 
Cure  
 
Complete resolution of all or most of the clinical signs and 
symptoms of VNP which were present at baseline, AND 
 
No new signs, symptoms or complications attributable to VNP, 
AND 
 
No additional antibiotic therapy administered for VNP*, except for 
the approved adjunctive therapy, AND 
 
Patient is alive 
 
*Subjects receiving potentially effective concomitant antibiotic therapy for an indication 
other than VNP may still be considered a clinical cure provided they meet all other Cure 
criteria. 
Failure 
 
Progression, relapse, or recurrence of new symptoms or 
complications attributable to VNP, OR 
 
Lack of resolution (persistence), insufficient improvement in signs 
and symptoms of VNP which were present at baseline, study drug 
discontinuation due to resistant LRT pathogens, or need for 
alternative or prolonged antibiotic therapy for treatment of VNP, OR 
 
Patient died of VNP 
Indeterminate 
 
 
Subject prematurely discontinued study drug due to No Growth or 
only S. aureus isolated from the baseline LRT culture, OR 
 
Study data are not available for the evaluation of efficacy for any 
reason including: 
o Lost to follow-up 
o Withdrawal of consent 
o Subject died from cause other than VNP 
o Randomized not treated 
13.3.1.2. Clinical Outcomes at the LFU Visit 
Clinical response at the LFU visit will be classified as sustained cure, relapse, or 
indeterminate only in subjects deemed a clinical cure at the TOC visit (Table 12).  A 
favorable clinical response is “sustained clinical cure.” 
 
 
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Table 12: 
Clinical Response Categories at the LFU Visit 
Outcome 
Definition 
Sustained Cure  
No recurrence of signs or symptoms of pneumonia and, in addition, did 
not receive any antibiotics for the treatment of VNP* since the TOC 
visit. 
 
*Subjects receiving potentially effective concomitant antibiotic therapy for an indication 
other than VNP may still be considered a clinical cure provided they meet all other Cure 
criteria. 
Relapse 
Recurrence of signs or symptoms of pneumonia or new radiologic 
evidence of pneumonia or received antibiotic after the TOC for 
treatment of pneumonia. 
Indeterminate 
 
Subject prematurely discontinued study drug due to No Growth or 
only S. aureus isolated from the baseline LRT culture, OR 
 
Study data are not available for the evaluation of efficacy for any 
reason including: 
 
Lost to follow-up 
 
Withdrawal of consent 
 
Subject died from cause other than VNP 
 Randomized not treated 
13.3.2. 
Microbiological Response Definitions 
Microbiological outcome assessments will be made at the EOT and TOC visits.  
Microbiological outcome assessments will be determined by the Sponsor, based on the 
results of the LRT culture from the appropriate visit. 
13.3.2.1. Per-pathogen Microbiologic Outcomes at the EOT and TOC Visits 
Microbiological response at the EOT and TOC visits will be classified per-pathogen as 
eradication, presumed eradication, persistence, presumed persistence, indeterminate, and 
recurrence (Table 13). 
Table 13: 
Per-pathogen Microbiologic Outcome Categories at the EOT and 
TOC Visits 
Outcome 
Definition 
Eradication 
Absence defined as a ≥1- log reduction in bacterial burden of the 
original baseline LRT pathogen AND a per pathogen count of 
≤104 CFU/mL for ETA or sputum specimens, ≤103 CFU/mL for a BAL 
specimen, and ≤102 CFU/mL for a PBS specimen) from a follow-up 
LRT culture. 
Presumed 
eradication 
Absence of material to culture (eg, inability to obtain a culture in an 
extubated subject) in a subject deemed a clinical cure. 
Persistence 
Continued presence of the original causative baseline pathogen(s) from 
a LRT culture obtained at or after EOT.  Presence is defined as <1-log 
reduction in bacterial burden of the baseline pathogen OR >104 CFU/mL 
for ETA or sputum specimens, >103 CFU/mL for a BAL specimen, and 
>102 CFU/mL for a PBS specimen OR baseline organism is still present, 
but no quantitative culture count was determined. 
 
 
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Outcome 
Definition 
Presumed 
persistence 
Absence of material to culture in a subject deemed a clinical failure. 
Indeterminate 
Absence of respiratory material to culture at the EOT or TOC in a 
subject with Indeterminate clinical response 
Recurrence (at the 
TOC visit)a 
Isolation of the original causative bacterial baseline pathogen(s) at the 
appropriate diagnostic threshold (ie, ≥105 CFU/mL for ETA or sputum 
specimens, ≥104 CFU/mL for a BAL specimen, and ≥103 CFU/mL for a 
PBS specimen) from a LRT culture in a subject with documented 
eradication at the EOT visit 
aRelatedness will be determined by Genus, species and antibiogram at the discretion of the Sponsor, the 
pathogen from the TOC visit will be further tested by pulsed field gel electrophoresis to confirm relatedness 
to the baseline pathogen. 
13.3.2.2. Per-subject Microbiologic Outcomes at the EOT and TOC Visits 
Microbiological response at the EOT and TOC visits will be classified per-subject as 
microbiologic cure or microbiologic failure (Table 14). 
Table 14: 
Per-subject Microbiologic Outcome Categories at the EOT and TOC 
Visits 
Outcome 
Definition 
Microbiologic cure 
or presumed cure 
All baseline pathogens are deemed eradicated/presumed eradicated or 
absence of respiratory material to culture at the EOT or TOC in a subject 
deemed a clinical cure. 
Microbiologic failure 
or presumed failure 
Any baseline pathogen is deemed persistent/presumed persistent or 
absence of material to culture in a subject deemed a clinical failure. 
Indeterminate 
Absence of respiratory material to culture at the EOT or TOC in a 
subject with Indeterminate clinical response 
13.3.2.3. Emergent Infection 
Qualifying pathogens other than the causative baseline pathogen isolated after baseline 
assessment will be assessed as a superinfection or new infection (Table 15).  A qualifying 
emergent pathogen is defined as one meeting the threshold of ≥ 105 CFU/mL (for an ETA 
specimen), ≥104 CFU/mL (for a BAL or mini-BAL specimen), or ≥103 CFU/mL (for a 
specimen obtained by PBS). 
Table 15: 
New Pathogens 
Outcome 
Definition 
Superinfection 
Isolation of a pathogen, other than the causative baseline pathogen, from 
a post baseline LRT specimen obtained while the subject is still on study 
therapy.  
New infection 
Isolation of a pathogen other than the causative baseline pathogen from 
an LRT culture obtained after completion of study therapy. 
 
 
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13.4. 
Data and Safety Monitoring Board 
An interim review will be performed at a single pre-defined interval by an independent 
Data Safety Monitoring Board (DSMB) to evaluate the safety of 3000 mg of 
ceftolozane/tazobactam compared with meropenem.  The interim analysis of safety is 
planned after approximately 30% of subjects have been enrolled and have completed the 
study.  The membership of the DSMB will comprise experts in infectious diseases, 
critical care, and biostatistics who are well versed in clinical research. 
The DSMB review will include the following: 
 Incidence and distribution between treatment arms of the following: deaths, 
related and unrelated SAEs, drug-related AEs, and premature discontinuation 
of study medication due to AEs 
 Day 28 all-cause mortality rate 
 Clinical response at the TOC visit 
 Relevant safety lab results. 
The DSMB will be provided with additional data upon request.  The governance of the 
DSMB, including its decision rules, will be specified in the DSMB charter in accordance 
with applicable regulatory guidance.  To maintain blinding of the study staff, an 
independent statistical reporting group will provide data to the DSMB.  The DSMB 
Charter along with minutes of the review meeting will be filed, as part of the Trial Master 
File.  The minutes of the review meeting will be filed at the end of the study, after the 
database has been hard-locked. 
Based on its review, the DSMB will make recommendations on the interim safety of 
ceftolozane/tazobactam compared to meropenem.  The Sponsor will have the final 
decision regarding disposition of the study based on the DSMB’s recommendation, its 
own review and discussions with relevant regulatory jurisdictions, as appropriate. 
 
 
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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of the 
Sponsor will visit the investigational study site to: 
 Determine the adequacy of the facilities; 
 Discuss with the Investigator(s) and other personnel their responsibilities with 
regard to protocol adherence, and the responsibilities of the Sponsor or its 
representatives.  This will be documented in a Clinical Study Agreement 
between the Sponsor and the Investigator. 
During the study, a monitor from the Sponsor or representative will have regular contacts 
with the investigational site, for the following: 
 Provide information and support to the investigator(s). 
 Confirm that facilities remain acceptable. 
 Confirm that the investigational team is adhering to the protocol, data are 
being accurately recorded in the case report forms, and investigational product 
accountability checks are being performed. 
 Perform source data verification.  This includes a comparison of the data in the 
case report forms with the subject’s medical records at the hospital or practice, 
and other records relevant to the study.  This will require direct access to all 
original records for each subject (eg, clinic charts). 
 Record and report any protocol deviations not previously sent to the Sponsor. 
 Confirm AEs and SAEs have been properly documented on eCRFs and 
confirm any SAEs have been forwarded to the Sponsor and those SAEs that 
met criteria for reporting have been forwarded to the IRB. 
Prior to study start, the Investigator will be informed of the anticipated frequency of the 
monitoring visits.  The Investigator will also receive a notification prior to each 
monitoring visit during the course of the study.  It is expected that the Investigator and/or 
his/her sub Investigator(s) and other appropriate staff are available on the day of the visit 
in case any questions arise.  The monitor will be available between visits if the 
Investigator(s) or other staff needs information or advice. 
14.1.1. 
Protocol Deviations/Amendments 
Any deviation from the protocol could result in a discontinuation from the study of the 
center involved.  Both the Sponsor and the IRB/EC that granted the original approval of 
the study prior to their implementation (unless only logistical or administrative aspects of 
the trial are involved) must approve any amendment(s) to the protocol. 
However, in the event of any medical emergency, the Investigator is free to institute any 
medical procedure s/he deems appropriate for proper management of the subject.  Such 
events must be promptly reported to the Medical Monitor and recorded in the source 
documents. 
 
 
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14.1.2. 
Discontinuation of the Study 
The Sponsor may stop the study at any time on the basis of new information regarding 
safety and/or efficacy.  Additionally, the Sponsor may terminate the study if progress is 
unsatisfactory. 
14.2. 
Audits and Inspections 
Authorized representatives of the Sponsor, a regulatory authority, an Institutional Review 
Board or an Independent Ethics Committee (IRB/EC) may visit the site to perform audits 
or inspections, including source data verification.  The purpose of a the Sponsor audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice 
guidelines of the ICH, and any applicable regulatory requirements.  The Investigator 
should contact the Sponsor immediately if contacted by a regulatory agency about an 
inspection. 
Audits for quality assurance of the database may be performed according to relevant 
Standard Operating Procedures within the clinical research organization or at the request 
of the Sponsor’s Quality Assurance department. 
On one or more occasions, the study site may be audited by either the Sponsor or by a 
third party on behalf of the Sponsor.  The Investigator will be informed in advance of 
such a visit.  On one or more occasions, the study site may be inspected by a regulatory 
agency. 
14.3. 
Institutional Review Board 
Prior to the initiation of the study, the Investigator will submit the following documents to 
an IRB/EC for approval: 
 The study protocol and any amendments; 
 The Informed Consent Form and any other written documents to be provided 
to the subject; 
 Details of any compensation to subject; 
 Any other requested document(s). 
A copy of the approval will be sent to the Sponsor along with all other correspondence 
with the IRB/EC.  The letter of approval should be dated and specify the protocol number 
and date of the protocol or amendment that was reviewed and approved.  It should also 
specify the date of the subject Informed Consent Form that was reviewed and approved. 
In order to comply with ICH GCP, the Investigator will submit a report to the IRB/EC at 
least annually updating the committee on the study’s progress. 
14.3.1. 
Informed Consent and Screening Data 
Subject Informed Consent Forms will be based on a master document provided by the 
Sponsor and must be approved by the Sponsor (or designee) prior to submission to the 
IRB/EC.  The Sponsor must approve any changes requested by the IRB/EC prior to the 
documents being used. 
 
 
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The Principal Investigator must obtain IRB/EC approval for the investigation.  Initial 
IRB/EC approval, and all materials approved by the IRB/EC for this study including the 
subject consent form and recruitment materials must be maintained by the Investigator 
and made available for inspection. 
 
 
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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices (GCPs) and all applicable regulatory 
requirements, the Sponsor may conduct a quality assurance audit.  Please see Section 14.2 
for more details regarding the audit process. 
 
 
 
 
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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must 
be approved or given a favorable opinion in writing by an IRB/EC as appropriate.  The 
Investigator must submit written approval to the Sponsor before he or she can enroll any 
subject/subject into the study. 
The Investigator is responsible for informing the IRB/EC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB/EC must approve all 
advertising used to recruit subjects for the study.  The protocol must be re-approved by 
the IRB/EC upon receipt of amendments and annually, as local regulations require. 
The Investigator is also responsible for providing the IRB/EC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the 
investigational product.  The Sponsor will provide this information to the Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to 
the IRB/EC according to local regulations and guidelines. 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with the protocol, ethical principles that have 
their origin in the Declaration of Helsinki, and are consistent with ICH E6 GCP:  
Consolidated Guideline, and any applicable local regulations. 
16.3. 
Written Informed Consent 
The Investigator or a designee is to explain the study and Informed Consent Form to the 
patient or the patient’s legally-authorized representative (LAR) and answer any questions.  
The Informed Consent Form is to be signed by the patient or the patient’s LAR, before 
any study-related procedures are performed.  A copy of the Informed Consent Form is to 
be provided to the patient or the patient’s LAR.  In some countries the consent may be 
signed by an authorized designee per local regulations or requirements, including but not 
limited to independent physicians qualified to provide consent for patients who are unable 
to provide consent for themselves. 
The signed Informed Consent Form is to remain in each patient’s study file and be 
available for verification by study monitors or authorized regulatory representatives at 
any time. 
 
 
 
 
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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
The Sponsor will be allowed to conduct site visits to the investigation facilities for the 
purpose of monitoring any aspect of the study.  The Investigator agrees to allow the 
monitor to inspect the drug storage area, study drug stocks, drug accountability records, 
subject charts and study source documents, and other records relative to study conduct. 
17.2. 
Retention of Records 
The Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or if not approved 2 years following 
the discontinuance of the test article for investigation.  If it becomes necessary for the 
Sponsor or the Regulatory Authority to review any documentation relating to the study, 
the Investigator must permit access to such records. 
 
 
 
 
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18. 
PUBLICATION POLICY 
The Sponsor supports the authorship criteria established by the International Committee 
of Medical Journal Editors.  
Minimum criteria for authorship credit based on: 
1. Substantial contributions to conception and design, (or) acquisition of data, or 
analysis and interpretation of data 
2. Drafting the article or revising it critically for important intellectual content; 
and  
3. Final approval of version to be published 
To be considered, all potential authors must meet conditions 1, 2, and 3. 
 
 
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19. 
LIST OF REFERENCES  
1. Baughman RP, Tapson V, McIvor A. The diagnosis and treatment challenges 
in nosocomial pneumonia. Diagn Microbiol Infect Dis. 1999;33(2):131-9. 
2. Schulgen G, Kropec A, Kappstein I, Daschner F, Schumacher M. Estimation 
of extra hospital stay attributable to nosocomial infections: heterogeneity and 
timing of events. J Clin Epidemiol. 2000 Apr;53(4):409-17. 
3. Chastre J, Fagon JY. Ventilator-associated pneumonia. Am J Respir Crit Care 
Med. 2002;165(7):867-903. 
4. Kalil AC, Metersky ML. Infectious Diseases Society of America Guideline. 
Management of adults with hospital-acquired and ventilator-associated 
pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases 
Society of America and the American Thoracic Society. Clin Infect Dis 2016; 
63(5): e61-e111. 
5. Jones RN. Microbial etiologies of hospital-acquired bacterial pneumonia and 
ventilator-associated bacterial pneumonia. Clin Infect Dis. 2010;Suppl 1:S81-
7. 
6. Sievert DM, Ricks P, Edwards JR, et al. Antimicrobial-resistant pathogens 
associated with healthcare-associated infections: summary of data reported to 
the National Healthcare Safety Network at the Centers for Disease Control and 
Prevention, 2009-2010. Infect Control Hosp Epidemiol. 2013;34:1-14.   
7. Richards MJ, Edwards JR, Culver DH, Gaynes RP, and the National 
Nosocomial Infections Surveillance System. Nosocomial infections in medical 
intensive care units in the United States. Crit Care Med. 1999;27(5):887-92. 
8. Joseph NM, Sistla S, Dutta TK, Badhe AS, Parija SC. Ventilator-associated 
pneumonia: a review. Eur J Intern Med. 2010;21(5):360-8. 
9. Iregui M, Ward S, Sherman G, Fraser VJ, Kollef MH. Clinical importance of 
delays in the initiation of appropriate antibiotic treatment for ventilator-
associated pneumonia. Chest. 2002;122(1):262-8. 
10. Torres A, Ewig S, Lode H, Carlet J. European HAP working group. Defining, 
treating and preventing hospital acquired pneumonia: European perspective. 
Intensive Care Med. 2009;35(1):9-29. 
11. Rhomberg PR, Jones RN. Summary trends for the Meropenem Yearly 
Susceptibility Test Information Collection Program: a 10-year experience in 
the United States (1999-2008). Diagn Microbiol Infect Dis. 2009;65(4):414-
26. 
12. Lee LS, Kinzig-Schippers M, Nafziger AN, et al. Comparison of 30-min and 
3-h infusion regimens for imipenem/cilastatin and for meropenem evaluated 
by Monte Carlo simulation. Diagn Microbiol Infect Dis. 2010;68(3):251-8. 
13. Jaruratanasirikul S, Sriwiriyajan S, Punyo J. Comparison of the 
Pharmacodynamics of Meropenem in Patients with Ventilator-Associated 
Pneumonia following Administration by 3-Hour Infusion or Bolus Injection. 
Antimicrob. Agents Chemother. 2005, 49(4):1337. 
 
 
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14. MERREM® IV (meropenem for Injection) [package insert]. Wilmington 
(DE): AstraZeneca Pharmaceuticals LP; 2013. 
15. Rea-Neto A, Niederman M, Lobo SM, Schroeder E, Lee M, Kaniga K, et al.  
Efficacy and safety of doripenem versus piperacillin/tazobactam in 
nosocomial pneumonia: a randomized, open-label, multicenter study.  Curr 
Med Res Opin. 2008;24(7):2113-26. 
16. Chastre J, Wunderink R, Prokocimer P, Lee M, Kaniga K, Friedland I.  
Efficacy and safety of intravenous infusion of doripenem versus imipenem in 
ventilator-associated pneumonia: a multicenter, randomized study.  Crit Care 
Med. 2008;36(4):1089-96. 
17. Bhavnani SM, Hammel JP, Cirincione BB, Wikler MA, Ambrose PG. Use of 
pharmacokinetic-pharmacodynamic target attainment analyses to support 
phase 2 and 3 dosing strategies for doripenem. Antimicrob Agents Chemother. 
2005;49(9):3944-7. 
18. Udy AA, Roberts JA, Boots RJ, Paterson DL, Lipman J. Augmented renal 
clearance: implications for antibacterial dosing in the critically ill. Clin 
Pharmacokinet. 2010;49(1):1-16. 
19. Ambrose PG, Bhavnani SM, Ellis-Grosse EJ, Drusano GL. Pharmacokinetic-
pharmacodynamic considerations in the design of hospital-acquired or 
ventilator-associated bacterial pneumonia studies: look before you leap! Clin 
Infect Dis. 2010;51 Suppl 1:S103-10. 
20. Chastre J, Wolff M, Fagon JY, et al. Comparison of 8 vs 15 days of antibiotic 
therapy for ventilator-associated pneumonia in adults: a randomized trial. 
JAMA. 2003;290(19):2588-98. 
21. Wunderink RG, Niederman MS, Kollef MH, Shorr AF, Kunkel MJ, Baruch A, 
et al. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial 
pneumonia: a randomized, controlled study. Clin Infect Dis. 2012;54(5):621-9.  
22. Mehrotra DV, Railkar R. Minimum risk weights for comparing treatments in 
stratified binomial trials. Statist Med. 2000;19:811-25. 
23. Yan X and Su XG. Stratified Wilson and Newcombe confidence intervals for 
multiple binomial proportions. Statist Biopharm Res. 2010; 2(3):329-35. 
24. US Department of Health and Human Services. Food and Drug 
Administration. Hospital-Acquired Bacterial Pneumonia and Ventilator-
Associated Bacterial Pneumonia: Developing Drugs for Treatment, Draft 
Guidance for Industry. May 2014. 
25. D’Agostino RB, Massaro JM, Sullivan LM. Non-inferiority trials: design 
concepts and issues: the encounters of academic consultants in statistics. 
Statistics in Medicine. 2003; (22):169-83. 
26. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity 
of disease classification system. Crit Care Med. 1985;13:818–29. 
 
 
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27. Singh N, Rogers P, Atwood CW, Wagener MM, Yu VL.  Short-course 
empiric antibiotic therapy for patients with pulmonary infiltrates in the 
intensive care unit: a proposed solution for indiscriminate antibiotic 
prescription.  Am J Respir Crit Care Med. 2000 Aug;162(2 Pt 1):505-11. 
28. Vincent JL, de Mendonça A, Cantraine F, Moreno R, Takala J, Suter PM, et al 
for the Working Group on "sepsis-related problems" of the European Society 
of Intensive Care Medicine. Use of the SOFA score to assess the incidence of 
organ dysfunction/failure in intensive care units: results of a multicenter, 
prospective study. Crit Care Med. 1998;26(11):1793-800. 
29. Severinghaus JW. Simple, accurate equations for human blood O2 
dissociation computations. J Appl Physiol Respir Environ Exerc Physiol. 1979 
Mar;46(3):599-602. 
 
 
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20. 
APPENDICES 
 
 
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APPENDIX A. SAFETY CONTACT INFORMATION 
SAEs must be reported within the eCRF within 24 hours of the Investigator’s awareness 
of the event.  Follow-up information to SAE reports must also be promptly entered into 
the eCRF. The Investigator will be required to electronically sign each SAE report.  In the 
event that the EDC system is nonfunctional, a completed and signed SAE form must be 
faxed or emailed within 24 hours to:  
 
Global SAE Fax Number: 
 
Email: 
 
Medical Emergency Contact: 
 
 
 
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APPENDIX B. Acute Physiological Assessment and Chronic Health 
Evaluation (Apache) II Scoring System 
Physiologic 
Variable† 
POINT SCORE 
+4 
+3 
+2 
+1 
0 
+1 
+2 
+3 
+4 
1 Temperature (°C) 
≥41° 
39–
40.9° 
— 
38.5–
38.9° 
36–
38.4° 
34–
35.9
° 
32–33.9° 
30–
31.9° 
≤29.
9 
2 Mean arterial 
pressure (mm Hg) 
Note: Mean Arterial 
Pressure can be 
calculated, if not 
available from a 
monitor/device, with the 
following equation: (2x 
diastolic + systolic) / 3 
≥160 
130–
159 
110–
129 
— 
70–109 
— 
50–69 
— 
≤49 
3 Heart rate 
≥180 
140–
179 
110–
139 
— 
70–109 
— 
55–69 
40–54 
≤39 
4 Respiratory rate 
(non-ventilated or 
ventilated) 
≥50 
35–49 
— 
25–34 
12–24 
10–
11 
6–9 
— 
≤5 
5 Oxygenation: 
Note: If a patient has both FiO2 less than and greater than 0.5, both 5a and5b must be 
calculated to identify and complete using the worst value. 
a) FIO2 ≥0.5: use 
A-aDO2 
≥500 
350–
499 
200–
349 
— 
<200 
— 
— 
— 
— 
b) FIO2 <0.5: use 
PaO2 (mm Hg) 
— 
— 
— 
— 
>70 
61–
70 
— 
55–60 
<55 
6 Arterial pH 
Note: if ABG is not 
available, use Serum 
HCO3 instead (#13)   
≥7.7 
7.6–
7.69 
— 
7.5–
7.59 
7.33–
7.49 
— 
7.25–
7.32 
7.15–
7.24 
<7.1
5 
7 Serum Na (mmol/L) 
≥180 
160–
179 
155–
159 
150–
154 
130–
149 
— 
120–129 
111–
119 
≤110 
8 Serum K (mmol/L) 
≥7 
6–6.9 
— 
5.5–5.9 
3.5–5.4 
3–
3.4 
2.5–2.9 
— 
<2.5 
9 Serum Creatinine 
(mg/dL) 
Note: Double point 
score for acute renal 
failure(as diagnosed by 
investigator)   
≥3.5 
2–3.4 
1.5–
1.9 
— 
0.6–1.4 
— 
<0.6 
— 
— 
10 Hct (%) 
≥60 
— 
50–
59.9 
46–
49.9 
30–
45.9 
— 
20–29.9 
— 
<20 
11 WBC (in1000s) 
≥40 
— 
20–
39.9 
15–
19.9 
3–14.9 
— 
1–2.9 
— 
<1 
 
 
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Physiologic 
Variable† 
POINT SCORE 
+4 
+3 
+2 
+1 
0 
+1 
+2 
+3 
+4 
12 Glasgow Coma 
score (GCS) 
Score =15 minus actual GCS 
Note: The Glasgow Coma Scale should not be calculated on obtunded or otherwise sedated 
subjects. In these subjects if a reliable pre-sedation Glasgow Coma Scale score is 
available, this should be used in calculating the APACHE II score.  If a reliable pre-
sedation score is not available, a score of 15 should be recorded for the Glasgow Coma 
Scale component of the APACHE II score (resulting in 0 points on this APACHE II score 
component). 
Acute physiology score is the sum of the 12 individual variable points. 
Add 0 points for age <44; 2 points, 45–54 yr; 3 points, 55–64 yr; 5 points, 65–74 yr; 6 points ≥ 75 yr. 
Add the following chronic health status points‡ if applicable:  
 
5 points for nonoperative or emergency postoperative subjects: 
 
2 points for elective postoperative subjects with immunocompromise or history of severe organ 
insufficiency as defined by: 
o 
LIVER: Biopsy proven cirrhosis and documented portal hypertension; episodes of past 
upper GI bleeding attributed to portal hypertension; or prior episodes of hepatic 
failure/encephalopathy/coma. 
o 
CARDIOVASCULAR: New York Heart Association Class IV 
o 
RESPIRATORY: Chronic restrictive, obstructive, or vascular disease resulting in severe 
exercise restriction, ie, unable to climb stairs or perform household duties; or documented 
chronic hypoxia, hypercapnia, secondary polycythemia, severe pulmonary hypertension 
(>40mmHg), or respiratory dependency. 
o 
RENAL: Receiving chronic dialysis 
o 
IMMUNO-COMPROMISED: The patient has received therapy that suppresses resistance 
to infection, eg, immune-suppression, chemotherapy, radiation, long term or recent high 
dose steroids, or has a disease that is sufficiently advanced to suppress resistance to 
infection, eg, leukemia, lymphomas, AIDS. 
Note: Organ insufficiency or immune-compromised state must have preceded current admission 
(13)§ Serum HCO3 
(venous–mmol/L) 
Note: only included if 
arterial pH is not 
available (#6)   
≥52 
41–
51.9 
— 
32–
40.9 
22–
31.9 
— 
18–21.9 
15–
17.9 
<15 
 
 
 
 
 
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Glasgow Coma Scale 
(Circle appropriate 
response) 
B     
Age  
Points C
  
Chronic Health 
Points 
Apache-II Score 
(sum of A+B+C) 
Eyes open 
4 - spontaneously 
3 - to speech 
2 - to pain 
1 - no response 
 
Motor response 
6 - to verbal command 
5 - localizes to pain 
4 - withdraws to pain 
3 – flexion to pain 
2 – extension to pain 
1 - no response 
verbal - 
nonintubated 
5 - oriented 
4 - confused 
3 - inappropriate 
words 
2 - 
incomprehensible 
sounds 
1 - no response 
 
verbal - intubated 
5 - seems able to 
talk 
3 - questionable 
ability to talk 
1 - generally 
unresponsive 
Age 
≤44 
45-54 
55-64 
65-74 
≥75 
 
Age 
points 
= 
Points 
0 
2 
3 
5 
6 
 
 
 
 
Refer to bottom of 
the chart above for: 
 
Chronic Health 
Status  
Points =  
   
   A APS points 
+ B Age points 
+ C Chronic Health 
Points 
__________ 
= Total Apache II 
 
Note: The Glasgow Coma Scale should not be 
calculated on obtunded or otherwise sedated 
subjects. In these subjects if a reliable pre-sedation 
Glasgow Coma Scale score is available, this should 
be used in calculating the APACHE II score.  If a 
reliable pre-sedation score is not available, a score 
of 15 should be recorded for the Glasgow Coma 
Scale component of the APACHE II score 
(resulting in 0 points on this APACHE II score 
component). 
*APACHE II score = acute physiology score + age points + chronic health points. Increasing score is 
associated with increasing risk of hospital death. 
†Choose worst value in the past 24 h. 
‡Chronic health status: Organ insufficiency (eg, hepatic, cardiovascular, renal, pulmonary) or 
immunocompromised state must have preceded current admission. 
§Optional variable; use only if no ABGs. 
A-aDO2 = Alveolar–arterial oxygen gradient; FIO2 = fractional inspired O2. 
 
Adapted from Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: A severity of disease 
classification system. Crit Care Med. 1985;13:818–29 [26]. 
 
 
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APPENDIX C. 
MODIFIED CLINICAL PULMONARY 
INFECTION SCORE 
1. 
Temperature, °C 
 ≥36.5 and ≤38.4 = 0 point 
 ≥38.5 and ≤38.9 = 1 point 
 ≥39 or ≤36.4 = 2 points 
2. 
Blood leukocytes, mm3 
 ≥4 000 and ≤11 000 = 0 point 
 <4 000 or >11 000 = 1 point + band forms ≥50% = + 1 point 
3. 
Tracheal secretions 
 Absence of tracheal secretions = 0 points 
 Presence of nonpurulent tracheal secretions = 1 point 
 Presence of purulent tracheal secretions = 2 points 
4. 
Oxygenation: PaO2/FiO2 
 >240 or acute respiratory distress syndrome (ARDS) = 0 point 
 ≤240 and no ARDS = 2 points 
5. 
Pulmonary radiography 
 No infiltrate = 0 points 
 Diffuse (or patchy) infiltrate = 1 point 
 Localized infiltrate = 2 points 
6. 
Progression of pulmonary infiltrate 
 No radiographic progression = 0 points 
 Radiographic progression (after CHF and ARDS excluded) = 2 
points 
7. 
Lower Respiratory Tract Culture 
 No pathogenic bacteria growth = 0 points 
 Pathogenic bacteria cultured = 2 points 
Adapted from Singh N, Rogers P, Atwood CW, Wagener MM, Yu VL.  Short-course empiric antibiotic 
therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for 
indiscriminate antibiotic prescription.  Am J Respir Crit Care Med. 2000 Aug;162(2 Pt 1):505-11 [27]. 
 
 
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APPENDIX D. SEPSIS-RELATED ORGAN FAILURE 
ASSESSMENT (SOFA) SCORE 
Points 
0 
1 
2 
3 
4 
Respiration 
PaO2/FiO2, 
mmHg 
>400 
≤400 
≤300 
≤200 with 
respiratory 
support 
≤100 with 
respiratory 
support 
Coagulation 
Platelets× 
103/mm3 
>150 
≤150 
≤100 
≤50 
≤20 
Liver 
Bilirubin, 
mg/dL 
<1.2 
1.2 – 1.9 
2.0 – 5.9 
6.0 – 11.9 
≥12.0 
Cardiovascular 
Hypotension 
No 
hypotension 
MAP 
<70 mm 
Hg 
Dopamine ≤5 or 
dobutamine (any 
dose)a 
Dopamine >5 or 
epinephrine ≤0.1 
or norepinephrine 
≤0.1a 
Dopamine >15 or 
epinephrine > 0.1 
or norepinephrine 
>0.1a 
Central 
nervous system 
Glasgow Coma 
Score 
15 
13 - 14 
10 – 12 
6 – 9 
<6 
Renal 
Creatinine, 
mg/dL or urine 
output 
<1.2 
1.2 – 1.9 
2.0 – 3.4 
3.5 – 4.9 
or urine output of 
<500 mL/day 
≥5.0 
or urine output of 
200 mL/day 
a Adrenergic agents administered for at least 1 h (doses given are in µg/kg*min). 
 
Adapted from Vincent JL, de Mendonça A, Cantraine F, Moreno R, Takala J, Suter PM, et al for the 
Working Group on "sepsis-related problems" of the European Society of Intensive Care Medicine. Use of 
the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a 
multicenter, prospective study. Crit Care Med. 1998;26(11):1793-800 [28]. 
 
 
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APPENDIX E. O2 SATURATION TO PaO2 CONVERSION TABLE  
Oxygen Saturation (SO2) 
Estimated PaO2 (mm Hg) 
99 
156 
98 
111 
97 
92 
96 
82 
95 
74 
94 
69 
93 
66 
92 
62 
91 
60 
90 
58 
88 
54 
86 
51 
84 
49 
82 
47 
80 
45 
78 
43 
76 
41 
74 
40 
72 
39 
70 
37 
Calculated from Severinghaus JW. Simple, accurate equations for human blood O2 dissociation 
computations. J Appl Physiol Respir Environ Exerc Physiol. 1979 Mar;46(3):599-602 [29]. 
 
 
 
 
 
 
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APPENDIX F. THE ASSESSMENT PLAN OF SEPSIS 
1. 
DEFINITION OF SEPSIS 
Sepsis is defined as bacteremia (positive blood culture at baseline) in the setting of 
systemic inflammatory symptoms/findings [1].  
2. 
RATIONALE OF SEPSIS ASSESSMENT 
Sepsis is associated with high mortality. Delays of treatment lead to complications of a 
variety of organ failure (circulatory failure, acute respiratory syndrome, disseminated 
intravascular coagulation, etc) and a poor outcome. Therefore, prompt therapy with 
effective antibiotics has been shown to be critical for effective for the treatment of sepsis. 
Sepsis assessment is based on the Japanese guidelines for clinical assessment of 
antibiotics on sepsis and definition of sepsis-1 of Society of Critical Care Medicine and 
American College of Chest Physicians [1,2,3,4]. 
3. 
TRIAL OBJECTIVES OF SEPSIS ASSESSMENT 
The efficacy and safety of ceftolozane/tazobactam in the population of patients with 
sepsis will be evaluated under a Japan-specific amendment. 
3.1. 
Study Objectives 
Primary objectives: 
 To evaluate the clinical response to ceftolozane/tazobactam in the treatment of 
sepsis at the TOC visit in the sepsis population.  
 To evaluate the safety and tolerability of ceftolozane/tazobactam in the sepsis 
population. 
Secondary objectives: 
 To evaluate the microbiological response to sepsis treatment at the TOC visit 
in the sepsis population. 
4. 
THE CRITERIA OF SEPSIS 
To be included in the sepsis population, a subject must satisfy all of the following criteria:  
1) Have at least 1 of the following clinical criteria within the 24 hours prior to the 
first dose of study drug: 
• 
Temperature >38°C (100.4°F) or < 36°C (96.8°F) 
• 
WBC count >12,000 cells/mm3, <4,000 cells/mm3 or >10 % immature 
neutrophils 
• 
Pulse rate (heart rate) >90 beats per minute 
• 
PaO2/FiO2≤240 mmHg 
 
 
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• 
Systolic blood pressure <90 mmHg 
• 
CRP ≥20 mg/dL 
2) Have positive blood culture at baseline.  
5. 
STATISTICS OF SEPSIS ASSESSMENT 
This section outlines the statistical analysis strategy and procedures for the assessment. 
5.1. 
Handling of Missing Data 
For efficacy endpoints, missing data will be handled with a Treatment Failure Approach 
(TFA) for the sepsis population defined as follows: 
• 
TFA:  All subjects with an outcome of efficacy endpoints as indeterminate at TOC 
visit will be considered as treatment failures. In other words, all subjects with 
efficacy endpoint of indeterminate at the TOC visit who meet the sepsis population 
criteria will be included in the denominator.  
• 
For microbiological outcome, missing of blood culture will be considered presumed 
eradication or indeterminate as defined in Table F-2.  
5.2. 
Populations for Analysis 
The definitions of population for analysis are outlined below. 
5.2.1. 
Sepsis Population 
Sepsis population will consist of all randomized subjects who received at least one dose 
of study treatment and who satisfy the sepsis criteria. Subjects who take incorrect study 
treatment for the entire treatment period will be included in the treatment group 
corresponding to the study treatment actually received. 
5.3. 
Study Endpoints 
Efficacy endpoints 
• 
Primary Endpoint: Clinical response at the TOC visit in the sepsis population 
• 
Secondary Endpoint: Microbiological response at the TOC visit in the sepsis 
population 
Safety endpoint 
• 
Adverse event in the sepsis population 
5.4. 
Efficacy Endpoint Analyses 
5.4.1. 
Primary Endpoint Analysis 
The point estimates and 95% CI by the Clopper-Pearson method will be presented for the 
clinical response rate at TOC in the sepsis population in each treatment group [5]. In 
addition, the treatment difference in proportions and the 95% CI for the treatment 
difference by using the Meittinen & Nurminen (M&N) method will be presented [6]. The 
clinical response rate is defined as a proportion of subjects who are confirmed to have a 
clinical outcome for sepsis as “Cure”. 
 
 
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5.4.2. 
Secondary Endpoint Analysis 
The point estimates and 95% CI by the Clopper-Pearson method will be presented for the 
microbiological response rate at TOC in the sepsis population in each treatment group. In 
addition, the treatment difference in proportions and the 95% CI for the difference by 
using the M&N method will be presented. The microbiological response rate is defined as 
a proportion of subjects who are confirmed to have a microbiological outcome for sepsis 
as “Eradication” or “Presumed eradication”. 
5.5. 
Safety Analysis 
5.5.1. 
Adverse Events 
The incidence (n and %) of TEAEs, SAEs, and early termination of study medication 
and/or study participation due to an AE will be presented for subjects in the sepsis 
population in each treatment arm. Additionally, AEs will be tabulated according to 
severity and relatedness to study treatment categories as reported by the Investigator.  
Adverse events will be presented in tables organized alphabetically by System Organ 
Class and Preferred Term.  Each subject will be counted only once for each AE reporting 
level. 
5.6. 
Evaluation Criteria of Sepsis 
5.6.1. 
Definition of Clinical Response for Sepsis 
Clinical outcome assessment for sepsis will be made at the TOC visit. 
5.6.1.1. 
Clinical Outcome for Sepsis 
Clinical response at the TOC visit will be classified as cure, failure, or indeterminate 
(Table F-1). 
Table F-1: 
Clinical Response Categories for Sepsis at the TOC Visit 
Outcome 
Definition 
Cure 
All clinical signs and symptoms of sepsis were resolved at the TOC visit, 
which means subject had all study data of the criteria of sepsis and did not 
meet any of the criteria of sepsis 1) in Section 4. 
Failure 
All clinical signs and symptoms of sepsis were not resolved at the TOC visit, 
which means subject met at least 1 of the available study data of the criteria 
of sepsis 1) in Section 4.  
Indeterminate 
Study data was not available for the evaluation of clinical outcome for any 
reason, which means at least 1 of study data of the criteria of sepsis 1) in 
Section 4 were not available even though subject had not met any of the other 
criteria of sepsis 1) in Section 4. 
5.6.2. 
Definition of Microbiological Response for Sepsis 
Microbiological outcome assessment for sepsis will be determined based on the results of 
last blood culture through TOC visit.  
 
 
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5.6.2.1. 
Microbiologic Outcome for Sepsis 
Microbiological response for sepsis at the TOC visit will be classified per-subject as 
eradication, presumed eradication, persistence / new pathogen or indeterminate (Table F-
2). 
Table F-2: 
Microbiologic Outcome Categories for Sepsis at the TOC Visit 
Outcome 
Definition 
Eradication 
Last blood culture after the administration of the first dose of study drug 
through the TOC visit showed no growth of any pathogens.  
Presumed 
eradication 
A blood culture was not performed after the administration of the first dose 
of study drug, AND a subject deemed “a clinical cure” for clinical outcome 
of sepsis at the TOC visit. 
Persistence / New 
Pathogen 
Last blood culture after the administration of the first dose of study drug 
through the TOC visit showed the presence of baseline pathogen and/or any 
pathogens other than baseline pathogen.   
Indeterminate 
A blood culture after the administration of the first dose of drug is not 
performed and a subject deem other than clinical cure (failure or 
indeterminate) for clinical outcome of sepsis at the TOC visit.  
 
 
 
 
 
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6. 
LIST OF REFERENCES  
1. Notification No1023-3, 2017 October 23, issued by the director of office of 
Pharmaceutical Safety and Environmental Health Bureau, Ministry of Health. 
Labour and Welfare. Japanese guideline for clinical assessment of antibiotics 
on sepsis. 
2. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA et al. 
Definitions for sepsis and organ failure and guidelines for the use of 
innovative therapies in sepsis. The ACCP/SCCM Consensus Conference 
Committee. American College of Chest Physicians/Society of Critical Care 
Medicine. Chest 1992;101 (6):1644-55. 
3. The JRS Guidelines for the Management of Pneumonia in Adults 2017 
Creating Committee. The JRS Guidelines for the Management of Pneumonia 
in Adults 2017. 
4. The JAID/JSC Guide and Guidelines for Management of Infection Creating 
Committee.Working Group for Sepsis. The JAID/JSC Guide and Guidelines 
for Management of Infectoin 2017-Sepsis and Catheter-related blood stream 
infections-.  
5. Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in 
the case of the binomial. Biometrika 1934;26(4):404-13.  
6. Miettinen O, Nurminen M. Comparative Analysis of Two Rates. Statistics in 
Medicine 1985;4:213-26. 
 
 
 
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