Assessment of the Safety Profile and Efficacy of Ceftolozane/Tazobactam

• Register: EUCTR
• Last refreshed on: 20 August 2018
• Main ID: EUCTR2012-002862-11-LV
• Date of registration: 26/08/2014
• Prospective Registration: Yes
• Primary sponsor: Cubist Pharmaceuticals LLC
• Public title: Assessment of the Safety Profile and Efficacy of Ceftolozane/Tazobactam
• Scientific 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 - Assessment of the Safety Profile and Efficacy of Ceftolozane/Tazobactam
• Date of first enrolment: 09/10/2014
• Target sample size: 726
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-002862-11
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: yes; Other specify the comparator: Meropenem; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Austria, Belgium, Brazil, Canada, China, Colombia, Croatia, Czech Republic, Estonia, France, Georgia, Germany, Greece, Guatemala, Honduras, Hong Kong, Hungary, India, Israel, Italy, Korea, Republic of, Latvia, Lebanon, Netherlands, New Zealand, Philippines, Portugal, Russian Federation, Serbia, Singapore, Slovakia, Slovenia, South Africa, Spain, Taiwan, Ukraine, United Kingdom

Contacts

• Name: Christopher Bruno
• Affiliation: Cubist Pharmaceuticals LLC, and indirect wholly owned subsidiary of Merck Sharp & Dohme Corp.

• Name: Christopher Bruno
• Affiliation: Cubist Pharmaceuticals LLC, and indirect wholly owned subsidiary of Merck Sharp & Dohme Corp.

Key inclusion & exclusion criteria

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 35 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 ratio)
For VABP, receiving mechanical ventilation =48 hours:
• 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
4. Chest radiograph 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
Investig
Exclusion 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 ß-lactam antibacterial;
Note: A history of a rash while on a ß-lactam antibiotic does not
automatically
exclude a subject
3. Received systemic or inhaled antibiotic therapy effective against
Gram-negative
pathogens that cause VNP, for >24 hours 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.
•?Signs and/or symptoms of VNP develop after receiving =48 hours of
prior
antibacterial therapy for an indication other than the current VNP.
•?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
Gramnegative
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/tazobactamresistant,
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 aminotra

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Bacterial Infections and Mycoses [C01]

Ventilated Nosocomial Pneumonia
MedDRA version: 19.0 Level: LLT Classification code 10052596 Term: Nosocomial pneumonia System Organ Class: 100000004862

Intervention(s)

Trade Name: ZERBAXA
Product Name: Ceftolozane/Tazobactam
Product Code: CXA-201
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: Ceftolozane
CAS Number: 936111-69-2
Current Sponsor code: CXA-101
Other descriptive name: CEFTOLOZANE SULFATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1000-
INN or Proposed INN: Tazobactam Sodium
CAS Number: 89785-84-2
Other descriptive name: TAZOBACTAM SODIUM
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-

Trade Name: Meronem
Product Name: Meropenem
Pharmaceutical Form: Powder for solution for injection/infusion
INN or Proposed INN: MEROPENEM
Other descriptive name: MEROPENEM TRIHYDRATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1000-

Primary Outcome(s)

Primary end point(s): Clinical response at the TOC visit in the CE population

Main 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 Clinically Evaluable (CE) population at the TOC visit (7 to 14 days after the EOT visit), using a non-inferiority margin of 12.5%

Secondary Objective: •To compare the clinical response rates of ceftolozane/tazobactam
versus meropenem in adult subjects with VNP at the TOC visit (7 to 14
days after the EOT visit) in the ITT 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

Timepoint(s) of evaluation of this end point: Test of Cure (TOC) visit

Secondary Outcome(s)

Secondary end point(s): Key Secondary Endpoints:
•Clinical response at the TOC visit in the ITT population
•Clinical response at the TOC visit in the mITT 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.
Other Secondary Endpoints:
•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 ITT 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
•Per-pathogen clinical response at TOC by baseline Kirby-Bauer zone diameter in the mITT and ME populations
•Pharmacokinetics

Timepoint(s) of evaluation of this end point: Test of Cure (TOC) visit

Secondary ID(s)

CXA-NP-11-04

2012-002862-11-GB

Source(s) of Monetary Support

Cubist Pharmaceuticals LLC, an indirect wholly owned subsidiary of Merck Sharp & Dohme Corp.