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• Register: EUCTR
• Last refreshed on: 20 August 2018
• Main ID: EUCTR2012-002862-11-HU
• Date of registration: 07/10/2014
• Prospective Registration: No
• Primary sponsor: Cubist Pharmaceuticals LLC, an indirect wholly-owned subsidiary of Merck Sharp & Dohme Corp.
• Public title: NA
• 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 (VNP) - Assessment of the Safety Profile and Efficacy of Ceftolozane/Tazobactam
• Date of first enrolment: 02/10/2014
• 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, Belarus, Belgium, Bosnia and Herzegovina, Brazil, Canada, China, Colombia, Croatia, Czech Republic, Estonia, France, Georgia, Germany, Greece, Guatemala, Honduras, Hong Kong, Hungary, India, Israel, Italy, Jordan, Kazakhstan, 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: Ellie Hershberger
• Affiliation: Cubist Pharmaceuticals LLC, an indirect wholly owned subsidiary of Merck Sharp & Dohme Corp.

• Name: Ellie Hershberger
• Affiliation: Cubist Pharmaceuticals LLC, an 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 or symptoms within 24 hours prior to intubation OR within the 48 hours after intubation of a patient hospitalized for =48 hours or have 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/FiO2ratio).
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 investigator). A computed tomography (CT) scan may be used in place of a chest X-ray, as appropriate
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 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 (i.e., chest trauma with paradoxical respiration)
2. Has a documented history of any moderate or severe hypersensitivity (or allergic) reaction to any ß-lactam antibacterial;
3. Received systemic or inhaled antibiotic therapy, effective against Gram-negative pathogens that cause VNP, regardless of the indication, for >24 hours (i.e., >1 dose of a once daily antibiotic, >2 doses of a twice daily antibiotic, etc.) in the last 72 hours.
Exceptions:
• Signs and/or symptoms of VNP are still present despite >48 hours on the prior antibacterial regimen for this episode of VNP, provided prior respiratory or
blood culture did not grow a meropenem-resistant Gram-negative pathogen, or only S. aureus (methicillin-susceptible S. aureus [MSSA] or methicillin-resistant S. aureus [MRSA]). Requires microbiological confirmation of a Gram-negative pathogen.
• Prior therapy with a non-absorbed antibiotic therapy used for gut decontamination (example, low-dose erythromycin) or to eradicate C. difficile.
4. Gram stain performed within 36 hours prior to randomization shows presence of only Gram-positive bacteria.
5. Active immunosuppression, including Acquired Immune Deficiency Syndrome (AIDS), 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 randomization);
6. Receipt of imipenem/cilastatin, meropenem, or doripenem within 15 days prior to the first dose of study drug;
7. Growth of an meropenem-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 × ULN
• Total bilirubin > 2 × ULN
• Alkaline phosphatase >4 × ULN. Subjects with a 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 (ANC) <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 subj

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

Health Condition(s) or Problem(s) studied

Ventilated Nosocomial Pneumonia
MedDRA version: 18.1 Level: LLT Classification code 10052596 Term: Nosocomial pneumonia System Organ Class: 100000004862

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

Intervention(s)

Trade Name: Zerbaxa
Product Name: Ceftolozane/Tazobactam
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: Meropenem
Product Name: Meropenem
Pharmaceutical Form: Powder for solution for injection/infusion
Other descriptive name: MEROPENEM
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1000-

Primary Outcome(s)

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.

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

Main Objective: To demonstrate the noninferiority 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 noninferiority margin of 12.5%.

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

Secondary Outcome(s)

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

Secondary end point(s): Key Secondary Endpoints:
• Clinical response at the TOC visit in the ITT 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 (to be specified in a separate Pharmacokinetic Analysis Plan).

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.