| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Ventilated Nosocomial Pneumonia |
| Ventilated Nosocomial Pneumonia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Ventilated Nosocomial Pneumonia |
| Ventilated Nosocomial Pneumonia |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052596 |
| E.1.2 | Term | Nosocomial pneumonia |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Objectives: To accommodate the unique requirements of different regulatory jurisdictions, the study objectives have been separated out in this section.
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%.
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 Clinically Evaluable (CE) population at the TOC visit (7 to 14 days after the EOT visit), using a non-inferiority margin of 12.5%
|
|
| E.2.2 | Secondary objectives of the trial |
Objectives per FDA:
To compare the Day 28 all-cause mortality rates of subjects in the ceftolozane/tazobactam versus meropenem arms in the Microbiological Intent-to-Treat (mITT) population
To compare the clinical response rates of ceftolozane/tazobactam versus meropenem in adult subjects with VNP at the Test of cure (TOC) visit (7 to 14 days after the End of therapy [EOT] visit)
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.
Objectives per EMA:
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
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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;
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 (oral or tympanic temperature >38°C [100.4°F] or a temporal, rectal or core temperature >38.3°C [101°F])
Hypothermia (oral, tympanic, rectal or core body temperature <35°C [95.2°F])
White blood cell (WBC) count >10,000 cells/mm3
WBC count <4,500/mm3
>15% immature neutrophils.
6. Have an Acute Physiology and Chronic Health Evaluation (APACHE) II score between 15 and 35 (inclusive);
7. Have a quantitative culture of either a bronchoscopic or nonbronchoscopic bronchoalveolar lavage (BAL) or mini-BAL, a protected brush specimen (PBS) or an endotracheal aspirate (ETA) obtained at baseline before administration of any study antibiotic therapy for the current VNP;
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.
8. Willing and able to comply with all study procedures and restrictions.
|
|
| E.4 | Principal 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 (i.e., 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 for treatment of the current VNP, 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 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 the 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.
• Develops signs and/or symptoms of VNP while receiving >48 hours of prior antibacterial therapy for indication other than the current VNP.
• 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 first dose shows presence of only Gram-positive bacteria.
Note: ETA specimens with an average of >10 SECs and <25 polymorphonuclear cells per low power field will be considered inadequate, and a repeat specimen will need to be obtained for Gram stain and subsequent quantitative culture.
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);
Note: Subjects infected with the human immunodeficiency virus (HIV) but who do not have AIDS, may be considered for enrollment.
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 subject or the quality of study data;
15. Participation in any clinical study of a therapeutic investigational product within 30 days prior to the proposed first day 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.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Study Endpoints per the US FDA:
Primary Endpoint:
• Day 28 all-cause mortality in the ITT population.
Study Endpoints per the EMA:
Primary Endpoint:
• Clinical response at the TOC visit in the CE population.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Study Endpoints per the US FDA:
Primary Endpoint:
• Day 28
Study Endpoints per the EMA:
Primary Endpoint:
• Test of Cure (TOC) visit |
|
| E.5.2 | Secondary end point(s) |
Study Endpoints per the US FDA:
Key Secondary Endpoints:
• Day 28 all-cause mortality in the mITT population
• Clinical response at the TOC visit in the ITT population
• Clinical response at the TOC visit 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.
Study Endpoints per the EMA:
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.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Study Endpoints per the US FDA:
Secondary Endpoints:
• Day 28
• Test of Cure (TOC) visit
Study Endpoints per the EMA:
Secondary Endpoints:
• Test of Cure (TOC) visit |
Study Endpoints per the US FDA:
Secondary Endpoints:
• Day 28
• Test of Cure (TOC) visit
Study Endpoints per the EMA:
Secondary Endpoints:
• Test of Cure (TOC) visit |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| 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 |
| Kazakhstan |
| Korea, Republic of |
| Latvia |
| Lebanon |
| Netherlands |
| New Zealand |
| Philippines |
| Portugal |
| Russian Federation |
| Serbia |
| Singapore |
| Slovakia |
| Slovenia |
| South Africa |
| Spain |
| Taiwan |
| Ukraine |
| United Kingdom |
| Jordan |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
Print
