| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Ventilated Nosocomial Pneumonia |
|
| E.1.1.1 | Medical condition in easily understood language |
| 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 | 20.1 |
| 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 |
| 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%. |
|
| E.2.2 | Secondary objectives of the trial |
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 are listed in the full protocol |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 orwho 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
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.
7. Willing and able to comply with all study procedures and restrictions. |
|
| E.4 | Principal 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 (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 effective against Gram-negative pathogens that cause VNP, for >24 hours (i.e., >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
• 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 <5/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 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.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Clinical response at the TOC visit in the ITT population. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Endpoint:
• Day 28 all-cause mortality in the ITT population.
Other 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
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | 3 |
| 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 |
| Austria |
| Belgium |
| Brazil |
| Canada |
| China |
| Colombia |
| Croatia |
| Czech Republic |
| France |
| Georgia |
| Germany |
| Guatemala |
| Honduras |
| Hong Kong |
| Hungary |
| India |
| Israel |
| Italy |
| Korea, Republic of |
| Netherlands |
| New Zealand |
| Philippines |
| Portugal |
| Russian Federation |
| Singapore |
| Slovenia |
| South Africa |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 21 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
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