Nosocomial pneumonia MedDRA version: 20.1 Level: LLT Classification code 10052596 Term: Nosocomial pneumonia System Organ Class: 100000004862
Conditions
Interventions
Sponsors
Polyphor Ltd.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Provide written informed consent prior to any study-related procedure not part of normal medical care. Surrogate consent/use of a legally-authorized representative may be provided, if permitted by local country and institution-specific guidelines. 2. Male or female subjects, = 18 years of age Women of childbearing potential are eligible only if the following applies: • Negative serum pregnancy test at baseline prior to enrollment (a urine pregnancy test may be used at the time of screening, but the result must be confirmed by a serum test) • Agreement to undertake an urine pregnancy test at the End of Study Visit (30-33 days after last dose ) • Agreement to use one of the methods of birth control described in the protocol from screening up to at least 30 days after study treatment discontinuation Non-vasectomized men are eligible only if they are willing to use a condom during study treatment and for at least 7 days after the last dose. 3. Subjects hospitalized for = 48 hours or those with prior hospital admission of = 48 hours if they were discharged within the last 7 days. 4. Intubated (via naso- or endotracheal tube, including tracheostomy subjects) and receiving mechanical ventilation for = 48 hours, and acute changes made in the ventilator support to maintain adequate PaO2 or SpO2. OR At least 2 of the following signs or symptoms presenting within 24 hours prior to randomization: • New onset of cough or worsening of baseline cough • Auscultatory findings on pulmonary examination of rales and/or evidence of pulmonary consolidation (e.g., dullness on percussion, bronchial breath sounds, or egophony) • Dyspnea, tachypnea (respiratory rate > 25/minute), particularly if any or all of these signs or symptoms are progressive in nature • Hypoxemia (e.g., a partial pressure of oxygen [PaO2] < 60 mm Hg while the subject is breathing on room air as determined by arterial blood gas (ABG) or oxygen saturation [SpO2] < 90% while the subject is breathing on room air as determined by pulse oximetry, or worsening (decline from any earlier finding) of the PaO2/FiO2 ratio, or respiratory failure requiring intubation and mechanical ventilation, or increased ventilator demand if on mechanical ventilation for < 48 hours prior to randomization • New onset of sputum or suctioned respiratory secretions characterized by purulent appearance indicative of bacterial infection or a worsening in character of purulent appearance. 5. Chest radiograph shows the presence of new or progressive infiltrate(s) characteristic of bacterial pneumonia (based on Investigator’s evaluation). A chest computed tomography (CT) scan may be used in place of a chest X-ray. 6. At least 1 of the following present within 24 hours prior to randomization: • Documented fever (oral = 38.0º°C [100.4º F] or a tympanic, temporal, rectal or core temperature = 38.3º°C [101.0º F], axillary or forehead scanner = 37.5 °C [99.5 °F]), OR • Hypothermia (rectal / core body temperature = 35.0º°C [95.2º F]), OR • Total peripheral white blood cell count (WBC) = 10,000 cells/mm3, OR • Leukopenia with WBC = 4,500 cells/mm3 7. Acute Physiolog
Exclusion criteria
Exclusion criteria: 1. Known or suspected community-acquired, viral, fungal, or parasitic pneumonia 2. Any of the following health conditions: • Confirmed legionella infection (Legionella pneumophila pneumonia), Aspergillus spp. pneumonia (testing is not required) • Cystic fibrosis • Known or suspected Pneumocystis jirovecii pneumonia • Known or suspected active tuberculosis • Lung abscess • Solid organ transplant within 6 months prior to randomization • Pleural empyema 3. Bronchial obstruction or a history of post-obstructive pneumonia (this does not exclude subjects with pneumonia who have an underlying chronic obstructive pulmonary disease) 4. Expected survival 40% of total body surface area 6. Current or anticipated neutropenia with absolute neutrophil count 5 i.v. doses of an antibiotic administered q.i.d. (e.g., piperacillin-tazobactam) • > 4 i.v. doses of an antibiotic administered t.i.d. (e.g., meropenem) EXCEPTIONS: • Progression of disease on the prior antibacterial regimen for this episode of pneumonia after > 72 hours of treatment, provided prior respiratory or blood culture did not grow an anti-pseudomonal ß-lactam-resistant P. aeruginosa pathogen, or only a Gram-positive pathogen. Requires microbiological confirmation of a Gram-negative pathogen, OR • Subject developed symptoms of pneumonia and a new infiltrate while receiving the prior antibacterial regimen for reasons other than the current pneumonia; if the pneumonia occurred while the subject was receiving antibiotics (as prophylaxis or for treatment of an unrelated infection, the antibacterial therapy will be considered ineffective irrespective of the susceptibility profile of the study qualifying pathogen, OR • Subject received systemic antibacterial therapy that does not cover P. aeruginosa, OR • Prior therapy with a non-absorbed antibiotic therapy used for gut decontamination or to eradicate Clostridium difficile. 10. Investigator’s opinion of clinically significant electrocardiogram (ECG) finding with immediate potential for a fatal outcome such as ischemia, infarct, or ventricular arrhythmia, or prior to the current infection, a history of New York Heart Association (NYHA) Class IV cardiac failure 11. Stroke (ischemic or intracerebral hemorrhage) within 5 days prior to randomization and there is an increased risk of fatal brain edema as indicated by a major early computerized tomography hypodensity exceeding 50% of the middle cerebral artery
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To demonstrate the non-inferiority (NI) in 28-day all cause mortality (ACM) rate of i.v. murepavadin given with ertapenem compared to an anti-pseudomonal- ß-lactam-based antibiotic (either piperacillin- tazobactam or meropenem) in the microbiological modified intention-to-treat (micro-MITT) analysis set in subjects with nosocomial pneumonia due to P. aeruginosa.; Secondary Objective: -To determine the superiority in 28-day ACM rate of i.v. murepavadin given with ertapenem compared to an anti-pseudomonal-ß-lactam-based antibiotic (either piperacillin-tazobactam or meropenem) in the micro-MITT analysis set in subjects with nososcomial pneumonia due to P. aeruginosa -To compare the clinical cure rates of i.v. murepavadin given with ertapenem to an antipseudomonal-ß-lactam-based antibiotic (either piperacillin-tazobactam or meropenem) at different timepoints -To compare the change in SOFA score and modified CPIS (intubated subjects) of i.v. murepavadin given with ertapenem to an anti-pseudomonal-ß-lactam-based antibiotic (either piperacillin-tazobactam or meropenem) from baseline to different timepoints -To compare the change in PaO2/FiO2 ratio of i.v. murepavadin given with ertapenem to an anti-pseudomonal-ß-lactam-based antibiotic (either piperacillin-tazobactam or meropenem) from baseline to different timepoints ;Primary end point(s): The primary efficacy variable is the incidence (Yes/No) of ACM within 28 days of randomization in the micro-MITT analysis set.; Timepoint(s) of evaluation of this end point: Please refer to Appendix I : Schedule of Assessment of Protocol: POL7080-010 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. 28 days ACM after randomization in the modified-MITT, and PP analysis sets 2. Clinical outcome status (cure, failure, indeterminate) on study day 3, 5, 7, 10, at the EoT and ToC visits determined by the Investigator and CEC. Clinical outcomes will be categorized as either: • Clinical cure: -Complete resolution or marked improvement or return to baseline of all signs and symptoms (e.g., changes in fever, oxygenation, purulence of respiratory specimen, absence of respiratory secretions) of pneumonia (unless there is an alternative reason other than pneumonia, for persistence of certain symptoms or considered residual signs and symptoms of pneumonia that do not require further anti-pseudomonal antibiotic treatment), and -None of the clinical failure criteria (see below) are fulfilled •Clinical failure (at least one of the following): -Worsening or no improvement in clinical signs and symptoms -Treatment-limiting AE leading to discontinuation of murepavadin/ertapenem/meropenem/piperacillin-tazobactam at any timepoint -Discontinuation of the study treatment for lack of efficacy after a minimum of 72 hours and initiation of therapy with a potentially effective anti-pseudomonal medication (change in therapy due to resistance when the subject’s condition did not show deterioration is not a failure), -Death at any time •Indeterminate: -Lack of clinical cure or clinical failure, -Inability to determine outcome, e.g., anti-pseudomonal coverage no longer needed, but coverage for other Gram-negative pathogen with an antibiotic effective against P. aeruginosa continuing at EoT. Assessment of clinical response will be done by the Investigator and the Clinical Evaluation Committee. The rate of clinical cure, defined as the number of su | — |
Countries
Brazil, Canada, Czech Republic, France, Hungary, Israel, Lithuania, New Zealand, Peru, Philippines, United Kingdom, United States
Contacts
Public ContactChief Medical & Development Officer
Polyphor Ltd.
Outcome results
None listed