Ventilator-associated bacterial pneumonia (VABP) MedDRA version: 20.1 Level: LLT Classification code 10065153 Term: Ventilator associated pneumonia System Organ Class: 100000004862
Conditions
Interventions
formerly RO7033877
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 8-
Product Name: P
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. If a subject regains 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 should be re-consented, if required by local country and institution-specific guidelines 2. Male or female subjects, =18 years of age 3. Hospitalized for = 48 hours, intubated (via endo- or nasotracheal tube, including tracheostomy subjects) and receiving mechanical ventilation for = 48 hours at the time of randomization, and with acute changes made in the ventilator support system to enhance oxygenation 4. Chest radiograph shows the presence of new or progressive infiltrate(s) characteristic of bacterial pneumonia (based on Investigator’s evaluation). A chest computerized tomography (CT) scan may be used in place of a chest X-ray. 5. Clinical findings to support diagnosis of VABP. At least one of the following must be present within 24 hours prior to randomization: • Documented fever (oral = 38.0°C [100.4°F] or a tympanic, temporal, rectal or core temperature = 38.3°C [101°F]), or an axillary or forehead scanner = 37.5°C [99.5°F] OR • Hypothermia (rectal / core body temperature = 35°C [95.2°F]), OR • Total peripheral white blood cell count (WBC) = 10,000 cells/mm3, OR • Leukopenia with WBC = 4500 cells/mm3 6. Acute Physiology and Chronic Health Evaluation (APACHE II) score between 8 and 30 inclusive, within 24 hours prior to randomization 7. High probability of pneumonia caused by P. aeruginosa, defined as follows: • A rapid diagnostic test (RDT), performed within 36 hours prior to randomization, using an acceptable respiratory sample (broncho-alveolar lavage [BAL], mini-BAL endotracheal aspirate [ETA], or sample from an exudative pleural effusion) positive for P. aeruginosa, OR • A surveillance culture from a respiratory sample positive for P. aeruginosa. Only if the above methods cannot be used, enrollment can be based on: • A Gram stain performed within 36 hours prior to randomization using an acceptable respiratory sample (protected brush specimen [PBS], BAL, mini-BAL, ETA (= 25 PMNs/LPF and = 10 squamous epithelial cells/LPF), or sample from an exudative pleural effusion) showing Gram-negative rods (with or without Gram-positive bacteria). The Gram stain will be performed in all subjects, even if the enrollment is based on a RDT. Note:if BAL, mini-BAL, or PBS is available at the site, these modalities are recommended rather than an ETA for obtaining the baseline lower respiratory tract specimen. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 75 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 75
Exclusion criteria
Exclusion criteria: 1. Known or suspected community-acquired bacterial, viral, fungal orparasitic 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 Pneumocystitis jiroveci pneumonia • Known or suspected active tuberculosis • Lung abscess • Solid organ transplant within 6 months prior to randomization • Pleural empyema • Evidence of deep-seated infection, e.g., endocarditis, osteomyelitis 3. Bronchial obstruction or a hisotry of post-obstructive pneumoniathis 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 (ANC) 8 i.v. doses of an antibiotic administered q.i.d. (e.g., piperacillin-tazobactam) - > 6 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 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 ECG finding such as ischemia, infarct, or ventricular arrhythmia with immediate potential for a fatal outcome, or, prior to the current infection, a history of New York Heart Association (NYHA) (Appendix X) Class IV cardiac failure 11. Stroke (ischemic or intracerebral hemorrhage) within 5 days prior to randomization 12. Women who are pregnant or nursing, or who are of childbearing potential and unwilling to use an acceptable method of birth control (e.g., 2 methods of contraception, one of which with a failure rate <1% per year, vasectomized male partner, or true abstinence (excluding women
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the clinical cure rates of intravenous (i.v.) murepavadin + one anti-pseudomonal antibiotic compared to two anti-pseudomonal antibiotics in the microbiological intention-to-treat (micro-ITT) analysis set in subjects with VABP due to P. aeruginosa at the Test-of-Cure (ToC) visit.; Secondary Objective: • To assess the all-cause mortality (ACM) rates at 14 and 28 days after randomization in different analysis sets • To assess the clinical cure rates at different timepoints and in different analysis sets ; Primary end point(s): The primary efficacy endpoint variable is the clinical cure rates determined by the CEC at the ToC visit in the micro-ITT analysis set. Clinical outcomes are defined as follows: • Clinical cure: o Complete resolution or marked improvement of all signs and symptoms (e.g., changes in fever, oxygenation, purulence of respiratory specimen, absence of respiratory secretions) of pneumonia (unless there is (i) an alternative reason other than pneumonia, (ii) occurrence/persistence of a non-pseudomonal pneumonia, that explains the persistence of certain symptoms, (iii) or presence of residual signs and symptoms of pneumonia that do not require further anti-pseudomonal antibiotic treatment), AND o None of the clinical failure criteria (see below) are fulfilled • Clinical failure: o Worsening or no improvement in clinical signs and symptoms, o Treatment-limiting AE leading to discontinuation of study drugs antibiotic, when subject requires alternative antimicrobial therapy to treat the pneumonia o Death The authorized anti-pseudomonal antibiotic(s) can be changed in either treatment arm. The decision to modify the authorized anti-pseudomonal treatment should be based on the absence of clinical improvement as per the investigator’s evaluation (i | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: Please refer to Apendix I : Schedule of Assessment of Prototcol: POL7080-011; Secondary end point(s): All-Cause Mortality (ACM) • ACM rate 28 days after randomization in the micro-ITT analysis set • ACM rate 14 days after randomization in the micro-ITT analysis set • ACM 28 days after randomization in the ITT, micro-MITT, IIAT/IAAT and PP analysis sets • ACM 14 days after randomization in the ITT, micro-MITT, IIAT/IAAT and PP analysis sets Clinical Response • Clinical cure rates at the ToC visit in the ITT, micro-MITT, IIAT/IAAT and PP analysis sets • Clinical cure rates at Day 3, 5, 7 10, the EoT visit in the ITT, micro- ITT, micro-MITT, IIAT/IAAT, and PP analysis sets | — |
Countries
Croatia, Estonia, France, Greece, Hungary, Ireland, Israel, Mexico, South Africa, Spain, Thailand, United States
Contacts
Public ContactChief Medical & Development Officer
Polyphor Ltd.
Outcome results
None listed