| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hospital-acquired pneumonia (HAP) or nosocomial pneumonia refers to any pneumonia contracted by a patient in a hospital at least 48–72 hours after being admitted. |
|
| 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 (NI) in 28-day all cause mortality (ACM) rate of i.v. murepavadin given with ertapenem compared to an anti-pseudomonal- β-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. |
|
| E.2.2 | Secondary objectives of the trial |
-To determine the superiority in 28-day ACM rate of i.v. murepavadin given with ertapenem compared to an anti-pseudomonal-β-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-β-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-β-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-β-lactam-based antibiotic (either piperacillin-tazobactam or meropenem) from baseline to different timepoints
|
|
| 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. 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 Physiology and Chronic Health Evaluation (APACHE II) score between 8 and 25, inclusive, within 24 hours prior to randomization
8. Strong clinical suspicion of pneumonia due to P. aeruginosa. Such evidence could be the following criteria, but is not limited to:
• a surveillance culture from a respiratory sample positive for P. aeruginosa
• a Gram stain performed within 36 hours prior to randomization using an acceptable respiratory sample (protected brush specimen [PBS], BAL, mini-BAL, ETA, sputum) showing Gram-negative rods (with or without Gram-positive bacteria)
• History of previous P. aeruginosa infection or colonization of a respiratory sample within the previous 12 months,
A rapid diagnostic test (RDT), performed within 36 hours prior to randomization on respiratory secretions, may further support the suspicion based on the above clinical criteria.
AND
At least one risk factor, including the following, but not limited to:
o Broad-spectrum antibiotics (carbapenems, broad-spectrum cephalosporins, aminoglycosides, fluoroquinolones) administered within 90 days prior to randomization,
o Current hospitalization of ≥ 5 days,
o Late onset (> 4 days after intubation) of VABP,
o History of chronic obstructive pulmonary disease,
o Immunosuppressive disease / therapy (e.g., steroid use). |
|
| E.4 | Principal 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 < 72 hours
5. Burns > 40% of total body surface area
6. Current or anticipated neutropenia with absolute neutrophil count < 500 cells/mm3
7. Severe renal disease defined as an estimated glomerular filtration rate as per the 6-point Modification of Diet in Renal Disease (eGFR-MDRD-6) < 30 mL/min/1.73 m2, or requirement for peritoneal dialysis, hemodialysis, hemofiltration, or a urine output < 20 mL/hour over a 24-hour period.
8. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 5 times upper limit of normal or Child-Pugh B and C in subjects with chronic hepatic function impairment
9. Received systemic or inhaled anti-pseudomonal antibiotic therapy within 72 hours prior to randomization as follows:
• > 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 β-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 territory
12. Women who are pregnant or nursing
13.Persisting hypotension requiring sympathomimetic agents (> 0.2 μg/kg/min norepinephrine or a total of all vasopressors > 0.2 μg/kg/min norepinephrine equivalents) to maintain a MAP ≥ 65
mmHg despite adequate fluid administration.
14.Evidence of co-infection with ertapenem-resistant Gram-negative pathogen(s). Evidence of infection with meropenem- AND piperacillin-tazobactam-resistant Pseudomonas aeruginosa or co-infection with meropenem- AND piperacillin-tazobactam-resistant Gram-negative pathogen(s).
15. Former exposure to murepavadin
16. Subjects with known hypersensitivity to any component of ertapenem, meropenem or to other drugs in the same class or demonstrated anaphylactic reactions to beta-lactams or a history of
allergic reactions to any of the penicillins, cephalosporins, or β lactamase inhibitors
17. Known or suspected neuro-muscular disease, e.g., myasthenia gravis
18. Subjects who are currently enrolled in, or have not yet completed at least 30 days since ending another investigational device or drug trial or are receiving other investigational agents
19. Subjects with other severe acute or chronic medical or laboratory abnormality that may, in the investigator’s opinion, interfere with the assessment of safety, tolerability or efficacy or interfere with the conduct or interpretation of the study.
20. Not willing to comply with all study procedures. |
|
| E.5 End points |
| E.5.1 | 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Please refer to Appendix I : Schedule of Assessment of Protocol:
POL7080-010 |
|
| E.5.2 | 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 subjects with clinical cure in a pre-defined efficacy population divided by the number of subjects at risk will be calculated on Day 3, 5, 7, 10
(if still on study medication), at EoT and ToC visits and analyzed in the PP, micro-MITT and modified-MITT analysis sets.
3. Change from baseline in SOFA score to Day 3, 5, 7, 10 and modified Clinical Pulmonary Infection Score at ToC (micro-MITT, modified-MITT and PP analysis sets)
4. Change from baseline in PaO2/FiO2 ratio (micro-MITT, modified-MITT, and PP analysis sets)
5. ACM rates within 14 days after randomization(micro ITT, modified-MITT and PP analysis sets) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please refer to Appendix I : Schedule of Assessment of Protocol:
POL7080-010 |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 |
| Brazil |
| Canada |
| Czech Republic |
| France |
| Israel |
| Lithuania |
| New Zealand |
| Peru |
| Philippines |
| 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
|
This clinical trial is not considered closed as long as:
-The target number of evaluable subjects in the micro-MITT analysis set has not been reached
-Any subject is still receiving any IMP or reference product
-Trial-related visits at the site are still taking place
-Procedures or interventions according to the clinical trial protocol are still being undertaken in any subject, or
-Any subject’s post-treatment follow-up period has not yet been completed. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 28 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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