Hospital-Acquired Bacterial Pneumonia, Ventilator-Associated Bacterial Pneumonia, Hospital-Acquired Pneumonia, Ventilator-Associated Pneumonia
Conditions
Brief summary
The purpose of this study is to determine the efficacy, safety, tolerability, and pharmacokinetics (PK) of meropenem-vaborbactam compared to piperacillin/tazobactam for 7 to 14 days in the treatment of hospitalized adults who meet clinical, radiographic, and microbiological criteria for hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP).
Interventions
meropenem 2 g and vaborbactam 2 g
DRUGPiperacillin/Tazobactam
piperacillin 4 g and tazobactam 0.5 g
Sponsors
Melinta Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Willingness to comply with all study procedures and provide a signed written informed consent prior to any study-specific procedures; however, if unable to do so, the participant's legally authorized representative may provide written consent as approved by institutional-specific guidelines. Participants who are unconscious or considered by the investigator to be clinically unable to consent at Screening and who are entered into the study by the consent of a legally authorized representative, should provide their own written informed consent for continuing to participate in the study as soon as possible on recovery, as applicable in accordance with local regulations. 2. Hospitalized male or female participants, ≥18 years of age. 3. Females must be surgically sterile or at least 2 years postmenopausal, or if of childbearing potential, have a negative screening urine pregnancy test and be willing to practice sexual abstinence or use an accepted form of contraception with her partner (for example, barrier or hormonal methods) during treatment and for at least 28 days after the last dose of study drug. 4. Expectation, in the opinion of the Investigator, that the participant's infection will require treatment with IV antibiotics for a minimum of 7 days. 5. Have a confirmed diagnosis of HABP or VABP requiring antibiotic therapy by meeting all clinical, microbiological, and radiographic criteria as defined in the following: For HABP participants: To meet the study definition of HABP, participants must meet all of the following clinical, microbiological, and radiographic criteria: 1. A chest radiograph (chest X-ray \[CXR\], magnetic resonance imaging \[MRI\] or computed tomography \[CT\]) reveals the presence of new or progressive pulmonary infiltrate(s) consistent with bacterial pneumonia within 48 hours prior to randomization. 2. Onset of symptoms at least 48 hours after hospitalization or within 7 days after discharge from an inpatient acute or chronic care facility (for example, long-term care, rehabilitation center, hospital, or skilled nursing home). 3. Have at least one of the following: 1. Temperature ≥38.0 degrees Celsius (100.4 degrees Fahrenheit) or ≤35 degrees Celsius (95.0 degrees Fahrenheit). 2. Peripheral white blood cell (WBC) count ≥10,000 cells/cubic millimeter (mm\^3) or ≤4,500 cells/mm\^3. 3. ≥15 percent immature neutrophils (band forms) regardless of total WBC count. 4. Have at least one of the following: 1. New onset of cough or expectorated sputum production (or worsening of baseline cough). 2. Auscultatory findings on pulmonary examination consistent with bacterial pneumonia or pulmonary consolidation (for example, rales, dullness on percussion, bronchial breath sounds, or ego phony). 3. Dyspnea or tachypnea (that is, respiratory rate greater than 25 breaths/minute). 4. Hypoxemia (O2 saturation ≤90 percent or pO2 ≤60 millimeters of mercury \[mmHg\] while breathing room air, or worsening of the O2 saturation/FiO2). 5. New onset need for mechanical ventilation. 6. A deep respiratory secretion specimen that was collected within 48 hours prior to randomization and after development of clinical signs and symptoms of HABP (ideally prior to administration of systemic antimicrobial therapy). This can be obtained via a sputum sample (expectorated sputum), bronchoalveolar lavage (BAL) (including protected BAL or mini-BAL), protected specimen brush (PSB), endotracheal tube aspirate (ETA), pleural fluid, or lung parenchyma (open-lung, transthoracic, or transbronchial biopsy). 7. This deep respiratory secretion sample must meet adequacy criteria for testing, and be sent to the local or regional laboratory for Gram stain and culture (results of Gram stain and culture do not have to be available for enrollment). For VABP participants: To meet the study definition of VABP, participants must meet all of the following clinical, microbiological, and radiographic criteria: 1. A chest radiograph (CXR, MRI or CT) revealing the presence of new or progressive pulmonary infiltrate(s) consistent with bacterial pneumonia within 48 hours prior to randomization. 2. Receiving mechanical ventilation via endotracheal intubation or tracheostomy for greater than or equal to 48 hours. 3. Have at least one of the following: 1. Temperature ≥38.0 degrees Celsius (100.4 degrees Fahrenheit) or ≤35 degrees Celsius (95.0 degrees Fahrenheit). 2. Peripheral white blood cell (WBC) count ≥10,000 cells/mm\^3 or ≤4,500 cells/mm\^3. 3. ≥15 percent immature neutrophils (band forms) regardless of total WBC count. 4. Have at least one of the following: 1. New onset of purulent respiratory secretions from the lungs or new onset of or increased need for respiratory secretion suctioning. 2. Auscultatory findings on pulmonary examination consistent with bacterial pneumonia or pulmonary consolidation (for example, rales, dullness on percussion, bronchial breath sounds, or egophony). 3. Worsening gas exchange (ratio of partial pressure of arterial oxygen to fraction of inspired oxygen \[PaO2/FiO2\] ≤240 or PaO2 ≤60 mmHg) leading to acute changes to the ventilator support system (minimum daily FiO2 values increased by at least 0.20 over the daily minimum FiO2 in the preceding 48 hours, or minimum daily positive end- expiratory pressure (PEEP) values increased by at least 3 centimeters (cm) H2O over the daily minimum PEEP in the preceding 48 hours). 5. A deep respiratory secretion specimen must be collected within 48 hours prior to randomization and after development of clinical signs and symptoms of VABP (ideally prior to administration of systemic antimicrobial therapy). This can be obtained via BAL (including protected BAL or mini-BAL), PSB, or ETA, pleural fluid, or lung parenchyma (open-lung, transthoracic, or transbronchial biopsy). 6. The above deep respiratory secretion sample must meet adequacy criteria for testing and be sent to the local or regional laboratory for Gram stain and culture (results of Gram stain and culture do not have to be available for enrollment).
Exclusion criteria
Participants who meet any of the following
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Rate of Participants with All-Cause Mortality at Day 28 in the Intent-to-Treat (ITT) Population | Day 28 |
| Percentage of Participants who Achieve a Clinical Outcome of Cure at the Test of Cure (TOC) Visit in the ITT and Clinically Evaluable (CE) Populations | 12-23 days (TOC visit) after first dose of study drug |
Secondary
| Measure | Time frame |
|---|---|
| Percentage of Participants with Clinical Outcome of Cure at EOT, TOC, and Last Follow Up (LFU) Visits in the ITT, CE, and ME Populations | 1 day (EOT visit), 12-23 days (TOC visit), and 19-30 days (LFU visit) after first dose of study drug |
| Percentage of Participants with Clinical Outcome of Cure per Pathogen at EOT, TOC, and LFU Visits in the mMITT and ME Populations | 1 day (EOT visit), 12-23 days (TOC visit), and 19-30 days (LFU visit) after first dose of study drug |
| Percentage of Participants with Microbiological Eradication Per-Participant and Per-Pathogen Microbiological Response at EOT and TOC visits in the mMITT and ME Populations | 1 day (EOT visit) and 12-23 days (TOC visit) after first dose of study drug |
| Percentage of Participants who Survive and Did Not Have a Major Nonfatal Event (Treatment-Emergent Events of Acute Respiratory Distress Syndrome, Septic Shock, or Pleural Empyema) up to Day 28 in the ITT and CE Populations | Up to Day 28 |
| Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Meropenem | Days 1 and 3 |
| Rate of Participants with All-Cause Mortality at Day 14 in the ITT, microbiological Modified ITT (mMITT), CE, and Microbiologically Evaluable (ME) Populations | Day 14 |
| Pharmacokinetics: Time to Maximum Plasma Concentration (Tmax) of Meropenem | Days 1 and 3 |
| Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Vaborbactam | Days 1 and 3 |
| Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Vaborbactam | Days 1 and 3 |
| Pharmacokinetics: Time to Maximum Plasma Concentration (Tmax) of Vaborbactam | Days 1 and 3 |
| Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Meropenem | Days 1 and 3 |
| Rate of Participants with All-Cause Mortality at Day 28 in the mMITT, CE, and ME Populations | Day 28 |
Outcome results
None listed