Imipenem/Cilastatin-XNW4107 Versus Imipenem/Cilastatin/Relebactam for Treatment of Participants With Bacterial Pneumonia (XNW4107-302, REITAB-2)

Phase 3CompletedNCT05204563

Evopoint Biosciences Inc.450 enrolled

Overview

This study aims to compare treatment with Imipenem/Cilastatin-XNW4107 (IMI-XNW4107) with imipenem/cilastatin/relebactam (IMI/REL) in participants with hospital-acquired or ventilator-associated bacterial pneumonia (HABP or VAPB, respectively). The primary hypothesis is that IMI-XNW4107 is non-inferior to IMI/REL in all-cause mortality.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

450

Conditions

Hospital Acquired Bacterial Pneumonia or Ventilator-Associated Bacterial Pneumonia

Interventions

Combination of Imipenem/Cilastatin and XNW4107DRUG

Imipenem/Cilastatin 500mg/500mg and XNW4107 250mg for Injection

Imipenem/Cilastatin/RelebactamDRUG

Imipenem/Cilastatin/Relebactam 1.25 g for Injection

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Has HABP or VABP as defined below and requires treatment with IV antibiotic therapy. Fulfills clinical criteria, with onset of criteria occurring after more than 48 hours of hospitalization or within 7 days after discharge from a hospital (for HABP); or at least 48 hours after mechanical ventilation (for VABP) 2. Fulfills clinical criteria with symptoms or signs of cough, expectorated sputum production, dyspnea, worsening oxygenation, increase in respiratory secretions, fever/ hypothermia.. 3. Fulfills laboratory test criteria with Leukocytosis/ Leukocytosis/ increase in immature neutrophils 4. Fulfill radiograph criteria with presence of new or progressive infiltrate(s) suggestive of bacterial pneumonia in X-ray/ Chest CT. 5. Female subjects of childbearing potential, who are willing to birth control during the study and for at least 30 days following the last dose of study medication. Male subjects with female sexual partners of childbearing potential are eligible for inclusion if they agree to use birth control for 90 days following the last dose of study medication. Male subjects must agree not to donate sperm Exclusion Criteria: 1. Gram stain from a respiratory sample shows only Gram-positive cocci. 2. Have known or suspected community-acquired bacterial pneumonia, atypical pneumonia, viral pneumonia including Coronavirus disease, or chemical pneumonia. 3. Have HABP/VABP caused by an obstructive process, including lung cancer or other known obstruction. 4. Have received effective antibacterial drug therapy for the index infection of HABP/VABP for more than 24 hours during the previous 72 hours . 5. Have central nervous system infection. 6. Documented presence of immunodeficiency or an immunocompromised condition 7. Documented or severe hypersensitivity or previous severe adverse drug reaction, especially to any beta-lactam antibiotics, or any of the excipients used in the study drug formulations. 8. History of a seizure disorder requiring ongoing treatment with anti-convulsive therapy or prior treatment with anti-convulsive therapy within the last 3 years. 9. eGFR \<15 mL/min/1.73㎡. 10. Patient is receiving hemodialysis or peritoneal dialysis. 11. Anticipated to be treated with any of Valproic acid or divalproex sodium, concomitant systemic Gram-negative antibacterial agents, or concomitant systemic antifungal or antiviral therapy for the index infection of HABP/VABP. 12. Life expectancy is \<3 days. 13. Patients in refractory septic shock 14. Patients with 1 or more of laboratory abnormalities in baseline specimens. 15. History of active liver disease or cirrhosis. 16. APACHE II score of \>30. 17. A female who is pregnant or breastfeeding or has a positive pregnancy test at Screening.

Locations (35)

Outcomes

Primary Outcomes

Day 14 All-cause Mortality Rate

The all-cause mortality rate at Day 14 was calculated as the percentage of participants in each treatment group who experienced mortality, regardless of the cause, from randomization up to Day 14.

Time frame: Day 14

Secondary Outcomes

Day 28 All-cause Mortality Rate

The all-cause mortality rate at Day 28 was calculated as the percentage of participants in each treatment group who experienced mortality, regardless of the cause, from randomization up to Day 28.

Time frame: Day 28

Day 14 and Day 28 All-cause Mortality Rate in the Micro-MITT Population

The all-cause mortality rate at Day 14 and Day 28 was calculated as the percentage of participants in each treatment group who experienced mortality, regardless of the cause, from randomization up to Day 14 and Day 28.

Time frame: Day 14, Day 28

Day 14 and Day 28 All-cause Mortality Rate in the Extended Micro-MITT

Time frame: Day 14, Day 28

Day 14 and Day 28 All-cause Mortality Rate in the Clinically Evaluable (CE) Population

Time frame: Day 14, Day 28

Day 14 and Day 28 All-cause Mortality Rate in the Microbiologically Evaluable (ME) Population

Data from ClinicalTrials.gov

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Denver Health and Hospital Authority

Denver, Colorado, United States

Hartford Hospital

Hartford, Connecticut, United States

Jackson Memorial Hospital (JMH) - Ryder Trauma Center

Miami, Florida, United States

USF-TGH

Tampa, Florida, United States

University of Maryland Medical Center

Baltimore, Maryland, United States

Cox Health

Springfield, Missouri, United States

VA medical center

Buffalo, New York, United States

Carolinas Medical Center

Charlotte, North Carolina, United States

University Hospitals Cleveland Medical Center

Cleveland, Ohio, United States

The University of Tennessee Medical Center

Knoxville, Tennessee, United States

...and 25 more locations

Time frame: Day 14, Day 28

Day 14 and Day 28 All-cause Mortality Rate in the Carbapenem-resistant MITT (CR-MITT) Population

Time frame: Day 14, Day 28

The Percentage of Participants With Clinical Success as Evaluated by the Investigator in the MITT Population

Clinical success was defined as: For Day 4 visit: a participant was alive with resolution or improvement in at least 1 baseline sign/symptom AND no worsening of any baseline signs/symptoms AND no development of new signs/symptoms of pneumonia requiring the initiation of a non-study antibacterial therapy for the index infection. For end of treatment (EOT) or test-of-cure (TOC) visits: a participant was alive with complete resolution or significant improvement of signs and symptoms that were present at baseline and no new signs/symptoms of pneumonia, such that no further antibacterial therapy is necessary. For LFU, Clinical success at TOC with sustained resolution or marked improvement of baseline signs and symptoms of pneumonia during TOC and LFU without antimicrobial therapy (pneumonia).

Time frame: Day 4, end of treatment (EOT) (up to Day 14), Test-of-Cure (TOC) (Day 21), and Late Follow-up (LFU) (Day 28)

The Percentage of Participants With Clinical Success as Evaluated by the Investigator in the Micro-MITT Population

Clinical success was defined as: For Day 4 visit: a participant was alive with resolution or improvement in at least 1 baseline sign/symptom AND no worsening of any baseline signs/symptoms AND no development of new signs/symptoms of pneumonia requiring the initiation of a non-study antibacterial therapy for the index infection. For EOT or TOC visits: a participant was alive with complete resolution or significant improvement of signs and symptoms that were present at baseline and no new signs/symptoms of pneumonia, such that no further antibacterial therapy is necessary. For LFU, Clinical success at TOC with sustained resolution or marked improvement of baseline signs and symptoms of pneumonia during TOC and LFU without antimicrobial therapy (pneumonia).

Time frame: Day 4, EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)

The Percentage of Participants With Clinical Success as Evaluated by the Investigator in the Extended Micro-MITT

Clinical success was defined as: For Day 4 visit: a participant was alive with resolution or improvement in at least 1 baseline sign/symptom AND no worsening of any baseline signs/symptoms AND no development of new signs/symptoms of pneumonia requiring the initiation of a non-study antibacterial therapy for the index infection. For EOT or TOC visits: a participant was alive with complete resolution or significant improvement of signs and symptoms that were present at baseline and no new signs/symptoms of pneumonia, such that no further antibacterial therapy is necessary. For LFU, Clinical success at TOC with sustained resolution or marked improvement of baseline signs and symptoms of pneumonia during TOC and LFU without antimicrobial therapy (pneumonia).

Time frame: Day 4, EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)

The Percentage of Participants With Clinical Success as Evaluated by the Investigator in the CE Population

Clinical success was defined as: For Day 4 visit: a participant was alive with resolution or improvement in at least 1 baseline sign/symptom AND no worsening of any baseline signs/symptoms AND no development of new signs/symptoms of pneumonia requiring the initiation of a non-study antibacterial therapy for the index infection. For EOT or TOC visits: a participant was alive with complete resolution or significant improvement of signs and symptoms that were present at baseline and no new signs/symptoms of pneumonia, such that no further antibacterial therapy is necessary. For LFU, Clinical success at TOC with sustained resolution or marked improvement of baseline signs and symptoms of pneumonia during TOC and LFU without antimicrobial therapy (pneumonia).

Time frame: Day 4, end of treatment (EOT) (up to Day 14), Test-of-Cure (TOC) (Day 21), and Late Follow-up (LFU) (Day 28)

The Percentage of Participants With Clinical Success as Evaluated by the Investigator in the ME Population

Clinical success was defined as: For Day 4 visit: a participant was alive with resolution or improvement in at least 1 baseline sign/symptom AND no worsening of any baseline signs/symptoms AND no development of new signs/symptoms of pneumonia requiring the initiation of a non-study antibacterial therapy for the index infection. For EOT or TOC visits: a participant was alive with complete resolution or significant improvement of signs and symptoms that were present at baseline and no new signs/symptoms of pneumonia, such that no further antibacterial therapy is necessary. For LFU, Clinical success at TOC with sustained resolution or marked improvement of baseline signs and symptoms of pneumonia during TOC and LFU without antimicrobial therapy (pneumonia).

Time frame: Day 4, end of treatment (EOT) (up to Day 14), Test-of-Cure (TOC) (Day 21), and Late Follow-up (LFU) (Day 28)

The Percentage of Participants With Clinical Success as Evaluated by the Investigator in the CR-MITT Population

Clinical success was defined as: For Day 4 visit: a participant was alive with resolution or improvement in at least 1 baseline sign/symptom AND no worsening of any baseline signs/symptoms AND no development of new signs/symptoms of pneumonia requiring the initiation of a non-study antibacterial therapy for the index infection. For EOT or TOC visits: a participant was alive with complete resolution or significant improvement of signs and symptoms that were present at baseline and no new signs/symptoms of pneumonia, such that no further antibacterial therapy is necessary. For LFU, Clinical success at TOC with sustained resolution or marked improvement of baseline signs and symptoms of pneumonia during TOC and LFU without antimicrobial therapy (pneumonia).

Time frame: Day 4, end of treatment (EOT) (up to Day 14), Test-of-Cure (TOC) (Day 21), and Late Follow-up (LFU) (Day 28)

The Percentage of Participants With Microbiological Success in the Micro-MITT Population

Microbiological success was defined as: • Eradication: Absence of the baseline Gram-negative pathogen from an appropriate clinical specimen • Presumed eradication: Absence of appropriate post-baseline culture material in a participant, but judged to be a clinical success.