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

A Multicenter, Randomized, Double-Blind, Comparative, Phase 3 Study to Evaluate the Efficacy and Safety of Intravenous Imipenem/Cilastatin/XNW4107 in Comparison With Imipenem/Cilastatin/Relebactam in Adults With Hospital-Acquired Bacterial Pneumonia or Ventilator-Associated Bacterial Pneumonia (EudraCT no. 2022-000081-18) (EUCTR no. 2022-501952-27-00) (IND no. 146614)

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 Overview

• Status: Completed
• Conditions: Hospital Acquired Bacterial Pneumonia or Ventilator-Associated Bacterial Pneumonia
• Intervention / Treatment: Drug: Combination of Imipenem/Cilastatin and XNW4107; Drug: Imipenem/Cilastatin/Relebactam

• Study Type: Interventional
• Enrollment (Actual): 450
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Argenteuil, France, 95100
    • CH Victor Dupouy
  • Alpes Maritimes
    • Nice, Alpes Maritimes, France, 06200
      • CHU de Nice
  • Alsace
    • Strasbourg, Alsace, France, 67000
      • Hôpitaux Universitaires de Strasbourg
  • Bas-Rhin
    • Strasbourg, Bas-Rhin, France, 67091
      • Nouvel Hopital CIVIL/ Medecine Intensive Reanimation
  • GARD
    • Nîmes, GARD, France, 30029
      • CHU Nimes
  • Grand Est
    • Reims, Grand Est, France, 51100
      • Chu Reims- Medical Icu
  • Paris
    • Paris, Paris, France, 75014
      • COCHIN
    • Paris, Paris, France, 75014
      • Groupe Hospitalier Paris Saint-Joseph
    • Paris, Paris, France, 75018
      • APHP
  • Picardie
    • Amiens, Picardie, France, 80054
      • intensive Unit Care CHU Amiens Picardie
  • Île-de-France Region
    • Suresnes, Île-de-France Region, France, 92150
      • Hôpital Foch
• Israel
  • Center
    • Ramat Gan, Center, Israel, 5262100
      • Sheba Medical Center
  • Central District
    • H̱olon, Central District, Israel, 58100
      • Wolfson Medical Center
  • HaMercaz
    • Be’er Ya‘aqov, HaMercaz, Israel, 70300
      • Shamir Medical Center
  • Haifa District
    • Haifa, Haifa District, Israel, 3339419
      • Bnei-Zion Medical Center
  • Israel
    • Hadera, Israel, Israel, 38100
      • Hillel Yaffe Medical Center
    • Haifa, Israel, Israel, 3525408
      • Rambam Critical Care division
    • Tel Aviv, Israel, Israel, 64239
      • Tel Aviv Medical Center
  • Western Galilee
    • Nahariya, Western Galilee, Israel, 2210001
      • Galilee Medical Center / Department int med A
• Spain
  • Barcelona
    • Barcelona, Barcelona, Spain, 08041
      • Hospital De La Santa Creu I Sant Pau
    • Barcelona, Barcelona, Spain, 08003
      • Hospital del Mar
    • Barcelona, Barcelona, Spain, 08035
      • Hospital Universitari Vall Hebron
    • Barcelona, Barcelona, Spain, 08036
      • Hospital Clinic of Barcelona
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Bellvitge University Hospital
  • Tarragona
    • Tarragona, Tarragona, Spain, 43007
      • Hospital Universitario de Tarragona Joan XXIII
• United States
  • Colorado
    • Denver, Colorado, United States, 80204
      • Denver Health and Hospital Authority
  • Connecticut
    • Hartford, Connecticut, United States, 37920
      • Hartford Hospital
  • Florida
    • Miami, Florida, United States, 33136
      • Jackson Memorial Hospital (JMH) - Ryder Trauma Center
    • Tampa, Florida, United States, 33606
      • USF-TGH
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Missouri
    • Springfield, Missouri, United States, 65807
      • Cox Health
  • New York
    • Buffalo, New York, United States, 14215
      • VA Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Carolinas Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • The University of Tennessee Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Imipenem/Cilastatin/XNW4107; Imipenem/Cilastatin 500mg/500mg in combination with XNW4107 250mg, Q6h (0.5h Infusion)	Drug: Combination of Imipenem/Cilastatin and XNW4107; Imipenem/Cilastatin 500mg/500mg and XNW4107 250mg for Injection
Active Comparator: Imipenem/Cilastatin/Relebactam; Imipenem/Cilastatin/Relebactam 1.25g Q6h (0.5h Infusion)	Drug: Imipenem/Cilastatin/Relebactam; Imipenem/Cilastatin/Relebactam 1.25 g for Injection; Other Names: Recarbrio

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	Day 14, Day 28
Day 14 and Day 28 All-cause Mortality Rate in the Extended Micro-MITT	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.	Day 14, Day 28
Day 14 and Day 28 All-cause Mortality Rate in the Clinically Evaluable (CE) 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.	Day 14, Day 28
Day 14 and Day 28 All-cause Mortality Rate in the Microbiologically Evaluable (ME) 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.	Day 14, Day 28
Day 14 and Day 28 All-cause Mortality Rate in the Carbapenem-resistant MITT (CR-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.	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).	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).	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).	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).	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).	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).	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.	EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)
The Percentage of Participants With Microbiological Success in the Extended 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.	EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)
The Percentage of Participants With Microbiological Success in the CR-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.	EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)
The Percentage of Participants With Microbiological Success in the ME 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.	EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)
The Percentage of Participants With Microbiological Success by Pathogen 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.	EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)
The Percentage of Participants With Microbiological Success by Pathogen in the Extended 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.	EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)
The Percentage of Participants With Microbiological Success by Pathogen in the ME 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.	EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)
The Percentage of Participants With Microbiological Success by Pathogen in the CR-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.	EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)
The Percentage of Participants With Overall Success in the Micro-MITT Population	Overall success was defined as clinical success and microbiological success at the visits of EOT or TOC, or sustained success for clinical outcome and microbiological success at the visit of LFU. Microbiological success included eradication or presumed eradication.	EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)
The Percentage of Participants With Overall Success in the Extended Micro-MITT Population	Overall success was defined as clinical success and microbiological success at the visits of EOT or TOC, or sustained success for clinical outcome and microbiological success at the visit of LFU. Microbiological success included eradication or presumed eradication.	EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)
The Percentage of Participants With Overall Success in the ME Population	Overall success was defined as clinical success and microbiological success at the visits of EOT or TOC, or sustained success for clinical outcome and microbiological success at the visit of LFU. Microbiological success included eradication or presumed eradication.	EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)
The Percentage of Participants With Overall Success in the CR-MITT Population	Overall success was defined as clinical success and microbiological success at the visits of EOT or TOC, or sustained success for clinical outcome and microbiological success at the visit of LFU. Microbiological success included eradication or presumed eradication.	EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	A TEAE was defined as any untoward medical occurrence after first dose associated with the use of a drug in humans, whether or not considered drug-related. An SAE was defined as any adverse event (AE) occurring at any dose that met one or more of the following criteria: resulted in death, was life-threatening, required participant hospitalization or prolongation of an existing hospitalization, resulted in persistent or significant disability or incapacity, a congenital anomaly or birth defect or an important medical event.	Day 1 to Day 28
Blood XNW4107, Imipenem, and Cilastatin Concentrations	Blood samples were taken for analysis of XNW4107, imipenem, and cilastatin concentrations. The data at each time point was calculated as an average across Days 4, 5 and 6.	Predose, 5-25 minutes post-dose, and 2-3 hours post-dose on Day 4, 5, or 6

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total number of days in hospital	Total number of days in hospital within 28 days after randomization for MITT population	Up to Day 28
Number of days in intensive care unit (ICU)	Number of days in intensive care unit (ICU) through 28 days after randomization for MITT population	Up to Day 28
Number of days on a ventilator and ventilator free days	Number of days on a ventilator and ventilator free days through 28 days after randomization for the subgroup of VABP patients includingand ventilated-HABP in the MITT population.	Up to Day 28

Collaborators and Investigators

• Sponsor: Evopoint Biosciences Inc.
• Investigators: Study Chair: Jason Le, Evopoint Biosciences USA, Inc.)

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2022
• Primary Completion (Actual): September 29, 2024
• Study Completion (Actual): September 29, 2024

Study Registration Dates

• First Submitted: January 5, 2022
• First Submitted That Met QC Criteria: January 10, 2022
• First Posted (Actual): January 24, 2022

Study Record Updates

• Last Update Posted (Estimated): November 6, 2025
• Last Update Submitted That Met QC Criteria: October 22, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Pneumonia; Pneumonia, Bacterial; Organic Chemicals; Fatty Acids; Lipids; Hydrocarbons; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Fatty Acids, Unsaturated; Fatty Acids, Monounsaturated; Cyclopropanes; Cilastatin; imipenem, cilastatin and relebactam
• Other Study ID Numbers: XNW4107-302

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No