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
- Trial ID
- 2022-501952-27-00
- Protocol
- XNW4107-302
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **all-cause mortality rate** through Day 14 post-randomization in subjects with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP) treated with imipenem/cilastatin-XNW4107 (IMI-XNW4107) compared to those treated with imipenem/cilastatin/relebactam (IMI/REL) in the Modified Intent-to-Treat (MITT) population. This objective is clinically relevant as it directly assesses the efficacy of the investigational treatment in reducing mortality, a critical outcome in severe bacterial infections.
Secondary objectives include:
- Evaluating the all-cause mortality rate through Day 28 post-randomization in the IMI-XNW4107 group compared to the IMI/REL group in various populations, including MITT, Microbiologic MITT (micro-MITT), extended micro-MITT, clinically evaluable (CE), microbiologically evaluable (ME), and Carbapenem-resistant MITT (CR-MITT).
- Assessing the clinical outcome of IMI-XNW4107 compared to IMI/REL at Day 4, End of Treatment (EOT), Test-of-Cure (TOC), and Late Follow-up (LFU) visits in the aforementioned populations.
- Evaluating the microbiological outcome and by-pathogen microbiological outcome of IMI-XNW4107 compared to IMI/REL at EOT, TOC, and LFU visits in the micro-MITT, extended micro-MITT, ME, and CR-MITT populations.
- Assessing the overall outcome of IMI-XNW4107 compared to IMI/REL at EOT, TOC, and LFU visits in the same populations.
- Evaluating the safety and tolerability of IMI-XNW4107 administered by intravenous infusion compared to IMI/REL in subjects with HABP or VABP in the Safety population (SAF).
- Evaluating the pharmacokinetics (PK) of IMI-XNW4107 in subjects with HABP/VABP and providing data for population PK (PopPK) modeling and exposure-response modeling analysis.
Participants
The clinical trial involves a total of **392 participants** diagnosed with **hospital-acquired bacterial pneumonia (HABP)**, including ventilated HABP (vHABP) and ventilator-associated bacterial pneumonia (VABP) caused by Gram-negative bacteria. The study population comprises both male and female subjects aged **18 years and older**. Participants were selected based on their ability to provide informed consent and their requirement for intravenous antibiotic therapy due to HABP or VABP. The trial includes individuals who are part of a vulnerable population, as defined by the study criteria. Participants are expected to adhere to specific lifestyle considerations, such as the use of effective birth control methods for females of childbearing potential and males with female partners of childbearing potential. The trial population was selected to ensure compliance with study assessments and protocol schedules. Key inclusion criteria include the presence of new or worsening pulmonary symptoms, hypoxemia, or changes in ventilator support, along with laboratory abnormalities such as fever, leukocytosis, or leukopenia. Participants must also have a chest radiograph or computed tomography scan indicating bacterial pneumonia and evidence of a Gram-negative infection in the lower respiratory tract.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, controlled, Phase 3 study designed to evaluate the efficacy and safety of intravenous **imipenem/cilastatin-XNW4107** compared to **imipenem/cilastatin/relebactam** in adults with **hospital-acquired bacterial pneumonia** (HABP) or **ventilator-associated bacterial pneumonia** (VABP) caused by Gram-negative bacteria. The trial aims to assess the all-cause mortality rate through Day 14 post-randomization in the Modified Intent-to-Treat (MITT) population. The study is expected to run from June 2023 to August 2024, with participant involvement lasting up to 14 days of treatment, followed by additional follow-up visits.
Participants will undergo a sequence of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, medical condition, and willingness to comply with study requirements. The screening will include assessments like chest radiographs and microbiological tests to confirm the presence of Gram-negative bacterial infection. Following randomization, participants will receive either the test drug, XNW4107, or the comparator, imipenem/cilastatin/relebactam, administered via **intravenous infusion**. The maximum treatment period is 14 days, with daily doses not exceeding the specified limits for each drug.
Follow-up visits will occur at Day 4, End of Treatment (EOT), Test of Cure (TOC), and Long-term Follow-up (LFU) to evaluate clinical and microbiological success. The primary endpoint is the Day 14 all-cause mortality rate, while secondary endpoints include Day 28 mortality rates and clinical success rates at various time points. Participants may be withdrawn from the study if they experience adverse events, fail to adhere to the protocol, or withdraw consent. The trial's design ensures rigorous monitoring and data collection to support the evaluation of the investigational drug's safety and efficacy.
Treatment
The clinical trial involves the administration of **XNW4107**, an experimental medication formulated as an **injection**. The active substance in XNW4107 is (1R,4S)-4-(5-((S)-2-iminioimidazolidin-4-yl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1'-cyclopropan]-7-yl sulfate. This compound is administered via **intravenous infusion**. The maximum daily dose is 1 gram, with a total maximum dose of 14 grams over a treatment period of 14 days. Participant compliance with the dosing schedule is monitored throughout the study.
**IMIPENEM** is used as a comparator treatment in the study. It is provided as a **powder for solution for infusion** and is also administered through **intravenous infusion**. The maximum daily dose for imipenem is 2 grams, with a total maximum dose of 28 grams over a 14-day treatment period. This medication is chemically derived and is not a pediatric formulation.
**CILASTATIN** is another comparator treatment, also formulated as a **powder for solution for infusion**. Like imipenem, cilastatin is administered via **intravenous infusion**. The dosing schedule allows for a maximum daily dose of 2 grams and a total maximum dose of 28 grams over 14 days. Cilastatin is chemically synthesized and is not intended for pediatric use.
**RECARBRIO**, a combination of cilastatin, imipenem, and relebactam, serves as a standard-of-care therapy in the trial. It is provided as a **powder for injection** and administered through **intravenous infusion**. The maximum daily dose is 5 grams, with a total maximum dose of 70 grams over a 14-day treatment period. This combination therapy is chemically derived and is not formulated for pediatric use. Compliance with the administration schedule is closely monitored to ensure adherence to the protocol.
Efficacy
The efficacy of the investigational treatment in this clinical trial will be assessed primarily by evaluating the **all-cause mortality rate** through Day 14 post-randomization in the Modified Intent-to-Treat (MITT) population. This primary endpoint will provide a direct measure of the treatment's impact on survival in patients with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP).
Secondary endpoints will include the Day 28 all-cause mortality rate in the MITT population, as well as the Day 14 and Day 28 all-cause mortality rates in various subpopulations, including micro-MITT, extended micro-MITT, CE, ME, and CR-MITT populations. Additionally, the proportion of subjects achieving clinical success, as evaluated by the investigator, will be assessed at Day 4, end-of-treatment (EOT), test-of-cure (TOC), and last follow-up (LFU) visits across these populations. Microbiological success rates at EOT, TOC, and LFU visits will also be evaluated, both overall and by pathogen, in the micro-MITT, extended micro-MITT, ME, and CR-MITT populations.
The collection and analysis of these efficacy parameters will be conducted at specified timepoints throughout the trial, ensuring a comprehensive evaluation of the investigational treatment's effectiveness in comparison to the control. The trial will utilize a randomized, double-blind, comparative design to maintain the integrity and reliability of the efficacy assessments.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subjects willing and able to provide written informed consent or where consent is provided by legally authorized representatives.
- Willing and able to comply with all study assessments and adhere to the protocol schedule.
- Male or female subjects ≥18 years on the day of signing informed consent.
- Has HABP or VABP as defined below and requires treatment with IV antibiotic therapy. NOTE: HABP is defined as the onset of acute bacterial pneumonia symptoms at least 48 hours after hospitalization or within 7 days after discharge from an inpatient acute or chronic care facility (e.g., long-term care, rehabilitation center, hospital, or skilled nursing home). Subjects may experience acute respiratory failure and require mechanical ventilation for HABP (vHABP). VABP is defined as acute bacterial pneumonia in a subject receiving mechanical ventilation via an endotracheal (or nasotracheal) tube or tracheostomy for ≥48 hours.
- All subjects must fulfill at least 1 of the following clinical criteria at screening: a. New onset or worsening of pulmonary symptoms or signs, such as cough, dyspnea, tachypnea (e.g., respiratory rate >25 breaths/minute), expectorated sputum production, or requirement for mechanical ventilation / b. Hypoxemia (e.g., partial pressure of oxygen [PaO2] <60 mmHg while the subject is breathing room air, as determined by arterial blood gas [ABG], or worsening of the ratio of the PaO2 to the fraction of inspired oxygen [PaO2/FiO2]) / c. Need for acute changes in the ventilator support system to enhance oxygenation, as determined by worsening oxygenation (ABG or PaO2/FiO2) or needed changes in the amount of positive end-expiratory pressure / d. New onset of or increase in (characteristics or quantity) suctioned respiratory secretions, demonstrating evidence of inflammation and absence of contamination.
- All subjects must have at least 1 of the following signs and symptoms/laboratory abnormalities at screening: a. Documented fever (i.e., core body temperature [tympanic, rectal, esophageal] ≥38°C [100.4°F], oral temperature ≥37.5°C [99.5°F], or axillary temperature ≥37°C [98.6°F]) / b. Hypothermia (i.e., core body temperature [tympanic, rectal, esophageal] ≤35°C [95.0°F], oral temperature ≤35.5°C [95.9°F] and axillary temperature ≤36°C [96.8°F]) / c. Leukocytosis with a total peripheral white blood cell (WBC) count ≥10,000 cells/mm^3 / d. Leukopenia with total peripheral WBC count <4500 cells/mm^3 / e. Greater than 15% immature neutrophils (bands) noted on peripheral blood smear.
- All subjects must have a chest radiograph during screening or have a previous chest radiograph within 48 hours prior to randomization showing the presence of new or progressive infiltrate(s) suggestive of bacterial pneumonia. A computed tomography scan in the same time window showing the same findings could also be acceptable.
- All subjects must have a suspected Gram-negative infection involving the lower respiratory tract by 1 or more of the following: a. Gram stain of lower respiratory tract secretions showing Gram-negative bacteria, either alone or mixed with Gram-positive bacteria at or within 48 hours prior to randomization / b. Microbiologic culture of lower respiratory tract secretions within 48 hours prior to randomization identifying Gram-negative aerobic bacteria / c. Other diagnostic tests, including molecular tests, which provide evidence of Gram-negative bacterial infection of the lower respiratory tract / d. Pneumonia highly suspected to be due to Gram-negative bacteria based on sites of primary infection, prior antibiotic use, or local epidemiologic evidence of Gram-negative infection outbreak.
- Agree to allow any bacterial isolates obtained from protocol-required specimens related to the current infection to be provided to the Central Microbiology Reference Laboratory for study-related microbiological testing, long-term storage, and other future testing.
- Female subjects of childbearing potential, who are willing to use a highly effective method of birth control during the study and for at least 30 days following the last dose of study medication. a. Childbearing potential is defined as any female who has experienced menarche and does not meet the criteria for postmenopausal, which is defined as the past 12 months with no menses without an alternative medical cause or permanently sterilized (e.g., has undergone bilateral tubal occlusion/ligation, hysterectomy, bilateral oophorectomy, bilateral salpingectomy) / b. A highly effective method of birth control is defined as one that results in a low failure rate (i.e., <1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, intrauterine devices, sexual abstinence, or a vasectomized partner.
- Male subjects with female sexual partners of childbearing potential are eligible for inclusion if they agree to use medically acceptable birth control for 90 days following the last dose of study medication. Sexual abstinence, vasectomy, or a condom used with a spermicide are medically acceptable birth control methods for males. Male subjects must agree not to donate sperm for a period of 90 days after the last dose of study treatment.
Exclusion Criteria
- If a Gram stain from a respiratory sample is available and shows only Gram-positive cocci.
- Subjects who have known or suspected community-acquired bacterial pneumonia, atypical pneumonia, viral pneumonia including Coronavirus disease (COVID-19), or chemical pneumonia (including aspiration of gastric contents, inhalation injury).
- Subjects who have HABP/VABP caused by an obstructive process, including lung cancer (or other malignancy metastatic to the lungs resulting in pulmonary obstruction) or other known obstruction.
- Have received effective systemic and inhaled Gram-negative antibacterial drug therapy for the index infection of HABP/VABP for a continuous duration of more than 24 hours during the previous 72 hours prior to randomization. NOTE: Subjects who have objective documentation of clinical failure (i.e., have persistent/worsening signs and/or symptoms of HABP/VABP at screening) while receiving any duration of prior antibacterial drug therapy for the treatment of HABP/VABP can be enrolled.
- Has a concurrent condition or infection that, in the investigator's judgment, would preclude evaluation of therapeutic response (e.g., active tuberculosis, cystic fibrosis, granulomatous disease, a disseminated fungal infection, invasive fungal pulmonary infection, or endocarditis).
- Subjects who have central nervous system infection (e.g., meningitis, brain abscess, shunt infection).
- Documented presence of immunodeficiency or an immunocompromised condition including hematologic malignancy, bone marrow transplant, known history of human immunodeficiency virus infection with a CD4 count <200/mm^3, or requiring frequent or prolonged use of systemic corticosteroids (≥20 mg of prednisone/day or equivalent for >4 weeks) or other immunosuppressive drugs (e.g., for organ transplantation or autoimmune conditions).
- Documented hypersensitivity to any carbapenem antibacterial agent or documented severe hypersensitivity to any other type of β-lactam antibacterial agent, or previous severe adverse drug reaction to any β-lactam antibiotics, or any of the excipients used in the study drug formulations.
- History of a seizure disorder (requiring ongoing treatment with anti-convulsive therapy or prior treatment with anti-convulsive therapy within the last 3 years).
- Renal function at screening as estimated glomerular filtration rate (eGFR) <15 mL/min or ＞250 mL/min, calculated as individual eGFR derived from Modification of Diet in Renal Disease formula.
- Subject is receiving hemodialysis or peritoneal dialysis or micro-dialysis or continuous venovenous hemofiltration or continuous venovenous hemodialysis.
- Subject is anticipated to be treated with any of the following medications during the course of study therapy: a. Valproic acid or divalproex sodium (or has used valproic acid or divalproex sodium in the 2 weeks prior to screening) NOTE: Subjects who are receiving valproic acid or divalproex sodium for seizure prophylaxis (e.g. for head trauma) without history of seizure disorder may be enrolled as judged by the investigator / b. Concomitant systemic (IV or oral) Gram-negative antibacterial agents in addition to those designated in the study treatment groups / c. Concomitant systemic (IV or oral) antifungal or antiviral therapy for the index infection of HABP/VABP.
- Life expectancy is <3 days.
- Subjects in refractory septic shock, defined as persistent hypotension despite adequate fluid resuscitation and vasopressive therapy at the time of randomization.
- Subjects with 1 or more of the following laboratory abnormalities in baseline specimens: aspartate aminotransferase, alanine aminotransferase >3 × the upper limit of normal (ULN), total bilirubin level >2 × ULN (except for isolated hyperbilirubinemia due to known Gilbert’s disease), neutrophils <500 cells/mm^3, platelet count <40,000/mm^3.
- History of active liver disease or cirrhosis.
- Subjects with an APACHE II score of >30.
- A female who is pregnant or breastfeeding or has a positive pregnancy test at screening.
- Subject is participating in any clinical study of any investigational medication (i.e., non-licensed medication) during the 30 days prior to randomization. COVID-19 vaccines that are given under emergency use authorization are not considered investigational agents.
- Any other condition or prior therapy, which, in the opinion of the investigator, would make the subject unsuitable for this study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 01 Jun 2023 | 35 |
 Spain | Not Recruiting | 01 Jun 2023 | 23 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
XNW4107 | Test | INJECTION | INTRAVENOUS INFUSION | 1 | 14 | PRD10089689 |
IMIPENEM | Test | — | INTRAVENOUS INFUSION | 2 | 14 | SUB08151MIG |
CILASTATIN | Test | — | INTRAVENOUS INFUSION | 2 | 14 | SUB06264MIG |
RECARBRIO | Comparator | POWDER FOR INJECTION | INTRAVENOUS INFUSION | 5 | 14 | PRD10147247 |