Efficacy and Safety of Cefepime/Nacubactam and Aztreonam/Nacubactam in Adults with CRE-Related Complicated Infections
- Trial ID
- 2024-515180-56-00
- Protocol
- OP0595-6
- Sponsor
- Meiji Seika Pharma Co. Ltd.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** and **safety** of cefepime/nacubactam and aztreonam/nacubactam administered by intravenous infusion. This evaluation is based on the composite endpoint of overall treatment success across all infection types, including complicated urinary tract infection (cUTI), acute uncomplicated pyelonephritis (AP), hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), and complicated intra-abdominal infection (cIAI) due to carbapenem-resistant Enterobacterales (CRE). The clinical relevance of this objective lies in addressing the challenge of treating infections caused by CRE, which are known for their resistance to multiple antibiotics, thereby posing significant treatment difficulties and increasing morbidity and mortality rates.
Secondary objectives include:
- Assessing the efficacy of cefepime/nacubactam and aztreonam/nacubactam in patients with secondary bacteremia due to each infection type.
- Evaluating the efficacy of these combinations in each infection type due to CRE.
- Investigating the pharmacokinetics of cefepime/nacubactam and aztreonam/nacubactam in each infection type.
- Assessing the clinical and microbiological response of these combinations per type of pathogen, type of resistance, and antimicrobial susceptibility.
Participants
The clinical trial involves a total of **54 participants** who are both male and female, aged 18 years and older. The study population includes individuals with medical conditions such as **complicated urinary tract infection (cUTI)**, acute uncomplicated pyelonephritis (AP), hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), and complicated intra-abdominal infection (cIAI). Participants were selected based on specific criteria, including the presence of carbapenem-resistant Enterobacterales (CRE) infections, and the ability to be hospitalized throughout the treatment period. The trial includes a vulnerable population, and participants must weigh 140 kg or less. Lifestyle factors such as diet and physical activity are not specified in the available data. The selection process ensures that participants have either a known or suspected CRE infection, with evidence from culture and susceptibility testing, and have met certain clinical criteria regarding previous antimicrobial treatment.
Plans and Procedures
The clinical trial is a **Phase 3**, multi-center, randomized, single-blind study designed to evaluate the efficacy and safety of **Cefepime/Nacubactam** and **Aztreonam/Nacubactam** compared to the best available therapy in adults with complicated urinary tract infection (cUTI), acute uncomplicated pyelonephritis (AP), hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), and complicated intra-abdominal infection (cIAI) due to carbapenem-resistant Enterobacterales. The trial is expected to commence recruitment on September 22, 2023, and conclude by March 31, 2025. The study involves intravenous administration of the investigational drugs over a maximum treatment period of 14 days.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, weight, and evidence of infection. The primary inclusion criteria require participants to be at least 18 years old and able to be hospitalized throughout the treatment period. The screening visit will also confirm the presence of a known or suspected CRE infection. Following the screening, participants will be randomized to receive either the investigational drugs or the best available therapy. The trial design ensures that neither the participants nor the investigators are aware of the treatment allocation, maintaining the single-blind nature of the study.
Throughout the trial, participants will attend follow-up visits to monitor treatment efficacy and safety. The primary efficacy endpoint is the proportion of patients achieving overall treatment success at the test-of-cure (TOC) visit across all infection types. Secondary endpoints will assess efficacy across individual infection types and other specific conditions. The end-of-study visit will occur after the treatment period to evaluate the final outcomes and any adverse events. Participant involvement is expected to last up to 14 days, with conditions for early termination including significant adverse reactions or withdrawal of consent.
Treatment
The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Tigecycline** is administered in a pharmaceutical form identified as PHF00200MIG. It is delivered intravenously with a maximum daily dose of 103.57 mg and a total maximum dose of 1450 mg over a treatment period of 14 days. **Amikacin sulfate** is provided in the form PHF00231MIG, also administered intravenously, with a maximum daily dose of 1.5 g and a total maximum dose of 21 g over the same treatment period.
**Cefepime**, marketed as Cefepime Panpharma, is supplied as a powder for solution for injection or infusion. It is administered intravenously with a maximum daily dose of 6 g and a total maximum dose of 84 g over 14 days. **Nacubactam** is provided as a powder for injection, with a maximum daily dose of 3 g and a total maximum dose of 42 g, administered intravenously over the same period.
The combination of **Imipenem, Cilastatin, and Relebactam** is delivered in the form PHF00230MIG, administered intravenously, with a maximum daily dose of 5 g and a total maximum dose of 70 g over 14 days. **Colistin** is administered in the form PHF00110MIG, with a maximum daily dose of 12 million IU and a total maximum dose of 168 million IU, also over 14 days.
**Aztreonam**, marketed as Azactam, is provided as a powder for solution for injection, administered intravenously with a maximum daily dose of 6 g and a total maximum dose of 84 g over the treatment period. All medications are administered intravenously, and participant compliance is monitored throughout the trial. The trial aims to assess the efficacy and safety of these treatments in adults with various infections, including complicated urinary tract infections and hospital-acquired bacterial pneumonia.
Efficacy
The efficacy of the clinical trial will be assessed using a composite endpoint of overall treatment success across all infection types, including complicated urinary tract infection (cUTI), acute uncomplicated pyelonephritis (AP), hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), and complicated intra-abdominal infection (cIAI) due to carbapenem-resistant Enterobacterales (CRE). The primary efficacy endpoint is the proportion of patients with overall treatment success at the test of cure (TOC) visit, which is derived from the efficacy outcomes of each infection type. This will be evaluated in the Microbiological CRE Modified Intent-to-Treat (mCRE-MITT) Population, focusing on patients with a treatment outcome of success.
Secondary efficacy endpoints will be assessed across all infection types, as well as for individual infection types, including cUTI/AP, HABP/VABP, cIAI, and secondary bacteremia. The study protocol includes detailed criteria for these secondary endpoints. The trial is designed as a Phase 3, multi-center, randomized, single-blind study, comparing the efficacy and safety of Cefepime/Nacubactam and Aztreonam/Nacubactam versus the best available therapy. The trial aims to provide comprehensive data on the efficacy of these treatments in adults with the specified infections.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female patients ≥ 18 years of age (or age of legal consent, whichever is older) at the time of obtaining informed consent and who can be hospitalized throughout the Treatment Period
- Weight ≤ 140 kg
- The following criteria must be satisfied: a. For known CRE infection, meets either of the following (i or ii): i. Has a known CRE infection, alone or as a single isolate of a polymicrobial infection, based on evidence from CRE culture, susceptibility testing, and possible carbapenemase phenotypic testing (or possible molecular testing) within 72 hours (or 96 hours for cIAI) prior to the first dose of study drug; AND Has received no more than 24 hours of an antimicrobial agent to which the known CRE is known to be susceptible within 72 hours (or 96 hours for cIAI) prior to the first dose of study drug; OR ii. Has a known CRE infection, alone or as a single isolate of a polymicrobial infection, based on evidence from CRE culture, susceptibility testing, and possible carbapenemase phenotypic testing (or possible molecular testing ) within 72 hours (or 96 hours for cIAI) prior to the first dose of study drug; AND Has documented clinical evidence of failure (ie, clinical deterioration or failure to improve) after at least 48 hours of treatment with an antimicrobial agent to which the known CRE is known to be susceptible within 72 hours (or 96 hours for cIAI) prior to the first dose of study drug; b. For suspected CRE infection, meets the following (i or ii): i. Has a suspected CRE infection, alone or as a single isolate of a polymicrobial infection, based on evidence which may be determined within 90 days prior to the first dose of study drug through rapid diagnostic tests, active surveillance cultures, other documentation of CRE colonization, or prior infection due to a CRE pathogen; AND Has received no more than 24 hours of empiric antimicrobial therapy for Gram-negative organisms within 72 hours (or 96 hours for cIAI) prior to the first dose of study drug; OR ii. Has a suspected CRE infection, alone or as a single isolate of a polymicrobial infection, based on evidence which may be determined within 90 days prior to the first dose of study drug through rapid diagnostic tests, active surveillance cultures, other documentation of CRE colonization, or prior infection due to a CRE pathogen; AND Has documented clinical evidence of failure (ie, clinical deterioration or failure to improve) after at least 48 hours of treatment with empiric antimicrobial therapy for Gram-negative organisms within 72 hours (or 96 hours for cIAI) prior to the first dose of study drug;
- Note: Complete list of inclusion criteria is in the protocol.
Exclusion Criteria
- Has a history of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious allergic reaction to carbapenems, cephems, penicillins, other B-lactam antibiotics, or any B-lactamase inhibitors (eg, tazobactam, sulbactam, or clavulanic acid) or to any of the excipients
- Has known or suspected single or concurrent infection with Acinetobacter spp., metallo-βlactamase (MBL) producing Pseudomonas aeruginosa, or other organisms that are not adequately covered by the study drug (eg, concurrent viral, mycobacterial, or fungal infection) and need to be managed with other anti-infectives; Note: Patients with qualifying Gram-negative pathogen coinfected (or suspected to be coinfected) with a Gram-positive pathogen may be administered narrow spectrum, open-label glycopeptide (eg, vancomycin), oxazolidinone (eg, linezolid), or daptomycin concomitantly with the study drug at the discretion of the Investigator. Patients with cIAI may receive metronidazole in addition to cefepime/nacubactam, aztreonam/nacubactam, or as part of best available therapy (BAT) if anaerobic coverage is deemed necessary. When these drugs are used as a concomitant drug, the Investigator should confirm the patient does not have hypersensitivity to that drug or excipient before use. Note: Patients in whom a carbapenem-resistant Pseudomonas aeruginosa is identified may be continued on the study drug only if the patient was (1) enrolled in this study as a suspected CRE, (2) the causative organism is found to be P. aeruginosa after randomization, (3) does not meet exclusion or discontinuation criteria, and (4) the patient is clinically improving on study drug.
- Has only a Gram-positive organism pathogen isolated from studyqualifying culture
- Note: Complete list of exclusion criteria is in the protocol.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Croatia | Not Recruiting | 22 Sept 2023 | 12 |
 Czechia | Not Recruiting | 22 Sept 2023 | 10 |
 France | Not Recruiting | 22 Sept 2023 | 28 |
 Greece | Not Recruiting | 22 Sept 2023 | 15 |
 Latvia | Not Recruiting | 22 Sept 2023 | 12 |
 Slovakia | Not Recruiting | 22 Sept 2023 | 7 |
 Spain | Not Recruiting | 22 Sept 2023 | 12 |
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 |
|---|---|---|---|---|---|---|
IMIPENEM, CILASTATIN AND RELEBACTAM | Comparator | PHF00230MIG | INTRAVENOUS USE | 5 | 14 | SCP40975146 |
AMIKACIN | Comparator | PHF00231MIG | INTRAVENOUS USE | 1.5 | 14 | SCP108746144 |
TIGECYCLINE | Comparator | PHF00200MIG | INTRAVENOUS USE | 103.57 | 14 | SCP236843 |
Nacubactam | Test | POWDER FOR INJECTION | INTRAVENOUS USE | 3 | 14 | PRD10351665 |
AZACTAM 1 g, poudre et solution pour usage parentéral | Test | POUDRE ET SOLUTION POUR USAGE PARENTÉRAL. | INTRAVENOUS USE | 6 | 14 | PRD10590282 |
COLISTIN | Comparator | PHF00110MIG | INTRAVENOUS USE | 12 | 14 | SCP105620723 |
Cefepime Panpharma, 2 g, proszek do sporządzania roztworu do wstrzykiwań lub infuzji | Test | PROSZEK DO SPORZĄDZANIA ROZTWORU DO WSTRZYKIWAŃ LUB INFUZJI | INTRAVENOUS USE | 6 | 14 | PRD2760505 |