Study to Assess the Efficacy and Safety of Cefepime/Nacubactam and Aztreonam/Nacubactam Versus Best Available Therapy in Adults With Complicated Urinary Tract Infection, Acute Uncomplicated Pyelonephritis, Hospital-Acquired Bacterial Pneumonia, Ventilator-Associated Bacterial Pneumonia, and Complicated Intra-Abdominal Infection due to Carbapenem-Resistant Enterobacterales

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Meiji Seika Pharma Co. Ltd.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

Trial duration

26 Jun 2023 → 2 Mar 2026

Decision date (initial)

2024-08-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Japan Agency for Medical Research and Development

External identifiers

EU CT number

2024-515180-56-00

EudraCT number

2021-001396-16

WHO UTN

U1111-1308-6461

ClinicalTrials.gov

NCT05905055

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Therapy, Pharmacodynamic, Safety

1. To assess the efficacy of cefepime/nacubactam and aztreonam/nacubactam administered by intravenous (IV) infusion using the composite endpoint of overall treatment success across all infection types (ie, cUTI, AP, HABP, VABP, and cIAI) due to carbapenemresistant Enterobacterales (CRE); and
2. To assess the safety of cefepime/nacubactam and aztreonam/nacubactam administered by IV infusion.

Secondary objectives 4

1. To assess the efficacy of cefepime/nacubactam and aztreonam/nacubactam administered by IV infusion in patients with secondary bacteremia due to each infection type (ie, cUTI, AP, HABP, VABP, and cIAI)
2. To assess the efficacy of cefepime/nacubactam and aztreonam/nacubactam administered by IV infusion in each infection type (ie, cUTI, AP, HABP, VABP, and cIAI) due to CRE
3. To assess the pharmacokinetics (PK) of cefepime/nacubactam and aztreonam/nacubactam administered by IV infusion in each infection type (ie, cUTI, AP, HABP, VABP, and cIAI)
4. To assess the clinical and microbiological response of cefepime/nacubactam and aztreonam/nacubactam administered by IV infusion per type of pathogen, type of resistance, and antimicrobial susceptibility

Conditions and MedDRA coding

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)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. 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
2. Weight ≤ 140 kg
3. 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;
4. Note: Complete list of inclusion criteria is in the protocol.

Exclusion criteria 4

1. 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
2. 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.
3. Has only a Gram-positive organism pathogen isolated from studyqualifying culture
4. Note: Complete list of exclusion criteria is in the protocol.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary efficacy endpoint is the proportion of patients with overall treatment success at TOC across all infection types (ie, cUTI, AP, HABP, VABP, and cIAI), which is a composite endpoint derived from the efficacy outcomes of each infection type. This is the proportion of patients in the Microbiological CRE Modified Intent to-Treat (mCRE-MITT) Population with a treatment outcome of success.

Secondary endpoints 1

1. Secondary efficacy endpoints across all infection types, for individual infection type and across all infection types, for cUTI/AP only, for HABP/VABP only, or cIAI only, for secondary bacteremia only are included in study protocol

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Comparator 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Meiji Seika Pharma Co. Ltd.

Sponsor organisation

Meiji Seika Pharma Co. Ltd.

Address

4-16 Kyobashi 2-chome Chuo-ku

City

Chuo

Postcode

104-8002

Country

Japan

Scientific contact point

Organisation

Meiji Seika Pharma Co. Ltd.

Contact name

Regulatory Submissions

Public contact point

Organisation

Meiji Seika Pharma Co. Ltd.

Contact name

Regulatory Submissions

Third parties 7

Locations

7 EU/EEA countries · 16 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 56 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications