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A Phase 3, Multi-Center, Randomized, Single-Blind 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 (Integral-2)

P3 Study to assess efficacy and safety of Cefepime/Nacubactam and Aztreonam/Nacubactam Versus Best Available Therapy for Adults With Infection due to Carbapenem Resistant Enterobacterales

Suwada Keisuke

Meiji Seika Pharma Co.,Ltd.

2-4-16, Kyobashi, Chuo-ku, Tokyo

clinical-trials@meiji.com

Clinical Development Dept.

Meiji Seika Pharma Co.,Ltd.

2-4-16, Kyobashi, Chuo-ku, Tokyo

+81-3-3273-3745

clinical-trials@meiji.com

Complete

May. 29, 2023

Interventional

randomized controlled trial

single blind

active control

parallel assignment

treatment purpose

1. Male or female patients at least 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 at most140 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 based on evidence from CRE culture and susceptibility testing or other phenotypic or molecular testing within 72 hours (or 96 hours for cIAI) prior to the first dose, alone or as a single isolate of a polymicrobial infection; 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;
OR
ii. Has a known CRE infection based on evidence from CRE culture and susceptibility testing or other phenotypic or molecular testing within 72 hours (or 96 hours for cIAI) prior to the first dose, alone or as a single isolate of a polymicrobial infection; 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;
b. For suspected CRE infection, meets the following (i or ii):
i. Has a suspected CRE infection based on evidence from CRE culture and susceptibility testing or other phenotypic or molecular testing, alone or as a single isolate of a polymicrobial infection, from any source within 90 days prior to Day 1; 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;
OR
ii. Has a suspected CRE infection based on evidence from CRE culture and susceptibility testing or other phenotypic or molecular testing, alone or as a single isolate of a polymicrobial infection, from any source within 90 days prior to Day 1; 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;
Note: CRE is defined as Enterobacterales by susceptibility data of minimum inhibitory concentration (MIC) at least 2 micro g/mL to imipenem or meropenem OR imipenem or meropenem disk diffusion (zone diameter less than 22 mm). If MIC or disk diffusion data are not available in the local laboratory or before the availability of MIC or disk diffusion results, each site can use other methods and criteria in the institution (eg, phenotypic or molecular testing) as the initial evidence of CRE for enrollment. In any case, pathogen identification and susceptibility testing performed at the central laboratory will be used to determine CRE in the final study analysis.

1. Has a history of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious allergic reaction to carbapenems, cephems, penicillins, other beta-lactam antibiotics, or any beta-lactamase inhibitors (eg, tazobactam, sulbactam, or clavulanic acid);
2. Has known or suspected single or concurrent infection with Acinetobacter spp., metallo-beta-lactamase (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 co-infected 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.
3. Has only a Gram-positive organism pathogen isolated from study-qualifying culture;

Both

cUTI, AP, HABP, VABP, cIAI

Patients will receive either cefepime 2 g/nacubactam 1 g or aztreonam 2 g/nacubactam 1 g every 8 hours (plus or minus 1 hour) for at least 5 days and up to 14 days or BAT, if CrCl is at least 60 and less than 120 mL/min. Study drug will be administered via IV infusion over a period of 60 minutes (plus or minus 15 minutes).
If CrCl is less than 30 mL/min, patients will receive cefepime 1 g/nacubactam 0.5 g or aztreonam 1 g/nacubactam 0.5 g every 12 hours. If CrCl is at least 30 and less than 60 mL/min, patients will receive cefepime 1 g/nacubactam 0.5 g or aztreonam 1 g/nacubactam 0.5 g every 8 hours. If CrCl is at least 60 and at most 240 mL/min, patients will receive cefepime 2 g/nacubactam 1 g every 8 hours or aztreonam 2 g/nacubactam 1 g every 8 hours. Patients treated with hemodialysis will receive cefepime 1 g/nacubactam 0.5 g or aztreonam 1 g/nacubactam 0.5 g every 12 hours and intermittent hemodialysis should be conducted just before study drug administration. Dosage of BAT will be based per standard of care of site.

OP0595, nacubactam, CRE

Efficacy: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.
Safety:The safety parameters include the incidence, severity, causality, and seriousness of TEAEs, and the evaluation of changes from baseline in safety laboratory test results, 12-lead ECGs, vital signs, and physical examinations.

+81-3-5712-5050

Mar. 06, 2023

No

Israel/Georgia/Turkey/Croatia/Czech Republic/Greece/Latvia/Slovakia/Spain/France/Taiwan/Thailand/China