| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | 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) | |
| E.1.1.1 | Medical condition in easily understood language | cUTI: occur in pre-existing metabolic, functional, or structural abnormalities of the urinary tract
AP: upper urinary tract infection
HAP: pneumonia occurs 48 hours or more after admission
| |
| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10080628 | | E.1.2 | Term | Complicated urinary tract infection | | E.1.2 | System Organ Class | 10021881 - Infections and infestations | |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10079985 | | E.1.2 | Term | Uncomplicated pyelonephritis | | E.1.2 | System Organ Class | 10021881 - Infections and infestations | |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10081414 | | E.1.2 | Term | Ventilator associated bacterial pneumonia | | E.1.2 | System Organ Class | 10021881 - Infections and infestations | |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10079983 | | E.1.2 | Term | Complicated intra-abdominal infection | | E.1.2 | System Organ Class | 10021881 - Infections and infestations | |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10081416 | | E.1.2 | Term | Hospital acquired bacterial pneumonia | | E.1.2 | System Organ Class | 10021881 - Infections and infestations | |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | The primary objectives of this study are the following:
- 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 carbapenem-resistant Enterobacterales (CRE); and
- To assess the safety of cefepime/nacubactam and aztreonam/nacubactam administered by IV infusion.
| |
| E.2.2 | Secondary objectives of the trial | The secondary objectives of this study are the following:
- 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);
- 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;
- 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);
and
- 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. | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | Patients who meet all of the following criteria will be eligible to participate in the study:
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;
Note: CRE is defined as Enterobacterales by susceptibility data of minimum inhibitory concentration (MIC) ≥ 2 µg/mL to imipenem or meropenem OR imipenem or meropenem disk diffusion (zone diameter < 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 susceptibility testing and criteria in the institution 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.
Note: Complete list of inclusion criteria is in the protocol. | |
| E.4 | Principal exclusion criteria | Patients who meet any of the following criteria will be excluded from participation in the study:
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 study-qualifying culture;
Note: Complete list of exclusion criteria is in the protocol. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | 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.
| |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | Assessment of
- Clinical Signs and Symptoms
- Clinical Outcome: at EA, EOT, TOC, FUP, and ET
- Microbiology assessments:
Urine Culture: at Screening, prior to study drug administration on Day 1, EA, EOT, TOC, FUP (if clinically indicated), and ET.
Blood Culture: at Screening and prior to randomization on Day 1
Intra-abdominal cultures: during the time of surgical (or percutaneous) intervention (cIAI patients). Specimen collection as per Protocol
Respiratory tract specimens: taken within 72 hours prior to first dose of study drug
Other culture samples: within 72 hours prior to first dose of study drug (if a tissue sample (ie, kidney biopsy, lung biopsy) is collected)
- Composite Clinical Outcome of Cure and Microbiological Outcome of Eradication: at EA, EOT, TOC, FUP, and ET
| |
| E.5.2 | Secondary end point(s) | | Secondary efficacy endpoints across all infection types, for individual infection type and across all infection types, for c,UTI/AP only, for HABP/VABP only, or cIAI only, for secondary bacteremia only are included in study protocol | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | Assessments at EA, EOT, TOC, and the FUP (at different timepoints for the secondary efficacy endpoints)
| |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | Yes |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 | The trial involves single site in the Member State concerned | Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | Taiwan | | China | | Georgia | | Israel | | Japan | | Thailand | | Croatia | | Czechia | | France | | Greece | | Latvia | | Slovakia | | Spain | | Türkiye | |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
