Complicated Urinary Tract Infection, Acute Pyelonephritis, Hospital-acquired Bacterial Pneumonia, Ventilator-associated Bacterial Pneumonia, Complicated Intra-abdominal Infection
Conditions
Keywords
nacubactam, OP0595, Integral-2
Brief summary
This study is a multi-center, randomized, single-blind, parallel-group study to assess the efficacy and safety, when nacubactam is coadministered with cefepime or aztreonam, compared with best available therapy (BAT), in the treatment of patients with cUTI, AP, HABP, VABP, and cIAI, due to Carbapenem Resistant Enterobacterales.
Interventions
2 g cefepime and 1 g nacubactam every 8 hours for at least 5 days and up to 14 days via IV infusion over a period of 60 minutes
2 g aztreonam and 1 g nacubactam every 8 hours for at least 5 days and up to 14 days via IV infusion over a period of 60 minutes
DRUGBAT
Dosage of BAT will be based per site's standard of care
Sponsors
Meiji Seika Pharma Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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 most 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； 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 MIC at least 2 microg/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 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.
Exclusion criteria
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 BLIs (eg, tazobactam, sulbactam, or clavulanic acid) 2. Has known or suspected single or concurrent infection with Acinetobacter spp., metallo-β-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 BAT if anaerobic coverage is deemed necessary 3. Has only a Gram-positive organism pathogen isolated from study-qualifying culture;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | TOC (Test of Cure visit): 7 [±2] days after EOT (end of treatment) [Day 10 to 23 after the start of treatment] | For cUTI and AP, the composite clinical outcome of cure and the microbiological outcome of eradication are defined as the outcome of cure. For HABP and VABP, the clinical success is defined as the outcome of cure. For cIAI, the clincal success is defined as the outcome of cure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The proportion of patients with overall treatment outcome of success across all infection types | Outcome measurements were assessed at various visits: EA (Earlly Assessment): Day 3 to 5 days, EOT: (End of Treatment): Day 5 to Day 14, FUP (Follow-Up visit): Day 17 to Day 30 | Overall treatment success was defined according to infection type. For cUTI/AP, it was defined as the composite of clinical outcome of cure and microbiological outcome of eradication. For HABP/VABP and cIAI, it was defined as clinical outcome of cure alone. |
| The proportion of patients with a clinical outcome of cure per type of resistance | 7 [±2] days after EOT [Day 10 to 23] | Assessment of clinical outcome was based on the Investigator's evaluation of the patient's clinical signs and symptoms, with cure defined as the complete resolution (or return to premorbid state) of the baseline signs and symptoms present at screening, such that no further antimicrobial therapy is warranted. For this endpoint, results were summarized per type of resistance. |
| The proportion of patients with a microbiological outcome of eradication per type of pathogen and per type of resistance | 7 [±2] days after EOT [Day 10 to 23] | For cUTI/AP, microbiological outcome was determined programmatically based on quantitative microbiological urine cultures, with eradication defined as the pathogen found at screening with 10\^5 CFU/ml or more reduced to less than 10\^3 CFU/ml. For HABP/VABP and cIAI, eradication was defined as the absence of the baseline Gram-negative pathogen(s) on repeat culture, or presumed eradication, which is no culture was done and the patient meets the clinical criteria for clinical cure. The results of subgroup analyses for only the three most frequent pathogens were shown because there were a large number of pathogen types, most of which were rare and sparsely represented in the dataset. |
| The all-cause mortality rate at Day 28 by each infection type (ie, cUTI/AP, HABP/VABP, or cIAI) and across all infection types | Day 28 (+ 2days) | The all-cause mortality rate at Day 28 was calculated as the percentage of participants who experienced mortality regardless of the cause at or before Day 28. |
| The proportion of patients with a clinical outcome of cure by each infection type (ie, cUTI/AP, HABP/VABP, or cIAI) and across all infection types | 7 [±2] days after EOT [Day 10 to 23] | Assessment of clinical outcome was based on the Investigator's evaluation of the patient's clinical signs and symptoms, with cure defined as the complete resolution (or return to premorbid state) of the baseline signs and symptoms present at screening, such that no further antimicrobial therapy is warranted. Results were summarized by each infection type (ie, cUTI/AP, HABP/VABP, or cIAI) and across all infection types. |
| The proportion of patients with a microbiological outcome of eradication (including presumed eradication) by each infection type (ie, cUTI/AP, HABP/VABP, or cIAI) and across all infection types | 7 [±2] days after EOT [Day 10 to 23] | For cUTI/AP, microbiological outcome was determined programmatically based on quantitative microbiological urine cultures, with eradication defined as the pathogen found at screening with 10\^5 CFU/ml or more reduced to less than 10\^3 CFU/ml. For HABP, VABP, and cIAI, eradication was defined as the absence of the baseline Gram-negative pathogen(s) on repeat culture, or presumed eradication, which is no culture was done and the patient meets the clinical criteria for clinical cure. Results were summarized by each infection type (ie, cUTI/AP, HABP/VABP, or cIAI) and across all infection types. |
| The proportion of patients with composite clinical and microbiological success for cUTI/AP patients | 7 [±2] days after EOT [Day 10 to 23] | Composite clinical and microbiological success is defined as the composite clinical outcome of cure and the microbiological outcome of eradication. Assessment of clinical outcome was based on Investigator's evaluation of the patient's clinical signs and symptoms, with cure defined as the complete resolution (or return to premorbid state) of the baseline signs and symptoms of cUTI or AP that were present at screening, such that no further antimicrobial therapy is warranted. Microbiological outcome was determined programmatically based on quantitative microbiological urine cultures, with eradication defined as the pathogen found at screening with 10\^5 CFU/ml or more reduced to less than 10\^3 CFU/ml. |
| The proportion of patients with composite clinical outcome of recurrence and/or microbiological outcome of recurrence at the FUP for cUTI/AP patients | 14 [±2] days after EOT [Day 17 to Day 30] | Composite clinical and microbiological success is defined as the composite clinical outcome of cure and the microbiological outcome of eradication. Assessment of clinical outcome was based on Investigator's evaluation of the patient's clinical signs and symptoms, with cure defined as the complete resolution (or return to premorbid state) of the baseline signs and symptoms of cUTI or AP that were present at screening, such that no further antimicrobial therapy is warranted. Microbiological outcome was determined programmatically based on quantitative microbiological urine cultures, with eradication defined as the pathogen found at screening with 10\^5 CFU/ml or more reduced to less than 10\^3 CFU/ml. |
| Change in the partial pressure of oxygen to FiO2 ratio from baseline to EOT for HABP/VABP patients | EOT [Day 5 to Day 16] | The partial pressure oxygen to fraction of inspired oxygen ratio at baseline and EOT and change from baseline is summarized by treatment group. |
| Time (days) to extubation in patients who are on the ventilator at baseline for HABP/VABP patients | Up to EOT [Day 5 to Day 16] | Time to extubation was defined as number of days from the date of the first dose of study drug to the last date at which the ventilator was removed. Kaplan-Meier estimates were used for the analysis of time to extubation for each treatment group, and hazard ratios along with 95% CI was used to analyze time to extubation differences between treatment groups. Patients who were on the ventilator at baseline but discontinued from the study without extubation were considered censored. |
| The proportion of patients with clinical outcome of recurrence at the FUP for HABP/VABP patients | 14 [±2] days after EOT [Day 17 to Day 30] | Clinical Outcome of Recurrence is defined as the reappearance of baseline clinical signs and symptoms at the Follow-up (FUP) visit after a prior assessment of cure. |
| The proportion of patients with clinical outcome of recurrence at the FUP for cIAI patients | 14 [±2] days after EOT [Day 17 to Day 30] | Clinical Outcome of Recurrence is defined as the reappearance of baseline clinical signs and symptoms at the Follow-up (FUP) visit after a prior assessment of cure. |
| The all-cause mortality rate at Day 28 for secondary bacteremia patients | Day 28 (+ 2days) | The all-cause mortality rate at Day 28 was calculated as the percentage of participants who experienced mortality regardless of the cause at or before Day 28. |
| The proportion of patients with overall treatment success across all infection types at TOC for secondary bacteremia patients | 7 [±2] days after EOT [Day 10 to 23] | Patients with isolation of a gram-negative bacteria from at least 1 blood culture at baseline and this isolated pathogen is also identified from the site of infection and signs and symptoms of secondary bacteremia were determined programmatically as secondary bacteremia. Overall treatment success was defined according to infection type. For cUTI/AP, it was defined as the composite of clinical outcome of cure and microbiological outcome of eradication. For HABP, VABP, and cIAI, it was defined as clinical outcome of cure alone. |
| The proportion of patients with a clinical outcome of cure across all infection types at TOC for secondary bacteremia patients | 7 [±2] days after EOT [Day 10 to 23] | Patients with isolation of a gram-negative bacteria from at least 1 blood culture at baseline and this isolated pathogen is also identified from the site of infection and signs and symptoms of secondary bacteremia were determined programmatically as secondary bacteremia. Assessment of clinical outcome was based on the Investigator's evaluation of the patient's clinical signs and symptoms, with cure defined as the complete resolution (or return to premorbid state) of the baseline signs and symptoms present at screening, such that no further antimicrobial therapy is warranted. |
| The proportion of patients with a microbiological outcome of eradication across all infection types at TOC for secondary bacteremia patients | 7 [±2] days after EOT [Day 10 to 23] | Patients with isolation of a gram-negative bacteria from at least 1 blood culture at baseline and this isolated pathogen is also identified from the site of infection and signs and symptoms of secondary bacteremia were determined programmatically as secondary bacteremia. Microbiological outcome will be determined programmatically based on blood cultures, with eradication defined as the pathogen found at screening is negative in blood culture. |
| The proportion of patients with a clinical outcome of cure from secondary bacteremia at TOC for secondary bacteremia patients | 7 [±2] days after EOT [Day 10 to 23] | Patients with isolation of a gram-negative bacteria from at least 1 blood culture at baseline and this isolated pathogen is also identified from the site of infection and signs and symptoms of secondary bacteremia were determined programmatically as secondary bacteremia. Clinical outcome of cure from secondary bacteremia is defined as complete resolution or significant improvement of the baseline signs and symptoms of secondary bacteremia. |
| The proportion of patients with a microbiological outcome of eradication from secondary bacteremia at TOC for secondary bacteremia patients | 7 [±2] days after EOT [Day 10 to 23] | Patients with isolation of a gram-negative bacteria from at least 1 blood culture at baseline and this isolated pathogen is also identified from the site of infection and signs and symptoms of secondary bacteremia were determined programmatically as secondary bacteremia. Microbiological outcome will be determined programmatically based on blood cultures, with eradication defined as the pathogen found at screening is negative in blood culture. |
| The proportion of patients who are free from secondary bacteremia at TOC for secondary bacteremia patients | 7 [±2] days after EOT [Day 10 to 23] | Patients with isolation of a gram-negative bacteria from at least 1 blood culture at baseline and this isolated pathogen is also identified from the site of infection and signs and symptoms of secondary bacteremia were determined programmatically as secondary bacteremia. Both clinical outcome and microbiological outcome were evaluated in patients with secondary bacteremia. Assessment of clinical outcome was based on signs and symptoms, with cure defined as complete resolution or significant improvement of the baseline signs and symptoms of secondary bacteremia. Microbiological outcome will be determined programmatically based on blood cultures, with eradication defined as the pathogen found at screening is negative in blood culture. |
| Total ventilator days measured from time of randomization to EOT for HABP/VABP patients | EOT [Day 5 to Day 16] | Total ventilator days are defined as number of days from the date of randomization to the date at which the ventilator is removed or date of end of treatment, whichever is earlier. |
| The proportion of patients free from the definition of secondary bacteremia and a clinical outcome of cure across all infection types and a microbiological outcome of eradication from all infection types at TOC for secondary bacteremia patients | 7 [±2] days after EOT [Day 10 to 23] | Patients with isolation of a gram-negative bacteria from at least 1 blood culture at baseline and this isolated pathogen is also identified from the site of infection and signs and symptoms of secondary bacteremia were determined programmatically as secondary bacteremia. For assessment of cUTI/AP, HABP/VABP, cIAI is done by the same way as clinical outcome and microbiological outcome. For secondary bacteremia, assessment of clinical outcome was based on signs and symptoms, with cure defined as complete resolution or significant improvement of the baseline signs and symptoms of secondary bacteremia. Microbiological outcome will be determined programmatically based on blood cultures, with eradication defined as the pathogen found at screening is negative in blood culture. |
Countries
China, Croatia, Czechia, France, Georgia, Greece, Israel, Japan, Latvia, Slovakia, Spain, Taiwan, Thailand, Turkey (Türkiye)
Outcome results
None listed