Efficacy and Safety of Cefepime/Nacubactam or Aztreonam/Nacubactam Compared to Imipenem/Cilastatin in Subjects With Complicated Urinary Tract Infections or Acute Uncomplicated Pyelonephritis

Meiji Seika Pharma Co., Ltd.614 enrolled

Overview

Phase 3 study to evaluate the efficacy and safety of cefepime/nacubactam or aztreonam/nacubactam compared to imipenem/cilastatin in the treatment of complicated urinary tract infections (cUTI) or acute uncomplicated pyelonephritis (AP).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

614

Conditions

Complicated Urinary Tract Infection Acute Pyelonephritis cUTI AP

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Male or female patients at least18 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. Expectation, in the opinion of the Investigator, that the patient's cUTI or AP will require treatment with at least 5 days of IV antibiotics; Exclusion Criteria: 1. Has a known imipenem- and/or meropenem-resistant Gram-negative uropathogen (at least 10\^5 CFU/mL), isolated from study-qualifying urine culture; Note: If after randomization the susceptibility testing indicates resistance to imipenem and/or meropenem, the patient may remain on the study drug at the Investigator's discretion. 2. Has known or suspected single or concurrent infection with Acinetobacter spp. or other organisms that are not adequately covered by the study drug (eg, concurrent viral, mycobacterial, or fungal infection) and needs to be managed with other anti-infectives; Note: Patients with qualifying pathogen 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 Investigator's discretion. 3. Has only a known Gram-positive primary uropathogen (at least 10\^5 CFU/mL), isolated from study qualifying urine culture;

Locations (61)

Meiji Research Site

Pleven, Bulgaria

Meiji Research Site

Rousse, Bulgaria

Meiji Research Site

Silistra, Bulgaria

Meiji Research Site

Sofia, Bulgaria

Meiji Research Site

Beijing, China

Meiji Research Site

Changchun, China

Outcomes

Primary Outcomes

Proportion of Patients Who Achieve Composite Clinical and Microbiological Success at TOC (Test of Cure Visit) in the Microbiological Modified Intent-to-Treat (m-MITT) Population

Composite clinical and microbiological success is defined as the composite clinical outcome of cure and the microbiological outcome of eradication.

Time frame: TOC (Test of Cure visit): 7 [±2] days after EOT (end of treatment) [Day 10 to 23 after the start of treatment]

Secondary Outcomes

Proportion of Patients Who Achieve Composite Clinical and Microbiological Outcome

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 results of subgroup analyses for only the two 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.

Time frame: Outcome measurements were assessed at various visits: EA (Earlly Assessment): Day4, EOT (End of Treatment): Day5 to Day14, TOC (Test of Cure visit): Day10 to Day 23, FUP (Follow-Up visit): Day17 to Day30

Proportion of Patients With a Clinical Outcome of Cure

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. The results of subgroup analyses for only the two 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.

Proportion of Patients With a Microbiological Outcome of Eradication

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 results of subgroup analyses for only the two 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.

Proportion of Patients With a Clinical Outcome of Cure at TOC in Patients With Secondary Bacteremia at Baseline

Time frame: TOC (Test of Cure visit): Day 10 to Day 23 after the start of treatment

Proportion of Patients With a Microbiological Outcome of Eradication at TOC in Patients With Secondary Bacteremia at Baseline

Time frame: TOC (Test of Cure visit): Day 10 to Day 23 after the start of treatment

Proportion of Patients Who Are Free From the Definition of Secondary Bacteremia AND a Clinical Outcome of Cure AND a Microbiological Outcome of Eradication From cUTI or AP at TOC in Patients With Secondary Bacteremia at Baseline

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 cUTI/AP,Assessment is done by the same way as "Proportion of patients who achieve composite clinical 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.

Time frame: TOC (Test of Cure visit): Day 10 to Day 23 after the start of treatment

Proportion of Patients Who Are Free From Secondary Bacteremia in Patients With Secondary Bacteremia at TOC

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 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.

Time frame: TOC (Test of Cure visit): Day 10 to Day 23 after the start of treatment