Efficacy and Safety of Cefepime/Nacubactam or Aztreonam/Nacubactam Compared to Imipenem/Cilastatin in Subjects With Complicated Urinary Tract Infections or Acute Uncomplicated Pyelonephritis (Integral-1)

A Phase 3, Multi-Center, Randomized, Double-Blind 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 or Acute Uncomplicated Pyelonephritis, in Adults

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 Overview

• Status: Completed
• Conditions: Acute Pyelonephritis; Complicated Urinary Tract Infection; cUTI; AP
• Intervention / Treatment: Drug: co-administration of cefepime and nacubactam; Drug: co-administration of aztreonam and nacubactam; Drug: imipenem/cilastatin

• Study Type: Interventional
• Enrollment (Actual): 614
• Phase: Phase 3

Contacts and Locations

Study Locations

• Bulgaria
  • Pleven, Bulgaria
    • Meiji Research Site
  • Rousse, Bulgaria
    • Meiji Research Site
  • Silistra, Bulgaria
    • Meiji Research Site
  • Sofia, Bulgaria
    • Meiji Research Site
• China
  • Beijing, China
    • Meiji Research Site
  • Changchun, China
    • Meiji Research Site
  • Chongqing, China
    • Meiji Research Site
  • Fuyang, China
    • Meiji Research Site
  • Ganzhou, China
    • Meiji Research Site
  • Huaian, China
    • Meiji Research Site
  • Huzhou, China
    • Meiji Research Site
  • Nanchang, China
    • Meiji Research Site
  • Nanning, China
    • Meiji Research Site
  • Quanzhou, China
    • Meiji Research Site
  • Shanghai, China
    • Meiji Research Site
  • Shantou, China
    • Meiji Research Site
  • Shijiazhuang, China
    • Meiji Research Site
  • Taian, China
    • Meiji Research Site
  • Tianjin, China
    • Meiji Research Site
  • Xuancheng, China
    • Meiji Research Site
  • Yunnan, China
    • Meiji Research Site
  • Zhejiang, China
    • Meiji Research Site
  • Zhengzhou, China
    • Meiji Research Site
• Czechia
  • Hradec Králové, Czechia
    • Meiji Research Site
  • Liberec, Czechia
    • Meiji Research Site
  • Prague, Czechia
    • Meiji Research Site
  • Ústí nad Labem, Czechia
    • Meiji Research Site
• Estonia
  • Kohtla-Järve, Estonia
    • Meiji Research Site
  • Tallinn, Estonia
    • Meiji Research Site
  • Tartu, Estonia
    • Meiji Research Site
  • Võrumaa
    • Meegomäe, Võrumaa, Estonia
      • Meiji Research Site
• Georgia
  • Kutaisi, Georgia
    • Meiji Research Site
  • Rustavi, Georgia
    • Meiji Research Site
  • Tbilisi, Georgia
    • Meiji Research Site
• Japan
  • Fukuyama, Japan
    • Meiji Research Site
  • Gifu, Japan
    • Meiji Research Site
  • Ibaraki-Town, Higashiibaraki-County, Japan
    • Meiji Research Site
  • Iwakuni, Japan
    • Meiji Research Site
  • Kanazawa, Japan
    • Meiji Research Site
  • Kawachi-Nagano, Japan
    • Meiji Research Site
  • Kofu, Japan
    • Meiji Research Site
  • Kumamoto, Japan
    • Meiji Research Site
  • Matsumoto, Japan
    • Meiji Research Site
  • Mizumaki-Town, Onga-County, Japan
    • Meiji Research Site
  • Nagasaki, Japan
    • Meiji Research Site
  • Nankoku, Japan
    • Meiji Research Site
  • Sagamihara, Japan
    • Meiji Research Site
  • Sapporo, Japan
    • Meiji Research Site
  • Shinjuku-ku, Japan
    • Meiji Research Site
  • Toyota, Japan
    • Meiji Research Site
  • Ueda, Japan
    • Meiji Research Site
  • Yokohama, Japan
    • Meiji Research Site
  • Ōita, Japan
    • Meiji Research Site
  • Ōtake, Japan
    • Meiji Research Site
• Latvia
  • Riga, Latvia
    • Meiji Research Site
  • Valmiera, Latvia
    • Meiji Research Site
• Lithuania
  • Kaunas, Lithuania
    • Meiji Research Site
  • Vilnius, Lithuania
    • Meiji Research Site
• Slovakia
  • Galanta, Slovakia
    • Meiji Research Site
  • Rimavská Sobota, Slovakia
    • Meiji Research Site
  • Svidník, Slovakia
    • Meiji Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: co-administration of cefepime and nacubactam; co-administration of 2 g cefepime and 1 g nacubactam q8h (60 min. infusion)	Drug: co-administration of cefepime and nacubactam; 2 g cefepime and 1 g nacubactam
Experimental: co-administration of aztreonam and nacubactam; co-administration of 2 g aztreonam and 1 g nacubactam q8h (60 min. infusion)	Drug: co-administration of aztreonam and nacubactam; 2 g aztreonama and 1 g nacubactam
Active Comparator: imipenem/cilastatin; combination of 1 g imipenem/1 g cilastatin q8h (60 min. infusion)	Drug: imipenem/cilastatin; 1 g imipenem/1 g cilastatin

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients With a Clinical Outcome of Cure 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. 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.	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	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.	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.	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.	TOC (Test of Cure visit): Day 10 to Day 23 after the start of treatment
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.	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.	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 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.	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

Collaborators and Investigators

• Sponsor: Meiji Seika Pharma Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): May 23, 2023
• Primary Completion (Actual): November 22, 2024
• Study Completion (Actual): November 26, 2024

Study Registration Dates

• First Submitted: April 25, 2023
• First Submitted That Met QC Criteria: May 24, 2023
• First Posted (Actual): June 5, 2023

Study Record Updates

• Last Update Posted (Actual): December 24, 2025
• Last Update Submitted That Met QC Criteria: December 5, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: OP0595; nacubactam; Integral
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Disease Attributes; Nephritis; Nephritis, Interstitial; Pyelitis; Infections; Communicable Diseases; Urinary Tract Infections; Pyelonephritis; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pharmaceutical Preparations; Fatty Acids; Lipids; Hydrocarbons; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Amides; Drug Combinations; beta-Lactams; Lactams; Carbapenems; Thienamycins; Fatty Acids, Unsaturated; Fatty Acids, Monounsaturated; Imipenem; Cilastatin; Cyclopropanes; Cilastatin, Imipenem Drug Combination; nacubactam
• Other Study ID Numbers: OP0595-5

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes