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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 (Integral-1)

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

614

A total of 608 subjects were included in both the MITT (Modified Intent-to-Treat) population and the safety population (306 subjects in the cefepime/nacubactam group, 152 subjects in the aztreonam/nacubactam group, and 150 subjects in the imipenem/cilastatin group). The age range was 18-94 years, with a mean age of 63.8 years in the cefepime/nacubactam group, 66.2 years in the aztreonam/nacubactam group, 65.0 years in the imipenem/cilastatin group respectively. As for gender, 54.1% were male and 45.9% were female, with a higher proportion of males. Regarding race, 84.9% of subjects were White, 9.5% were Chinese, 5.4% were Japanese, and 0.2% were other Asian, with White subjects comprising the largest proportion. Based on clinical pharmacology study results, renal function had a significant impact on clearance in the cefepime/nacubactam group and aztreonam/nacubactam group; accordingly, dose and regimen adjustments were implemented based on renal function in this study. By creatinine clearance category, in all treatment groups, the highest proportion of subjects had creatinine clearance was >=90 and <=240 mL/min, with no major differences between groups.

Overall, 614 subjects were randomized, and 610 subjects received the study drug. The primary efficacy analysis population was mMITT (Microbiological Modified Intent-to-Treat) population that comprised 431 subjects: 214 subjects in the cefepime/nacubactam group, 112 subjects in the aztreonam/nacubactam group, and 105 subjects in the imipenem/cilastatin group. The safety population comprised 608 subjects (306 subjects in the cefepime/nacubactam group, 152 subjects in the aztreonam/nacubactam group, and 150 subjects in the imipenem/cilastatin group). 34 (5.5%) subjects discontinued from the study drug early. The most common primary reasons for study drug discontinuation were adverse event (9 subjects), withdrawal of consent (8 subjects), ineligibility after the start of the study(5 subjects), and physician decision (5 subjects).

- A total of 434 TEAEs (Treatment-emergent adverse events) occurred in 210 patients (34.5%): 100 (32.7%) patients in the cefepime/nacubactam group experienced 203 TEAEs, 45 (29.6%) patients in the aztreonam/nacubactam group experienced 99 TEAEs, and 65 (43.3%) patients in the imipenem/cilastatin group experienced 132 TEAEs. A total of 86 (14.1%) patients experienced 127 study drug-related TEAEs: 44 (14.4%) patients in the cefepime/nacubactam group experienced 58 study drug-related TEAEs, 15 (9.9%) patients in the aztreonam/nacubactam group experienced 29 study drug-related TEAEs, and 27 (18.0%) patients in the imipenem/cilastatin group experienced 40 study drug-related TEAEs. - Diarrhoea and headache were the most common TEAEs in the cefepime/nacubactam group (14 and 10 patients, respectively), headache and asymptomatic bacteriuria were the most common TEAEs in the aztreonam/nacubactam group (8 and 7 patients, respectively), while nausea, diarrhoea and headache were the most common TEAEs in the imipenem/cilastatin group (10, 6, and 6 patients, respectively). - The majority of TEAEs across all treatment groups were mild in severity. 9 (1.5%) patients experienced severe TEAEs. Of these, 3 (0.5%) patients experienced severe study drug-related TEAEs. The severe study drug-related TEAEs included encephalopathy (1 patient in the cefepime/nacubactam group); acute kidney injury (1 patient in the aztreonam/nacubactam group); and nausea and vomiting (1 patient in the imipenem/cilastatin group). - A total of 15 (2.5%) patients experienced TESAEs (Treatment-emergent serious adverse events): 6 (2.0%) patients in the cefepime/nacubactam group, 4 (2.6%) patients in the aztreonam/nacubactam group, and 5 (3.3%) patients in the imipenem/cilastatin group. TESAEs considered related to the study drug were included encephalopathy (1 patient in the cefepime/nacubactam group); acute kidney injury (1 patient in the aztreonam/nacubactam group); and pyrexia (1 patient in the imipenem/cilastatin group). - 1 (0.3%) patient in the cefepime/nacubactam group experienced an AE leading to death which was due to disease progression (lung cancer progression). No death occurred in aztreonam/nacubactam and imipenem/cilastatin groups due to AEs. - The incidence of TEAEs leading to discontinuation of study drug for the Safety Population was low and similar across all treatment groups (7 [2.3%] patients in the cefepime/nacubactam group and 2 [1.3%] patients in the aztreonam/nacubactam group and in the imipenem/cilastatin group). The study drug-related TEAEs leading to discontinuation of the study drug included Clostridium difficile colitis, anaphylactic reaction, encephalopathy, nausea, dermatitis allergic (each in 1 patient) in the cefepime/nacubactam group, acute kidney injury, ECG QT prolonged (each in 1 patient) in the aztreonam/nacubactam group, and nausea (2 patients) and vomiting (1 patient) in the imipenem/cilastatin group.

The primary efficacy endpoints achieved include the following: - Cefepime/nacubactam (176 of 214 [82.2%] patients) was found to be non-inferior and superior to imipenem/cilastatin (64 of 105 [61.0%] patients) for the composite clinical and microbiological success at the TOC Visit for the m-MITT Population with the treatment difference of 21.3% (95% CI [10.9, 32.0]). The lower bound of the 2-sided 95% CI met the prespecified non-inferiority margin of >-15% and superiority margin of >0.0%; and - Aztreonam/nacubactam (81 of 112 [72.3%] patients) was found to be non-inferior to imipenem/cilastatin (64 of 105 [61.0%] patients) for the composite clinical and microbiological success at the TOC Visit for the m-MITT Population with the treatment difference of 11.4% (95% CI [-1.2, 23.7]). The lower bound of the 2-sided 95% CI met the prespecified non-inferiority margin of >-15%. The secondary efficacy endpoints conclusions include the following: - For the m-MITT Population, a greater proportion of patients in the cefepime/nacubactam group (195 of 214 [91.1%] patients) and the aztreonam/nacubactam group (103 of 112 [92.0%] patients) achieved the clinical outcome of cure at the TOC Visit compared to the imipenem/cilastatin group (92 of 105 [87.6%] patients), with the treatment differences of 3.5% (95% CI [-3.3, 11.8]) and 4.3% (95% CI [-3.9, 13.0]), respectively; - For the m-MITT Population, a greater proportion of patients in the cefepime/nacubactam group (184 of 214 [86.0%] patients) and the aztreonam/nacubactam group (83 of 112 [74.1%] patients) achieved the microbiological outcome of eradication at the TOC Visit compared to imipenem/cilastatin group (67 of 105 [63.8%] patients), with the treatment differences of 22.2% (95% CI [12.2, 32.7]) and 10.3% (95% CI [-2.0, 22.5]), respectively; - For the m-MITT Population, in patients who had Escherichia coli infection at baseline, a greater proportion of patients in the cefepime/nacubactam group (148 of 162 [91.4%] patients) and the aztreonam/nacubactam group (82 of 89 [92.1%] patients) achieved the clinical outcome of cure at the TOC Visit compared to the imipenem/cilastatin group (67 of 76 [88.2%] patients), with the treatment differences of 3.2% (95% CI [-4.5, 13.1]) and 4.0% (95% CI [-5.3, 14.2]), respectively; - For the m-MITT Population, in patients who had Klebsiella pneumoniae infection at baseline, a greater proportion of patients in the cefepime/nacubactam group (30 of 32 [93.8%] patients) and the aztreonam/nacubactam group (11 of 12 [91.7%] patients) achieved the clinical outcome of cure at the TOC Visit compared to the imipenem/cilastatin group (13 of 16 [81.3%] patients), with the treatment differences of 12.5% (95% CI [-6.0, 38.0]) and 10.4% (95% CI [-20.5, 37.3]), respectively; - For the m-MITT Population, in patients who had Escherichia coli infection at baseline, a greater proportion of patients in the cefepime/nacubactam group (141 of 162 [87.0%] patients) and the aztreonam/nacubactam group (63 of 89 [70.8%] patients) achieved the microbiological outcome of eradication at the TOC Visit compared to the imipenem/cilastatin group (47 of 76 [61.8%] patients), with the treatment differences of 25.2% (95% CI [13.5, 37.5]) and 8.9% (95% CI [-5.5, 23.3]), respectively. - For the m-MITT Population, in patients who had Klebsiella pneumoniae infection at baseline, a greater proportion of patients in the cefepime/nacubactam group (27 of 32 [84.4%] patients) and the aztreonam/nacubactam group (11 of 12 [91.7%] patients) achieved the microbiological outcome of eradication at the TOC Visit compared to the imipenem/cilastatin group (10 of 16 [62.5%] patients), with the treatment differences of 21.9% (95% CI [-3.4, 48.5]) and 29.2% (95% CI [-4.4, 56.0]), respectively. - For the m-MITT Population, in patients who had Escherichia coli infection at baseline, a greater proportion of patients in the cefepime/nacubactam group (135 of 162 [83.3%] patients) and the aztreonam/nacubactam group (62 of 89 [69.7%] patients) achieved the composite clinical and microbiological outcome of success at the TOC Visit compared to 45 of 76 [59.2%] patients in imipenem/cilastatin group, with the treatment differences of 24.1% (95% CI [12.0, 36.6]) and 10.5% (95% CI [-4.2, 24.9]), respectively; - For the m-MITT Population, in patients who had Klebsiella pneumoniae infection at baseline, a greater proportion of patients in the cefepime/nacubactam (27 of 32 [84.4%] patients) and the aztreonam/nacubactam groups (11 of 12 [91.7%] patients) achieved the composite clinical and microbiological outcome of success at the TOC Visit compared to 9 of 16 (56.3%) patients in the imipenem/cilastatin group, with the treatment differences of 28.1% (95% CI [1.8, 54.1]) and 35.4% (95% CI [1.1, 61.6]), respectively; - For the m-MITT Population, in patients who had secondary bacteremia (defined as an organism[s] isolated from a non-contaminated blood culture that was the same as the cUTI (Complicated urinary tract infection)/AP (Acute uncomplicated pyelonephritis)-qualifying organism[s] isolated from a concurrent Screening/baseline urine culture) at baseline, a greater proportion of patients in the cefepime/nacubactam group (11 of 15 [73.3%] patients) and the aztreonam/nacubactam group (4 of 9 [44.4%] patients) were free from secondary bacteremia and achieved the clinical outcome of cure from cUTI or AP and the microbiological outcome of eradication from cUTI or AP at the TOC Visit compared to the imipenem/cilastatin group (2 of 10 [20.0%] patients), with the treatment difference of 53.3% (95% CI [12.8, 78.1]) and 24.4% (95% CI [-18.4, 60.5]), respectively;

This study demonstrated that cefepime/nacubactam was non-inferior and superior to imipenem/cilastatin, and aztreonam/nacubactam was non-inferior to imipenem/cilastatin. This study also demonstrated that cefepime/nacubactam and aztreonam/nacubactam are safe and well tolerated in the treatment of patients with cUTI or AP caused by Gram-negative bacteria who required hospitalization.

Feb. 06, 2026

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2031230075

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. 19, 2023

Interventional

randomized controlled trial

double blind

active control

parallel assignment

treatment purpose

Patients who meet all of the following criteria will be eligible to participate in the study:
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. Expectation, in the opinion of the Investigator, that the cUTI or AP of patient will require treatment with at least 5 days of IV antibiotics

Patients who meet any of the following criteria will be excluded from participation in the study:
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 discretion of Investigator.
2. Has known or suspected single or concurrent infection with Acinetobacter species 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 discretion of Investigator.
3. Has only a known Gram-positive primary uropathogen (at least 10^5 CFU/mL), isolated from study qualifying urine culture;

Both

Complicated urinary tract infection (cUTI) and acute uncomplicated pyelonephritis (AP)

Patients will receive either 2 g cefepime/1 g nacubactam, 2 g aztreonam/1 g nacubactam, or 1 g imipenem/1 g cilastatin every 8 hours (plus or minus 1 hour) for at least 5 days and up to 14 days. Study drug will be administered via IV infusion over a period of 60 minutes (plus or minus 15 minutes). If CrCl is at least 30 and less than 60 mL/min, patients will receive 1 g cefepime/0.5 g nacubactam or 1 g aztreonam/0.5 g nacubactam or 0.5 g imipenem/0.5 g cilastatin every 8 hours. If CrCl is at least 60 and less than 90 mL/min, patients will receive 2 g cefepime/1 g nacubactam or 2 g aztreonam/1 g nacubactam or 0.75 g imipenem/0.75 g cilastatin every 8 hours. If CrCl is at least 90 and at most 240 mL/min, patients will receive 2 g cefepime/1 g nacubactam or 2 g aztreonam/1 g nacubactam or 1 g imipenem/1 g cilastatin every 8 hours.

OP0595, nacubactam, cUTI, AP

The primary efficacy endpoint is the proportion of patients who achieve composite clinical and microbiological success at TOC 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.

+81-3-5712-5050

Mar. 13, 2023

Bulgaria/Croatia/Czech Republic/Estonia/Georgia/Latvia/Lithuania/Slovakia/China