| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Complicated urinary tract infection (cUTI) and acute uncomplicated pyelonephritis (AP) |
|
| E.1.1.1 | Medical condition in easily understood language |
Complicated urinary tract infection is a urinary tract infection that doesn't respond to traditional treatments
Acute pyelonephritis is a common bacterial infection of the renal pelvis and kidney
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| 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 |
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| 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 | 10001032 |
| E.1.2 | Term | Acute pyelonephritis |
| 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 objective of this study is to assess the efficacy and safety of cefepime/nacubactam and to assess the safety of aztreonam/nacubactam administered by intravenous (IV) infusion compared to imipenem/cilastatin in patients with cUTI or AP. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are the following:
• To assess the efficacy of aztreonam/nacubactam administered by IV infusion in patients with cUTI or AP;
• To assess the efficacy of cefepime/nacubactam and aztreonam/nacubactam administered by IV infusion in patients with secondary bacteremia due to cUTI or AP;
• To assess the pharmacokinetics (PK) of cefepime/nacubactam and aztreonam/nacubactam administered by IV infusion in patients with cUTI or AP; and
• To assess 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 |
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. 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;
Complete list of inclusion criteria is in the protocol. |
|
| E.4 | Principal exclusion criteria |
1. Has a known imipenem- and/or meropenem-resistant Gram-negative uropathogen (≥ 105 CFU/mL), isolated from study-qualifying urine culture;
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;
3. Has only a known Gram-positive primary uropathogen (≥ 105 CFU/mL), isolated from study qualifying urine culture;
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 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. At the assessment of Clinical Signs and Symptoms
2. At the assessment of clinical outcome
3. At the assessment of Microbiological Outcome:
- urine culture: Urine samples will be obtained at Screening, prior to the first dose of study drug on Day 1, EA (Early Assessment), EOT, TOC, FUP (if clinically indicated), and ET (Early Termination).
- blood culture: Two sets of blood culture samples from 2 separate venipuncture sites will be obtained at Screening and prior to the first dose of study drug on Day 1 for baseline blood cultures.
3. At the assessment of Composite Clinical and Microbiological Success: The algorithm for composite clinical and microbiological success at EA, EOT, TOC, FUP, and ET |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints for cUTI and AP include the following:
• The proportion of patients with composite clinical and microbiological success at TOC in the Clinically Evaluable (CE) and Microbiologically Evaluable (ME) Populations;
• The proportion of patients with composite clinical and microbiological success at EA, EOT, and FUP in the m MITT Population;
• The proportion of patients with a microbiological outcome of eradication at EA, EOT, TOC, and FUP in the m MITT Population and at TOC in the ME Population;
• The proportion of patients with a clinical outcome of cure at EA, EOT, TOC, and FUP in the m MITT Population and at TOC in the CE and ME Populations;
• The proportion of patients with a clinical outcome of cure at EA, EOT, TOC, and FUP in the m-MITT Population and at TOC in the CE and ME Populations and microbiological outcome of eradication at EA, EOT, TOC, and FUP in the m-MITT Population and at TOC in the ME Population per type of pathogen, type of resistance, and antimicrobial susceptibility; and
• The proportion of patients with composite clinical outcome of recurrence and/or microbiological outcome of recurrence at the FUP in the m-MITT, CE, and ME population.
Secondary Efficacy Endpoints for Secondary Bacteremia:
Patients with cUTI who meet the following conditions will be determined programmatically as secondary bacteremia:
• 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
• At least 1 of the following within 24 hours prior to the first dose of study drug:
a. Fever (oral or tympanic temperature ≥ 38°C [≥ 100.4°F] or rectal/core temperature ≥38.3°C [≥ 100.9°F]) OR hypothermia (rectal/core temperature < 35°C [< 95°F]);
b. Elevated peripheral WBC count (> 10,000/mm3);
c.> 15% immature polymorphonuclear neutrophils (bands) regardless of peripheral WBC count;
d. Leukopenia (WBC < 4,500/mm3);
e. Tachycardia > 100 bpm;
f. Tachypnea > 20 breaths/min;
g. Hypotension, systolic < 90 mmHg; or
h. C-reactive protein > 20 mg/dL.
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 secondary efficacy endpoints for secondary bacteremia include the following:
• The proportion of patients with composite clinical and microbiological success of cUTI or AP at TOC in the m-MITT, CE, and ME Populations;
• The proportion of patients with a clinical outcome of cure from cUTI or AP at TOC in the m-MITT, CE, and ME Populations;
• The proportion of patients with a microbiological outcome of eradication from cUTI or AP at TOC in the m-MITT and ME Populations;
• The proportion of patients with a clinical outcome of cure from secondary bacteremia at TOC in the m-MITT, CE, and ME Populations;
• The proportion of patients with a microbiological outcome of eradication from secondary bacteremia at TOC in the m-MITT and ME Populations;
• The proportion of patients in the m-MITT and ME Populations free from the definition of secondary bacteremia AND a clinical outcome of cure from cUTI or AP AND a microbiological outcome of eradication from cUTI or AP at TOC; and
• The proportion of patients who are free from secondary bacteremia at TOC in the m-MITT and ME Populations. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Efficacy Endpoints for cUTI and AP:
- different endpoints assessed at EA, EOT, TOC, and FUP
Secondary Efficacy Endpoints for Secondary Bacteremia:
- different endpoints at TOC |
|
| 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 | No |
| 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 | No |
| E.8.1.4 | Double blind | Yes |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 |
| China |
| Georgia |
| Japan |
| Bulgaria |
| Czechia |
| Estonia |
| Latvia |
| Lithuania |
| Slovakia |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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