Phase 3 Randomized Double-Blind Study of Cefepime/Nacubactam and Aztreonam/Nacubactam Versus Imipenem/Cilastatin in Complicated UTI and Acute Pyelonephritis

The primary objective of this study is to evaluate the **efficacy** and safety of cefepime/nacubactam and to assess the safety of aztreonam/nacubactam when administered by intravenous infusion, compared to imipenem/cilastatin, in patients with complicated urinary tract infections (cUTI) or acute uncomplicated pyelonephritis (AP). This is clinically relevant as it aims to determine the potential of these treatments to effectively manage these infections, which are often challenging due to resistance issues and the need for effective therapeutic options.

Secondary objectives include:

• Assessing the efficacy of aztreonam/nacubactam in patients with cUTI or AP.
• Evaluating the efficacy of cefepime/nacubactam and aztreonam/nacubactam in patients with secondary bacteremia due to cUTI or AP.
• Investigating the pharmacokinetics of cefepime/nacubactam and aztreonam/nacubactam in patients with cUTI or AP.
• Assessing the clinical and microbiological response of cefepime/nacubactam and aztreonam/nacubactam based on pathogen type, resistance type, and antimicrobial susceptibility.

The clinical trial involves a total of **164 participants** diagnosed with **complicated urinary tract infection (cUTI)** and **acute uncomplicated pyelonephritis (AP)**. The study population includes both male and female subjects aged **18 years and older**, with a weight not exceeding **140 kg**. Participants were selected based on the expectation that their condition would necessitate at least five days of intravenous antibiotic treatment. The trial includes a vulnerable population, indicating that special considerations are in place for the participants' safety and well-being. The study does not specify particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants can be hospitalized throughout the treatment period, which is crucial for the administration of the intravenous therapies being evaluated.

The clinical trial is a **Phase 3**, multi-center, randomized, double-blind study designed 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) in adults. The trial is expected to run from May 22, 2023, to November 29, 2024. Participants will be randomly assigned to receive one of the investigational treatments or the comparator, with all medications administered via intravenous infusion. The study will include several key visits: an inclusion (screening) visit, multiple follow-up visits, and an end-of-study visit. The inclusion visit will determine eligibility based on criteria such as age (≥18 years), weight (≤140 kg), and the necessity for at least 5 days of intravenous antibiotic treatment. Follow-up visits will assess the primary endpoint, which is the proportion of patients achieving composite clinical and microbiological success at the Test of Cure (TOC) visit. Secondary endpoints will evaluate various measures of clinical and microbiological success across different populations and time points, including Early Assessment (EA), End of Treatment (EOT), and Follow-Up (FUP) visits. The expected length of participant involvement is up to 14 days of treatment, with conditions for early termination including adverse events or withdrawal of consent. The trial aims to provide comprehensive data on the efficacy and safety of the investigational treatments compared to the standard comparator in the specified patient population.

The clinical trial involves the administration of **Nacubactam**, an experimental medication provided in the form of a **powder for injection**. The active substance, nacubactam, is of chemical origin and is manufactured by MEIJI SEIKA PHARMA CO., LTD. The medication is administered intravenously with a maximum daily dose of 3 grams and a total maximum dose of 42 grams over a treatment period of up to 14 days. The dosing schedule is designed to ensure optimal efficacy while monitoring participant compliance through regular assessments.

**Imipenem/Cilastatin Kabi** serves as the comparator treatment in this study. It is provided as a **solution for infusion** containing the active substances cilastatin sodium and imipenem monohydrate, both of chemical origin. Manufactured by FRESENIUS KABI DEUTSCHLAND GMBH, this medication is also administered intravenously. The maximum daily dose is 6 grams, with a total maximum dose of 84 grams over a 14-day treatment period. The administration schedule is structured to maintain therapeutic levels while ensuring participant adherence to the treatment protocol.

**Cefepime PANPHARMA** is another test medication used in the trial, available as a **solution for injection/infusion**. The active substance, cefepime, is of chemical origin and produced by PANMEDICA. This medication is administered intravenously, with a maximum daily dose of 6 grams and a total maximum dose of 84 grams over a 14-day period. The dosing regimen is carefully monitored to ensure compliance and effectiveness in treating the targeted conditions.

**AZACTAM**, containing the active substance aztreonam, is provided as a **powder for solution for injection**. Manufactured by AMDIPHARM LIMITED, this chemical-origin medication is administered intravenously. The maximum daily dose is 6 grams, with a total maximum dose of 84 grams over a 14-day treatment period. The administration schedule is designed to optimize therapeutic outcomes while ensuring participant adherence to the study protocol.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint is the proportion of patients who achieve composite clinical and microbiological success at the Test of Cure (TOC) visit in the Microbiological Modified Intent-to-Treat (m MITT) Population. This composite success is defined as the combination of a clinical outcome of cure and a microbiological outcome of eradication.

Secondary efficacy endpoints for complicated urinary tract infections (cUTI) and acute uncomplicated pyelonephritis (AP) include several measures. These encompass the proportion of patients with composite clinical and microbiological success at TOC in the Clinically Evaluable (CE) and Microbiologically Evaluable (ME) Populations, as well as at various timepoints such as Early Assessment (EA), End of Treatment (EOT), and Follow-Up (FUP) in the m MITT Population. Additionally, the trial will evaluate the proportion of patients with a microbiological outcome of eradication and a clinical outcome of cure at these timepoints in the respective populations.

For secondary bacteremia, the secondary efficacy endpoints include 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 trial will also assess the clinical outcome of cure and microbiological outcome of eradication from cUTI or AP and secondary bacteremia at TOC in these populations. Furthermore, the trial will determine the proportion of patients free from secondary bacteremia and achieving clinical and microbiological success at TOC.