Evaluation of Gentamicin and Narrow-Spectrum Beta-Lactams Versus Broad-Spectrum Beta-Lactams in Empirical Treatment of Suspected Community-Acquired Sepsis

The primary objective of this clinical trial is to evaluate the **safety** and non-inferiority of combination therapy using narrow spectrum **betalactam** antibiotics (penicillin, ampicillin, cloxacillin) and **aminoglycoside** (gentamicin) compared to broad spectrum antibiotics (cefotaxime, piperacillin-tazobactam) in patients with suspected community-acquired **sepsis**. This assessment is clinically relevant as it aims to determine if a narrower spectrum antibiotic regimen can be as effective and safe as the broader spectrum alternatives, potentially reducing the risk of antibiotic resistance and adverse effects associated with broad spectrum antibiotic use.

The clinical trial involves **adults** aged 18 years and older, both **male** and **female**, who are hospitalized with a clinical suspicion of community-acquired **sepsis**. The study population is selected based on the indication for empirical antibiotic therapy and a National Early Warning Score 2 (NEWS2) of 5 or higher. Participants must provide signed informed consent in accordance with ICH GCP and national/local regulations. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the safety and efficacy of combination therapy with narrow spectrum **betalactam** antibiotics and **aminoglycoside** in patients with suspected community-acquired **sepsis**. This trial is a randomized, double-blind, controlled study comparing the combination therapy to broad spectrum antibiotics. The trial is categorized as low intervention, as all investigational medicinal products are authorized and used in accordance with their marketing authorizations. The trial is expected to commence recruitment on June 1, 2025, and conclude by June 30, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as being hospitalized, aged 18 years or older, and having a clinical suspicion of community-acquired sepsis with a National Early Warning Score 2 (NEWS2) of 5 or higher. Informed consent will be obtained in accordance with ICH GCP and national regulations. Following randomization, participants will receive either the combination therapy or broad spectrum antibiotics for a maximum treatment period of three days. The primary endpoints include death and acute kidney injury up to 30 days post-randomization, while secondary endpoints encompass in-hospital mortality, duration of hospital and intensive care stays, and hospital readmissions up to 30 days post-discharge.

Participants will be involved in the study for a duration that includes the treatment period and a follow-up period of up to 30 days post-randomization. Conditions that may lead to early termination from the study include withdrawal of consent or the occurrence of adverse events that necessitate discontinuation of the investigational product. The trial aims to provide valuable insights into the comparative safety and efficacy of these antibiotic regimens in the management of sepsis, contributing to optimized treatment strategies in clinical practice.

The clinical trial involves the administration of several **antibacterial** agents, each with specific roles and characteristics. **Benzylpenicillin**, a combination of **benzylpenicillin procaine** and **benzathine benzylpenicillin**, is administered intravenously. The pharmaceutical form is coded as PHF00243MIG. The maximum daily dose is 18 grams, with a treatment period not exceeding three days. This formulation is not a pediatric formulation and is used as a test product in the trial.

**Piperacillin sodium** combined with **tazobactam sodium** is another test product used in the study. It is administered intravenously in a pharmaceutical form coded as PHF00230MIG. The maximum daily dose is 16 grams, and the treatment duration is limited to three days. This combination serves as a broad-spectrum antibacterial agent.

**Cefotaxime**, paired with **lidocaine**, is used as a comparator treatment. It is administered intravenously, with a pharmaceutical form coded as PHF00231MIG. The maximum daily dose is 12 grams, and the treatment period is capped at three days. This formulation is also not intended for pediatric use.

**Cloxacillin** is administered intravenously in a pharmaceutical form coded as PHF00231MIG. It is used as a test product with a maximum daily dose of 12 grams and a treatment period of up to three days. This formulation is not a pediatric formulation.

**Gentamicin**, combined with **betamethasone valerate**, is administered intravenously. The pharmaceutical form is coded as PHF00017MIG. The maximum daily dose is 700 milligrams, with a treatment period not exceeding three days. This formulation is used as a test product in the trial.

**Ampicillin sodium** is administered intravenously in a pharmaceutical form coded as PHF00243MIG. It is used as a test product with a maximum daily dose of 12 grams and a treatment period of up to three days. This formulation is not intended for pediatric use.

The efficacy of the clinical trial titled "Aminoglycosides in early sepsis (AGES)" will be assessed using both primary and secondary endpoints. The primary endpoints include the evaluation of mortality up to 30 days post-randomization and the occurrence of any acute kidney injury within the same timeframe. These endpoints are critical in determining the safety and effectiveness of the treatment regimens being compared.

Secondary endpoints will provide additional insights into the treatment's impact and include in-hospital mortality, mortality up to 30 days after discharge, duration of hospital stay, duration of intensive care stay, duration of ventilator therapy, duration of vasopressor therapy, hospital readmissions up to 30 days after discharge, and the duration of antibiotic treatment. These parameters will be measured and collected systematically throughout the trial to ensure comprehensive data analysis.

The trial aims to compare the safety and non-inferiority of combination therapy with narrow spectrum **betalactam** antibiotics and aminoglycoside (gentamicin) against broad spectrum antibiotics in patients with suspected community-acquired sepsis. The trial is designed as a low-intervention study, with all investigational medicinal products authorized by the Norwegian Medical Products Agency and used according to their marketing authorizations. The trial will not involve additional diagnostic or monitoring procedures beyond standard clinical practice.