Comparative Efficacy of Meropenem Trihydrate Versus Piperacillin/Tazobactam in Critically Ill Adults with Sepsis: A Randomized Controlled Trial

The primary objective of the EMPRESS trial is to assess the effects of empirical **meropenem** versus **piperacillin/tazobactam** on mortality and other patient-important outcomes in critically ill adults with **sepsis**. This evaluation is clinically relevant as it aims to determine the most effective empirical antibiotic therapy for reducing mortality in patients with sepsis, a life-threatening condition characterized by a dysregulated immune response to infection. The study focuses on comparing two commonly used antibiotics to provide evidence-based guidance for clinicians in selecting the optimal treatment strategy for sepsis management.

The clinical trial involves a study population of critically ill adults diagnosed with **sepsis**, including **septic shock**, as defined by the Sepsis-3 criteria. Participants are aged 18 years and older, encompassing both male and female subjects. The trial includes individuals who are critically ill, requiring interventions such as invasive or non-invasive mechanical ventilation, continuous positive airway pressure (CPAP) for hypoxia, oxygen supplementation with a flow of at least 10 liters per minute, or continuous infusion of vasopressors or inotropes. The trial population is selected based on the clinical indication for empirical treatment with either meropenem or piperacillin/tazobactam. The sponsor has not provided information regarding the total number of participants. The study includes a vulnerable population, highlighting the critical health status of the participants. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the effects of **meropenem** versus **piperacillin/tazobactam** on mortality and other patient-important outcomes in critically ill adults with **sepsis**. This study is a randomized, double-blind, controlled trial, ensuring that neither the participants nor the investigators know which treatment is being administered, thus minimizing bias. The trial is expected to commence recruitment on March 1, 2024, and conclude by June 30, 2028. Participants will be involved in the study for a maximum treatment period of 30 days, with follow-up assessments extending to 180 days post-randomization.

Study visits are structured to include an initial screening visit to confirm eligibility based on criteria such as age (≥18 years), presence of sepsis or septic shock as per Sepsis-3 criteria, and critical illness requiring specific interventions. Following randomization, participants will receive either **meropenem** or **piperacillin/tazobactam** intravenously. The primary endpoint is all-cause mortality at day 30, with secondary endpoints including serious adverse reactions, days alive without life support, and health-related quality of life (HRQoL) at day 180.

Participants will undergo regular follow-up visits to monitor for adverse reactions and assess clinical outcomes. The end-of-study visit will occur at day 180, where final assessments will be conducted. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that necessitate discontinuation of the study drug. The trial's design and procedures are meticulously structured to ensure the collection of robust and reliable data, contributing to the understanding of optimal empirical treatment strategies for sepsis.

The clinical trial involves the administration of **Piperacillin/Tazobactam Fresenius Kabi**, a **solution for infusion**. This experimental medication is composed of active substances including **piperacillin sodium**, **tazobactam sodium**, **piperacillin**, **tazobactam**, and **piperacillin monohydrate**. The pharmaceutical form is specifically designed for **intravenous use**. The maximum daily dose is 16 grams, with a total maximum dose of 480 grams over a treatment period of up to 30 days. The medication is manufactured by Fresenius Kabi AB and is authorized for use in Denmark under the marketing authorization number 40178. Participant compliance with the dosing schedule will be monitored throughout the trial.

The comparator treatment in this study is **Meropenem Fresenius Kabi**, which is provided as a **solution for injection/infusion**. The active substance in this medication is **meropenem trihydrate**. Similar to the experimental medication, it is administered via **intravenous use**. The maximum daily dose for Meropenem is 3 grams, with a total maximum dose of 90 grams over a 30-day treatment period. This medication is also produced by Fresenius Kabi AB and holds a marketing authorization in Denmark with the number 45320. The trial will ensure adherence to the dosing regimen and monitor participant compliance accordingly.

The efficacy of the clinical trial titled "Empirical Meropenem versus Piperacillin/Tazobactam for Adult Patients with **Sepsis** (EMPRESS) trial" will be assessed using a combination of primary and secondary endpoints. The primary endpoint is all-cause mortality at day 30 after randomization. This endpoint will provide a direct measure of the treatment's impact on survival in critically ill adults with sepsis.

Secondary endpoints include several measures to evaluate patient outcomes and safety. These are: the number of participants experiencing one or more serious adverse reactions within 30 days of randomization, the number of participants requiring new isolation precautions due to resistant bacteria within 30 days, and the number of days alive without life support from randomization to day 30 and day 90. Additionally, the trial will assess days alive and out of hospital from randomization to day 30 and day 90, all-cause mortality at day 90 and day 180, and health-related quality of life (HRQoL) at day 180 using EQ-5D-5L index values and EQ VAS.