STRAtified Dosing based on Augmented renal clearance for CEFtriaxone in patients with severe community-acquired pneumonia: the STRADA-CEF trial

The primary objective of the STRADA-CEF trial is to evaluate the clinical benefit and safety of **stratified** dosing of ceftriaxone, administered every 24 hours (q24h) versus every 12 hours (q12h), in critically ill patients with severe community-acquired pneumonia (sCAP). This evaluation is based on the risk for the development of augmented renal clearance (ARC). The clinical relevance of this objective lies in optimizing antibiotic therapy to improve patient outcomes and minimize potential adverse effects in a population at risk for altered drug clearance.

Secondary objectives include investigating the dose-exposure-(biomarker-)response-cost relationship of ceftriaxone through population pharmacokinetics (PK), exposure-response analysis, and pharmacoeconomic (PE) analysis. These analyses aim to provide deeper insights into the study results, potentially guiding more effective and cost-efficient treatment strategies.

The clinical trial involves participants diagnosed with **Severe Community-Acquired Pneumonia** (sCAP), as defined by the current IDSA/ATS guideline. The study population includes both male and female subjects aged 18 years or older, with a confirmed diagnosis of sCAP and planned admission to an ICU ward. Participants are required to have initiated ceftriaxone treatment for sCAP. The trial population is selected based on voluntary written informed consent, obtained either from the participant or their legally authorized representative. The study includes individuals who are part of a vulnerable population, and participants are expected to use highly effective methods of birth control throughout the trial. The sponsor has not provided information regarding the total number of participants. The trial aims to evaluate the clinical benefit and safety of stratified every 24-hour versus every 12-hour 2g ceftriaxone therapy in critically ill patients with sCAP, based on the risk for development of augmented renal clearance (ARC).

The clinical trial is designed to evaluate the **clinical benefit** and safety of stratified dosing of **ceftriaxone** in patients with severe community-acquired pneumonia (sCAP). This trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The trial is expected to commence on January 1, 2024, and conclude by January 1, 2026, with an estimated duration of two years. Participants will be randomly assigned to receive either a 24-hour or 12-hour dosing regimen of 2g ceftriaxone, administered via intravenous infusion, based on their risk for developing augmented renal clearance (ARC).

The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are assessed, including obtaining voluntary written informed consent and confirming a diagnosis of sCAP. Participants must be 18 years or older, have initiated ceftriaxone treatment for sCAP, and have a planned admission to an ICU ward. Follow-up visits will be conducted to monitor primary and secondary endpoints, such as ICU length of stay, delta SOFA score, ICU mortality, and clinical cure at day 14. The end-of-study visit will evaluate the overall outcomes and safety of the treatment.

Participant involvement is expected to last for the duration of their ICU stay, with additional follow-up assessments up to 28 days post-treatment. Conditions that may lead to early termination from the study include withdrawal of consent, adverse events, or any situation where continued participation is deemed unsafe by the investigator. The trial aims to provide valuable insights into the optimal dosing strategy for ceftriaxone in critically ill patients, with a focus on improving clinical outcomes and minimizing the emergence of resistance.

The clinical trial involves the administration of **CEFTRIAXONE**, an antimicrobial agent, as the experimental medication. **CEFTRIAXONE** is provided in the form of a **SOLUTION FOR INJECTION** and is administered via **INTRAVENOUS INFUSION**. The dosing regimen for this trial includes two stratified dosing schedules: every 24 hours (q24h) and every 12 hours (q12h), with a dosage of 2 grams per administration. The maximum daily dose is set at 4 grams, and the total treatment period does not exceed 8 days. The trial aims to evaluate the clinical benefit and safety of these dosing strategies in critically ill patients with severe community-acquired pneumonia (sCAP), particularly focusing on those at risk for developing augmented renal clearance (ARC).

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified for this study. The trial is designed to assess the efficacy of the stratified dosing of **CEFTRIAXONE** alone. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol. The trial does not involve any pediatric formulations, and **CEFTRIAXONE** is not classified as an orphan drug in this context.

Efficacy in the clinical trial titled "STRAtified Dosing based on Augmented renal clearance for CEFtriaxone in patients with severe community-acquired pneumonia: the STRADA-CEF trial" will be assessed using a combination of primary and secondary endpoints. The primary endpoint for evaluating efficacy is the **Intensive Care Unit (ICU) Length of Stay (LOS)**. Secondary endpoints include a range of clinical and laboratory measures: Delta SOFA score, ICU mortality, 28-day mortality, hospital LOS, alive ICU free days at day 28, ventilator-free days at day 28, clinical cure at day 14, microbial eradication at day 14, emergence of resistance at day 14, PK/PD target attainment, assessment of safety, and concentrations of procalcitonin and C-reactive protein.

The trial aims to evaluate the clinical benefit and safety of stratified dosing of ceftriaxone administered every 24 hours versus every 12 hours in critically ill patients with severe community-acquired pneumonia (sCAP), based on the risk for development of augmented renal clearance (ARC). The efficacy parameters will be collected and analyzed at specified timepoints, including day 14 and day 28, to assess both short-term and longer-term outcomes. The trial is designed as a low interventional study, focusing on a stratified dosing strategy for an approved investigational medicinal product (IMP), ceftriaxone, administered via intravenous infusion.