Intraperitoneal Administration of Fosfomycin, Metronidazole, and Molgramostim in Multiquadrant Peritonitis: A Randomized, Placebo-Controlled Trial

The primary objective of this study is to evaluate the efficacy of **intraperitoneal** administration of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), metronidazole, and fosfomycin in optimizing the treatment of patients with multi-quadrant **peritonitis** undergoing abdominal surgery. This is clinically relevant as peritonitis is a severe inflammatory condition that can lead to significant morbidity and mortality, and optimizing treatment could improve patient outcomes.

The clinical trial focuses on patients diagnosed with **peritonitis**, specifically those undergoing surgical intervention due to a lesion in the large intestine affecting two or more quadrants. The study population includes both male and female participants aged 18 years and older. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants were selected based on their medical condition and surgical findings, with no specific lifestyle considerations such as diet or physical activity mentioned. The trial aims to evaluate the efficacy of intraperitoneal administration of GM-CSF, metronidazole, and fosfomycin in optimizing treatment outcomes for this patient group.

The clinical trial is designed to evaluate the efficacy and safety of **intraperitoneal** administration of **metronidazole**, **molgramostim**, and **fosfomycin** in patients with multi-quadrant **peritonitis** undergoing abdominal surgery. This is a randomized, placebo-controlled trial, conducted in a double-blind manner to ensure unbiased results. The trial is categorized as Phase 3, focusing on testing the safety and efficacy of the treatment regimen. The estimated duration of the trial is from April 2025 to April 2030, with participant involvement expected to last for a maximum of one day, corresponding to the treatment period.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the principal inclusion criteria, which require patients to be aged 18 or older and undergoing surgical intervention with findings of peritonitis involving at least two quadrants. The primary endpoints of the study include changes in cytokine levels in peritoneal dialysate and the Quality of Recovery-15 (QoR-15) score. Secondary endpoints involve macrophage phagocytosis assays on peripheral blood mononuclear cells (PBMCs) and changes in cytokine levels in peripheral blood, as well as various blood values such as hematology, potassium, sodium, C-reactive protein (CRP), albumin, and creatinine.

Study visits will include follow-up assessments to monitor the primary and secondary endpoints, with the end-of-study visit marking the conclusion of participant involvement. Conditions that may lead to early termination from the study include adverse reactions to the treatment or withdrawal of consent by the participant. The trial aims to optimize treatment for patients with secondary peritonitis through the intraperitoneal application of the investigational drugs, with the placebo group receiving a saline solution for infusion. The trial's design ensures rigorous assessment of the investigational treatment's impact on the specified clinical and translational endpoints.

The clinical trial involves the administration of **METRONIDAZOLE**, a chemical active substance, in the form of a **SOLUTION FOR INJECTION/INFUSION**. The maximum daily dose is 500 mg, with a total dose not exceeding 500 mg over a treatment period of one day. The route of administration is intra-abdominal, ensuring direct delivery to the site of infection. This medication is not formulated for pediatric use and is classified as a test product in the trial.

**MOLGRAMOSTIM** is another test product used in this study, provided as a **LYOPHILISATE AND SOLVENT FOR SOLUTION FOR INJECTION**. The maximum daily and total dose is 50 µg, administered intra-abdominally over a single day. This recombinant human granulocyte-macrophage colony-stimulating factor is intended to enhance immune response in patients with multi-quadrant peritonitis. It is not a pediatric formulation.

The trial also includes **FOSFOMYCIN**, administered as a **SOLUTION FOR INFUSION**. The maximum daily and total dose is 2000 mg, delivered intra-abdominally within a one-day treatment period. This antibiotic is used to combat bacterial infections in the peritoneal cavity. Like the other test products, it is not designed for pediatric use.

As a comparator treatment, the study utilizes **Saline Solution Basi 9 mg/ml solution for infusion**, containing **SODIUM CHLORIDE** as the active substance. This solution is administered intra-abdominally, with a maximum daily and total dose of 500 ml over one day. It serves as a placebo in the trial, providing a baseline for evaluating the efficacy of the test medications. The saline solution is produced by Laboratórios Basi – Indústria Farmacêutica, S.A. and is not a pediatric formulation.

The efficacy of the clinical trial will be assessed through a combination of primary and secondary endpoints. The primary translational endpoint involves measuring the change in cytokine levels in peritoneal dialysate, while the primary clinical endpoint focuses on the change in the Quality of Recovery-15 (QoR-15) score. Secondary endpoints include a macrophage phagocytosis assay on peripheral blood mononuclear cells (PBMCs), changes in cytokine levels in peripheral blood, specifically **TNF-α**, **IL-1β**, **IL-6**, **IL-8**, **IL-10**, **MCP-1**, and **GM-CSF**, as well as changes in various blood values such as hematology, potassium (K+), sodium (Na+), C-reactive protein (CRP), albumin, and creatinine, including estimated glomerular filtration rate (eGFR).