Efficacy of Dexamethasone Phosphate and Sodium Chloride in Severe Hospital-Acquired Pneumonia with Proinflammatory Phenotype: A Phase III Randomized Trial

The primary objective of this randomized trial is to determine the efficacy of **dexamethasone** plus standard of care (SOC) compared to placebo plus SOC for the treatment of severe hospital-acquired pneumonia in patients with a pro-inflammatory profile. This is clinically relevant as it aims to improve treatment outcomes for critically ill patients suffering from this condition, potentially reducing morbidity and mortality associated with severe hospital-acquired pneumonia.

Secondary objectives include:

• To demonstrate the efficacy of dexamethasone on pneumonia-associated morbidity and mortality reduction.
• To describe the safety of dexamethasone.
• To assess the economic efficiency of dexamethasone.
• To assess the suitability and acceptability of dexamethasone from the patients’ perspectives.
• To develop biomarkers for the stratification of patients into responders and non-responders to dexamethasone.
• To create a biobank of blood and respiratory samples collected from humans with hospital-acquired pneumonia to enhance the statistical power of studies using high-throughput analyses for biomarker development and to improve understanding of the pathophysiology of hospital-acquired pneumonia.

The clinical trial focuses on evaluating the efficacy of dexamethasone plus standard of care compared to placebo plus standard of care in treating severe **hospital-acquired pneumonia** in patients with a pro-inflammatory profile. The study population comprises adult patients aged 18 to 85 years, including both male and female participants. The trial includes individuals diagnosed with hospital-acquired pneumonia according to European guidelines, with specific criteria such as body temperature, leukocyte count, and pulmonary secretions. Participants must have a PaO2/FiO2 ratio of less than 300 under mechanical ventilation and a biological systemic inflammatory response indicated by a CRP level of 150 mg/L or higher. The trial population is selected based on these criteria, and participants must be receiving curative antimicrobial therapy for less than 48 hours for the current episode of pneumonia. The study includes a vulnerable population, and informed consent is obtained from a legal representative or through an emergency procedure when necessary. Female participants of childbearing age are required to comply with effective contraception methods during the study. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy of **dexamethasone phosphate** in combination with standard of care (SOC) compared to a placebo plus SOC for the treatment of severe **hospital-acquired pneumonia** in patients with a pro-inflammatory profile. This is a phase III, double-blind, placebo-controlled, randomized trial. The trial is expected to commence recruitment on February 1, 2024, and conclude by August 1, 2026. Participants will be randomly assigned to receive either dexamethasone phosphate or a placebo, both administered via intravenous use, with a maximum daily dose of 0.2 mg/kg and a total dose not exceeding 1 mg/kg over a treatment period of up to 5 days.

The study will include several key visits: an initial screening visit, follow-up visits, and an end-of-study visit. During the screening visit, eligibility will be assessed based on criteria such as age (18 to 85 years), diagnosis of hospital-acquired pneumonia according to European guidelines, and severity of the condition. Follow-up visits will monitor clinical outcomes, including the primary endpoints of clinical cure at the test-of-cure visit and all-cause mortality at Day 28. Secondary endpoints will include all-cause mortality at Month 3 and Month 6, rate of pleural empyema, microbiological failure, and other health-related outcomes.

Participants are expected to be involved in the study for a duration that includes the treatment period and follow-up assessments up to 6 months post-randomization. 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 aims to provide comprehensive data on the efficacy and safety of dexamethasone phosphate in this patient population, contributing to the understanding of treatment options for severe hospital-acquired pneumonia.

The clinical trial involves the administration of **DEXAMETHASONE PHOSPHATE**, a chemical compound used as the experimental medication. This medication is provided in the form of a **solution for injection/infusion**. The active substance, dexamethasone phosphate, is administered intravenously. The dosing regimen includes a maximum daily dose of 0.2 mg/kg and a total maximum dose of 1 mg/kg over a treatment period of up to 5 days. The trial aims to evaluate the efficacy of dexamethasone phosphate in combination with standard-of-care therapy for the treatment of severe hospital-acquired pneumonia in patients with a pro-inflammatory profile.

In addition to the experimental treatment, the study utilizes **SODIUM CHLORIDE** as a placebo. Sodium chloride is also provided as a **solution for injection** and is administered intravenously. The dosing schedule for sodium chloride mirrors that of dexamethasone phosphate, with a maximum daily dose of 0.2 mg/kg and a total maximum dose of 1 mg/kg over a 5-day period. This placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment allocations.

The efficacy of **dexamethasone phosphate** in the treatment of severe hospital-acquired pneumonia will be assessed through a series of co-primary and secondary endpoints. The co-primary endpoints include the clinical cure at the test-of-cure (TOC) visit and all-cause mortality at Day 28. These endpoints are designed to demonstrate the efficacy of dexamethasone plus standard of care (SOC) compared to placebo plus SOC.

Secondary endpoints will be evaluated to provide additional insights into the treatment's efficacy. These include all-cause mortality at Month 3 and Month 6, the rate of pleural empyema at Day 28, and the rate of microbiological failure, defined as a positive respiratory culture at the TOC visit. Other secondary measures include the rate of pneumonia relapse and recurrence at Day 28, time course evaluations of body temperature, cardiac pulse rate, oxygen saturation, PaO2/FiO2, type of mechanical ventilation support, and leukocyte counts over a 10-day period. Additionally, the study will assess rates of non-respiratory hospital-acquired infections, antibiotic-free days, duration of invasive mechanical ventilation, and hospital-free days at Month 6.

Further assessments will include the rate of serious adverse reactions, metabolic adverse events during the treatment period, and the rate of gastric ulcers. Economic endpoints such as the Incremental Cost-Effectiveness Ratio (ICER) at 6 months will also be considered. Changes in health-related quality of life, anxiety, depression, subjective well-being, and rates of major cardiovascular events at Day 28 will be measured using validated scales such as the Short Form (SF)-36, HADS, and Satisfaction With Life Scale (SWLS).