Evaluation of Baricitinib in the Treatment of Hospital-Acquired Pneumonia in Critically Ill Patients with a Proinflammatory Phenotype: A Phase II/III Randomized Controlled Trial

The primary objective of this randomized trial is to evaluate the **safety** (phase II) and **efficacy** (phase III) of **baricitinib** in combination with standard of care (SOC) compared to SOC alone for the treatment of **hospital-acquired pneumonia** in patients exhibiting a pro-inflammatory profile. This is clinically relevant as it aims to improve treatment outcomes for critically ill patients with this condition, potentially reducing morbidity and mortality associated with hospital-acquired pneumonia.

Secondary objectives include:

• Demonstrating the efficacy of baricitinib on pneumonia-associated morbidity and mortality reduction.
• Describing the safety profile of baricitinib.
• Assessing the economic efficiency of baricitinib compared to standard of care.
• Evaluating the suitability and acceptability of baricitinib from the patients' perspectives.
• Developing biomarkers for stratifying patients into responders and non-responders to baricitinib.
• Creating a biobank of blood and respiratory samples from patients with hospital-acquired pneumonia.

The clinical trial focuses on evaluating the safety and efficacy of baricitinib in combination with standard of care for the treatment of **hospital-acquired pneumonia** in patients exhibiting a pro-inflammatory profile. The study population comprises adult patients aged between 18 and 85 years, including both male and female participants. The trial includes individuals diagnosed with ventilator-associated pneumonia or hospital-acquired pneumonia requiring invasive ventilation. Participants must have a biological systemic inflammatory response as defined by the on-site standard of care and should be receiving antimicrobial therapy for the current episode of hospital-acquired pneumonia for less than 72 hours. The trial population is selected based on these criteria, and informed consent is obtained from a legal representative or through an emergency procedure when necessary. The sponsor has not provided information regarding the total number of participants. The study includes a vulnerable population, and all participants are required to be insured under a health insurance scheme.

The clinical trial is designed to evaluate the **safety** and **efficacy** of **baricitinib** in combination with standard of care (SOC) compared to SOC alone for the treatment of **hospital-acquired pneumonia** in patients with a pro-inflammatory profile. This is an international, phase II/III, randomized, controlled trial. The trial employs a double-blind methodology to ensure unbiased results, with participants randomly assigned to either the treatment group receiving baricitinib plus SOC or the control group receiving SOC alone. The trial is expected to conclude by November 30, 2025, with recruitment having commenced on June 1, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18-85 years), diagnosis of ventilator-associated pneumonia or hospital-acquired pneumonia requiring invasive ventilation, and receipt of antimicrobial therapy for less than 72 hours. Informed consent will be obtained from a legal representative or through emergency procedures as per national regulations. Follow-up visits will be scheduled to monitor the participants' response to treatment and to assess the primary endpoints, which include clinical cure at the test-of-cure visit and all-cause mortality at Day 28. Secondary endpoints will evaluate the rate of serious adverse effects, economic efficiency, and changes in health-related quality of life over a period of six months.

The expected duration of participant involvement is up to six months, with the possibility of early termination if significant adverse effects occur or if the participant withdraws consent. The trial will adhere to rigorous safety monitoring protocols to ensure participant well-being throughout the study. The use of **baricitinib** in this trial is intended to provide insights into its potential benefits and risks in the treatment of hospital-acquired pneumonia, contributing valuable data to the field of critical care medicine.

The clinical trial involves the administration of **Olumiant** in two different dosages as the experimental medication. **Olumiant 2 mg film-coated tablets** contain the active substance **baricitinib**, a chemical compound. The pharmaceutical form is a film-coated tablet, and the route of administration is gastroenteral. The maximum daily dose is 2 mg, with a total maximum dose of 20 mg over a treatment period of up to 10 days. The tablets are manufactured by ELI LILLY NEDERLAND B.V. and are identified by the marketing authorization number EU/1/16/1170/001. Participants are required to take the medication as per the dosing schedule, and compliance will be monitored throughout the study.

Additionally, the trial includes the use of **Olumiant 4 mg film-coated tablets**, also containing **baricitinib**. This formulation is similarly administered gastroenterally. The maximum daily dose for this variant is 4 mg, with a total maximum dose of 40 mg over the same 10-day treatment period. The marketing authorization number for this dosage is EU/1/16/1170/009. As with the 2 mg tablets, participant adherence to the dosing regimen will be closely monitored to ensure compliance and accurate assessment of the treatment's efficacy and safety.

In this study, the experimental treatments are compared against the standard of care (SOC) therapy, which serves as the non-experimental treatment. The trial aims to evaluate the safety and efficacy of baricitinib in combination with SOC versus SOC alone for the treatment of hospital-acquired pneumonia in patients with a pro-inflammatory profile. The SOC therapy will be administered according to the current medical guidelines and practices, ensuring that all participants receive the best available care during the trial.

The efficacy of **baricitinib** in the treatment of hospital-acquired pneumonia in critically ill patients will be assessed through a randomized, controlled trial. The primary endpoints for evaluating efficacy include a clinical cure at the test-of-cure (TOC) visit and all-cause mortality at Day 28. These endpoints are designed to demonstrate the effectiveness of baricitinib plus standard of care (SOC) compared to SOC alone.

Secondary endpoints will be considered if there is no significant difference in the rate of clinical cure. These include the rate of serious adverse effects and suspected unexpected serious adverse reactions (SUSAR) at Day 28, economic endpoints at 6 months to assess the Incremental Cost-Effectiveness Ratio (ICER), and changes in health-related quality of life (HRQoL) from three to six months after randomization. HRQoL will be measured using validated instruments such as SF-36, HADS, and SWLS. The trial will follow a structured schedule for measuring and collecting data at specified timepoints to ensure comprehensive analysis of the efficacy parameters.