Evaluation of Pirfenidone in Preventing Fibrosis in Acute Respiratory Distress Syndrome: A Randomized Controlled Trial

The primary objective of the PIONEER trial is to evaluate the efficacy of **Pirfenidone** in increasing the number of ventilator-free days (VFD) at day 28 in patients with **Acute Respiratory Distress Syndrome (ARDS)**, compared to a placebo group. This outcome is clinically significant as it may indicate improved respiratory function and reduced dependency on mechanical ventilation, which is crucial for patient recovery and reducing healthcare resource utilization.

Secondary objectives include reducing the duration of mechanical ventilation, the length of Intensive Care Unit (ICU) stay, and the rate of mechanical ventilation-related complications such as pneumonia. These objectives are important for enhancing patient outcomes, minimizing potential complications, and optimizing ICU resource management.

The clinical trial involves a total of **30 participants** diagnosed with **Acute Respiratory Distress Syndrome (ARDS)**. The study population includes both male and female subjects, with an age range of 18 to 65 years. Participants were selected based on specific inclusion criteria, including moderate to severe ARDS as defined by the Berlin definition and an inflammatory ARDS phenotype. The trial population is characterized by a vulnerable group, as indicated by the selection criteria. Participants' general health status is compromised due to the presence of ARDS, and lifestyle considerations such as diet and physical activity are not specified. The selection process ensures that participants have provided informed consent, either personally or through a legal representative, or as indicated by an Ethical Committee.

The clinical trial is designed as a **randomized, controlled** study to evaluate the efficacy of **pirfenidone** in preventing fibrosis in patients with **Acute Respiratory Distress Syndrome (ARDS)**. The trial aims to document an increase in the number of ventilator-free days at day 28 in the pirfenidone group compared to the placebo group. The study will involve the administration of **Esbriet 267 mg film-coated tablets** and **SODIO CLORURO 0,9% BAXTER Soluzione per infusione**. The trial is expected to run from September 20, 2021, to June 15, 2025, with a maximum treatment period of 28 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the Berlin definition of moderate to severe ARDS and specific inflammatory markers. Informed consent must be obtained from the patient or their legal representative. Follow-up visits will be scheduled to monitor the primary and secondary endpoints, including ICU-free days, cumulative SOFA-free scores, and reduction in hospital length of stay. The end-of-study visit will assess outcomes such as mortality at ICU/hospital discharge, pulmonary function tests, and quality of life measures.

Participant involvement is expected to last up to 28 days, with conditions for early termination including adverse events or withdrawal of consent. The trial will adhere to rigorous scientific standards to ensure the validity and reliability of the results, contributing valuable data to the understanding of ARDS treatment. The study will also evaluate secondary endpoints such as the reduction in fibroproliferative changes on high-resolution CT, better pulmonary function, and improved quality of life, among others.

The clinical trial involves the administration of **Pirfenidone**, marketed under the name Esbriet, which is provided in the form of **film-coated tablets**. Each tablet contains 267 mg of the active substance, **pirfenidone**, a chemical compound. The tablets are administered orally, with the option of using a nasogastric tube or percutaneous endoscopic gastrostomy tube if necessary. The maximum daily dose is 2403 mg, and the treatment period extends up to 28 days. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

In addition to the experimental treatment, the study utilizes **Sodium Chloride 0.9%**, branded as SODIO CLORURO 0,9% BAXTER, which is a **solution for infusion**. This non-experimental treatment serves as a placebo comparator in the trial. The solution is administered via infusion, with a maximum daily volume of 2403 ml, matching the treatment period of up to 28 days. The administration route is consistent with the oral, nasogastric tube, or percutaneous endoscopic gastrostomy tube use, ensuring uniformity in the trial's methodology. Compliance with the administration protocol is closely monitored to maintain the integrity of the study outcomes.

Efficacy in the clinical trial titled "PIrfenidone to prevent fibrOsis in ARDS. A RaNdomizEd controllEd tRial - PIONEER" will be assessed using both primary and secondary endpoints. The primary endpoint is the increase in the number of ventilator-free days (VFD) at day 28 in the group receiving **pirfenidone** compared to the placebo group. This will be measured by documenting the number of days patients are alive and free from mechanical ventilation within the 28-day period.

Secondary endpoints include several parameters: an increase in ICU-free days at day 28, an increase in cumulative SOFA-free score at day 28, reduction in hospital length of stay, and reduction in fibroproliferative changes on high-resolution CT at ICU discharge. Mortality rates at ICU and hospital discharge will also be evaluated. Additional assessments involve pulmonary function tests (spirometry) at hospital discharge, distance covered in the 6-minute walk test at 6-12 months, and quality of life improvements measured by the EQ-5D Health Questionnaire and SF-36 questionnaire. Right and left heart dysfunction will be assessed via echocardiography at ICU discharge. The trial will also monitor adverse event rates and the use of rescue therapies for severe hypoxemia.