Pirfenidone to Prevent Fibrosis in Ards. (PIONEER)

May 5, 2026 updated by: Giovanni Landoni, Università Vita-Salute San Raffaele

Pirfenidone to Prevent Fibrosis in ARDS. A Randomized Controlled Trial - PIONEER

Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury and a major cause of Intensive Care Unit (ICU) admission worldwide. Despite a large number of randomized clinical trials, a specific and effective pharmacological approach for patients with ARDS is still lacking.

Fibroproliferation is a crucial part of the host defence response, and severe fibrotic lung disease affects ARDS patients even years after acute phase resolution.

Pirfenidone is an oral anti-fibrotic drug, approved and largely used for treatment of idiopathic pulmonary fibrosis (IPF). The effect of Pirfenidone in ARDS has been evaluated only in animal models.

This is a randomized controlled study to evaluate for the first time the efficacy of Pirfenidone in ARDS.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Acute respiratory distress syndrome (ARDS) is an acute inflammatory lung injury, associated with increased pulmonary vascular permeability, increased lung weight, and loss of aerated lung tissue.

ARDS represents 10.4% of total ICU admissions and 23.4% of all patients requiring mechanical ventilation and the hospital mortality rate remains as high as 40%.

Optimal care for patients with ARDS includes PEEP, muscle relaxation, protective ventilation, prone position, conservative fluid strategy.

Pharmacological interventions focused on dampening the pro-inflammatory response in the initial phase of ARDS, on reduction of pulmonary oedema and on improvement of repair mechanisms. Besides treatment with glucocorticosteroids, none of the other pharmacological interventions tested so far in clinical trials showed a significant reduction in morbidity and mortality.

Many ARDS patients survive the acute inflammation phase but develop remarkable pulmonary fibrosis. In hospital mortality is significantly lower (24%) than 1-y mortality after hospital discharge (41%) regardless of the etiology of ARDS. Although a protective ventilation strategy can improve short-term survival in ARDS subjects, there is no difference in pulmonary function compared with standard ventilation treatment up to 2 years after the acute-phase resolution.

Pulmonary fibrosis was observed in 53% of ventilated patients who had ARDS for five days and their mortality rate was 57% compared with 0% in patients without pulmonary fibrosis.

The purpose of this study is to provide a large multicenter RCT with an adequate size to explore the efficacy of Pirfenidone in ARDS patients.

Study Type

Interventional

Enrollment (Estimated)

130

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Italy
      • Bari, Italy
        • Recruiting
        • Ospedale Santa Maria
        • Contact:
          • Michele Gerardi
      • Brescia, Italy, 25123
      • Cagliari, Italy, 09123
        • Recruiting
        • Ospedale San Giovanni di Dio - Azienda Ospedaliera Universitaria di Cagliari
        • Contact:
      • Merano, Italy
      • Milan, Italy
        • Recruiting
        • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
        • Contact:
          • Giacomo Grasselli
        • Contact:
          • Alessio Caccioppola
      • Milan, Italy, 20070
      • Palermo, Italy
        • Recruiting
        • AOU Policlinico Paolo Giaccone
        • Contact:
          • Andrea Cortegiani, MD
      • Pisa, Italy, 56126
      • Pisa, Italy
        • Recruiting
        • AOU Pisana
        • Contact:
          • Francesco Corradi, MD
      • Potenza, Italy
      • Rome, Italy, 00133
        • Recruiting
        • Fondazione PTV - Policlinico Tor Vergata
        • Contact:
      • Siena, Italy, 53100
      • Torino, Italy, 10126
      • Udine, Italy, 33100
    • MI
      • Milan, MI, Italy, 20132
        • Recruiting
        • IRCCS San Raffaele Scientific Institute
        • Contact:
    • Piedmont
      • Alessandria, Piedmont, Italy, 15121
  • Kazakhstan
      • Astana, Kazakhstan, 010000
        • Recruiting
        • Astana Medical University
        • Contact:
          • Aidos Konkayev, Full Professor
          • Phone Number: +77475339215
          • Email: konkaev@mail.ru

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

Concomitant presence of:

  • ARDS (moderate and severe) - Berlin definition

    1. Within 1 week of a known clinical insult or new or worsening respiratory symptoms
    2. Bilateral opacities on CXR which are not fully explained by effusions, lobar/lung collapse or nodules
    3. Respiratory failure not fully explained by cardiac failure or fluid overload
    4. PaO2/FiO2<200 mmHg with PEEP<=5 cmH2O (invasive mechanical ventilation)

  • Inflammatory ARDS phenotype (28), defined by at least one of the following:

    1. High plasma levels of inflammatory biomarkers
    2. Vasopressor dependence
    3. Lower serum bicarbonate or increased serum lactate
  • Informed consent expressed by the patient or by legal representative or on the Ethical Committee indication.
  • Age >=18 years

Exclusion Criteria:

  • Intubated and mechanically ventilated via an endotracheal or tracheostomy tube (>7 days) up to the time of randomization
  • ARDS severe or moderate for more than 36 hours
  • Untreated pulmonary embolism, pleural effusion or pneumothorax as the primary cause of ARF
  • ARF fully explained by left ventricular failure or fluid overload
  • Consent declined
  • Severe chronic respiratory disease requiring domiciliary ventilation
  • Clinical suspicion for significant restrictive lung disease
  • Pregnant women or women of childbearing potential who are sexually active
  • Known allergy to pirfenidone
  • Concomitant use of fluvoxamine
  • Known severe hepatic failure
  • Known severe renal failure or necessity of dialysis not related to acute disease
  • Little chance of survival (SAPS II score>75)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Pirfenidone
Patients randomized to Pirfernidone Group will receive tables of 267 mg
Drug: Pirfenidone
From days 1-7: 801mg/day; from days 8-14:1602mg/day, from day 15 to ICU discharge 2403 mg/day. All drugs will be delivered by a nasogastric tube divided in 3 daily doses.
Placebo Comparator: Placebo
Patients randomized to Placebo Group will receive 5 ml of Water
Drug: Placebo
All drugs will be delivered by a nasogastric tube divided in 3 daily doses.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The number of ventilator free days (VFD) at day 28.
Time Frame: 28 days

The primary outcome will be calculated following these rules:

  1. the total number of days from day 1 to 28 post randomization on which a patient is alive and receives no assistance from mechanical ventilation, if any period of ventilator liberation lasts at least 48 consecutive hours.
  2. study day 1 is the day of enrolment.
  3. if patients are on mechanical ventilation they will be classified as being on mechanical ventilation for that entire study day.
  4. to be considered liberated from mechanical ventilation, the patient will need to have at least 48 consecutive hours without mechanical ventilation.
  5. non-invasive mechanical ventilation will not be considered assistance if it is provided by face or nasal mask.
  6. patients dead before weaning will be allocated the value of 0 ventilator free days. Any patient who dies after weaning from mechanical ventilation but before day 28 will not have the days after their death until day 28 considered as a VFD.
28 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
ICU-free days at day 28
Time Frame: 28 days
Number of days from randomization to day 28 (or death) in which the subject is outside the ICU. For any discharge lasting less than 48h, no ICU-free days will be computed. Re-admission lasting less than 24 hours will not reduce ICU-fd. Patients that will not survive outside ICU for at least 48 hours.
28 days
Cumulative SOFA-free point at day 28
Time Frame: 28 days
Sequential organ failure assessment score to describe the extent of a patient's organ function and the rate of failure
28 days
Hospital length of stay.
Time Frame: 28 days or until discharge
The total number of days of hospital stay or until dead
28 days or until discharge
Fibroproliferative changes on high-resolution CT performed at ICU discharge
Time Frame: 28 days or until discharge
High-resolution CT (HRCT) scan will be performed at ICU discharge. HRCT scans will be evaluated by two independent observers - radiologists with experience and will be unaware of patient condition. According to specific interpretation guidelines, the presence and extent of areas of ground-glass attenuation, air-space consolidation, traction bronchiectasis, traction bronchiolectasis and honeycombing will be assessed. (Am J Respir Crit Care Med. 2017 May 1;195(9):1253-1263).
28 days or until discharge
Mortality at ICU/hospital discharge
Time Frame: 28 days or until discharge
28 days or until discharge
Quality of life assessment at follow-up (6 12 months) with SF-36 .
Time Frame: through study completion, an average of 1 year
The SF-36 assesses health across eight dimensions using 36 items, such as physical functioning, social functioning and vitality. The SF-36 produces one reported score on a 0-100 scale from the combination of different measurements.
through study completion, an average of 1 year
Quality of life assessment at follow-up (6 12 months) with EQ-5D score.
Time Frame: through study completion, an average of 1 year

The EQ-5D is the most widely used generic preference- based measure of health-related quality of life.

It is based on five dimension (mobility, self-care, usual activity, pain/discomfort and anxiety/depression) and 3 levels (no problems, some problems, extreme problems)which combined, create 243 potential health states.
through study completion, an average of 1 year
Percentage change in the spirometric values, such as FEV1 (% and L/min), FVC (% and L/min) and DLCO (%).
Time Frame: 28 days or until discharge
FEV1-Forced expiratory volume in one second; the volume of air exhaled in the first second under force after a maximal inhalation. It will be used as a baseline pulmonary function parameter. It will be performed via standard office spirometry. It will be calculated as an absolute value (in liters) and as a percentage (compared to the normal population data) FVC- Forced Vital Capacity; the total volume of air that can be exhaled during a maximal forced expiration effort. It will be calculated as an absolute value (in liters) and as a percentage (compared to the normal population data) DLCO-Diffusion Lung Carbon monOxide. It describes the lung capacity of gas exchange.
28 days or until discharge
Proportion of subjects who develop right and/or left heart dysfunction
Time Frame: 28 days or until discharge

Percentage change in the echocardiographic parameters from the baseline to the discharge.

Tricuspid regurgitation (scored from 1 to 4) in the absence of organic tricuspid valve pathology.

Tricuspid annular plane systolic excursion (TAPSE), reflects longitudinal shortening of the RV, measured in mm.

Tissue doppler Index-S' (TDI) reflects the longitudinal velocity of the tricuspid annulus during systole. Measured in cm/sec.

Pulmonary artery systolic pressure (PAPs) has a reasonable accuracy to diagnose exercise-induced pulmonary hypertension. Measured in mmHg.

Telediastolic Diameter (TDD) meaning the measurement of the internal diameter of left ventricle in diastole. Measured in mm.

Ejection Fraction (EF) calculated by dividing the volume of blood pumped from the left ventricle per beat, by the volume of blood collected in the left ventricle at the end of diastolic filling.

Regional Wall Motion Abnormalities (RWMA)
28 days or until discharge
Adverse event rate
Time Frame: 28 days or until discharge
Number of patients who experience at least one adverse event and number of total adverse events
28 days or until discharge
Use of rescue therapies for severe hypoxaemia
Time Frame: 28 days or until discharge
Inhaled nitric oxide, inhaled prostacyclin, prone position, high frequency oscillatory ventilation and extracorporeal membrane ventilation (ECMO)
28 days or until discharge
Broncoalveolar lavage fluid (BAL) speciments
Time Frame: 28 days or until discharge
Cell biology of pulmonary sputum or tissue
28 days or until discharge

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Università Vita-Salute San Raffaele

Investigators

  • Study Chair: Giovanni Landoni, Professor, Università Vita-Salute San Raffaele

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 1, 2022

Primary Completion (Estimated)

June 1, 2026

Study Completion (Estimated)

December 1, 2026

Study Registration Dates

First Submitted

May 25, 2021

First Submitted That Met QC Criteria

September 29, 2021

First Posted (Actual)

October 12, 2021

Study Record Updates

Last Update Posted (Actual)

May 8, 2026

Last Update Submitted That Met QC Criteria

May 5, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PIONEER
  • 2020-005306-25 (EudraCT Number)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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