Pirfenidone to Prevent Fibrosis in Ards.

NCT05075161 | Recruiting Phase 3 DMC

• 2 other identifiers: PIONEER2020-005306-25
• Study Type: interventional
• Target: 130
• Locations: 2 countries
• Sites: 17

Brief Summary

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.

Conditions

Acute Respiratory Distress Syndrome (ARDS)

Keywords

ARDS; Pulmonary Fibrosis; Mechanical Ventilation; Antifibrotic drug; Intensive Care Unit; ICU discharge; Mortality; Spirometry; Quality of life

Outcome Measures

Primary Outcomes (1)

• The number of ventilator free days (VFD) at day 28.

  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 Outcomes (12)

• ICU-free days at day 28

  28 days

• Cumulative SOFA-free point at day 28

  28 days

• Hospital length of stay.

  28 days or until discharge

• Fibroproliferative changes on high-resolution CT performed at ICU discharge

  28 days or until discharge

• Mortality at ICU/hospital discharge

  28 days or until discharge

Study Arms (2)

Pirfenidone

EXPERIMENTAL

Patients randomized to Pirfernidone Group will receive tables of 267 mg

Drug: Pirfenidone

Placebo

PLACEBO COMPARATOR

Patients randomized to Placebo Group will receive 5 ml of Water

Drug: Placebo

Interventions

Pirfenidone DRUG

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.

Pirfenidone

Placebo DRUG

All drugs will be delivered by a nasogastric tube divided in 3 daily doses.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Concomitant presence of:
• ARDS (moderate and severe) - Berlin definition
• Within 1 week of a known clinical insult or new or worsening respiratory symptoms
• Bilateral opacities on CXR which are not fully explained by effusions, lobar/lung collapse or nodules
• Respiratory failure not fully explained by cardiac failure or fluid overload
• PaO2/FiO2\<200 mmHg with PEEP\<=5 cmH2O (invasive mechanical ventilation)
• Inflammatory ARDS phenotype (28), defined by at least one of the following:
• High plasma levels of inflammatory biomarkers
• Vasopressor dependence
• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Università Vita-Salute San Raffaele: lead

Study Sites (17)

IRCCS San Raffaele Scientific Institute

Milan, MI, 20132, Italy

RECRUITING

Ospedale Cesare Arrigo

Alessandria, Piedmont, 15121, Italy

RECRUITING

Ospedale Santa Maria

Bari, Italy

RECRUITING

ASST Spedali Civili di Brescia

Brescia, 25123, Italy

RECRUITING

Ospedale San Giovanni di Dio - Azienda Ospedaliera Universitaria di Cagliari

Cagliari, 09123, Italy

RECRUITING

Ospedale di Merano

Merano, Italy

RECRUITING

Ospedale Uboldo di Cernusco sul Naviglio

Milan, 20070, Italy

RECRUITING

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, Italy

RECRUITING

AOU Policlinico Paolo Giaccone

Palermo, Italy

RECRUITING

Azienda Ospedaliero Universitaria Pisana

Pisa, 56126, Italy

RECRUITING

AOU Pisana

Pisa, Italy

RECRUITING

A.O.R San Carlo

Potenza, Italy

RECRUITING

Fondazione PTV - Policlinico Tor Vergata

Rome, 00133, Italy

RECRUITING

Azienda Ospedaliero Universitaria Senese

Siena, 53100, Italy

RECRUITING

AOU Città della Salute e della Scienza

Torino, 10126, Italy

RECRUITING

Azienda Sanitaria Universitaria Integrata di Udine

Udine, 33100, Italy

RECRUITING

Astana Medical University

Astana, 010000, Kazakhstan

RECRUITING

Related Publications (26)

• ARDS Definition Task Force; Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012 Jun 20;307(23):2526-33. doi: 10.1001/jama.2012.5669.

  PMID: 22797452 BACKGROUND

• Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, van Haren F, Larsson A, McAuley DF, Ranieri M, Rubenfeld G, Thompson BT, Wrigge H, Slutsky AS, Pesenti A; LUNG SAFE Investigators; ESICM Trials Group. Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA. 2016 Feb 23;315(8):788-800. doi: 10.1001/jama.2016.0291.

  PMID: 26903337 BACKGROUND

• Bos LD, Martin-Loeches I, Schultz MJ. ARDS: challenges in patient care and frontiers in research. Eur Respir Rev. 2018 Jan 24;27(147):170107. doi: 10.1183/16000617.0107-2017. Print 2018 Mar 31.

  PMID: 29367411 BACKGROUND

• Gao Smith F, Perkins GD, Gates S, Young D, McAuley DF, Tunnicliffe W, Khan Z, Lamb SE; BALTI-2 study investigators. Effect of intravenous beta-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial. Lancet. 2012 Jan 21;379(9812):229-35. doi: 10.1016/S0140-6736(11)61623-1. Epub 2011 Dec 11.

  PMID: 22166903 BACKGROUND

• Davidson WJ, Dorscheid D, Spragg R, Schulzer M, Mak E, Ayas NT. Exogenous pulmonary surfactant for the treatment of adult patients with acute respiratory distress syndrome: results of a meta-analysis. Crit Care. 2006;10(2):R41. doi: 10.1186/cc4851.

  PMID: 16542488 BACKGROUND

• Zhang Y, Ding S, Li C, Wang Y, Chen Z, Wang Z. Effects of N-acetylcysteine treatment in acute respiratory distress syndrome: A meta-analysis. Exp Ther Med. 2017 Oct;14(4):2863-2868. doi: 10.3892/etm.2017.4891. Epub 2017 Aug 7.

  PMID: 28928799 BACKGROUND

• Iwata K, Doi A, Ohji G, Oka H, Oba Y, Takimoto K, Igarashi W, Gremillion DH, Shimada T. Effect of neutrophil elastase inhibitor (sivelestat sodium) in the treatment of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS): a systematic review and meta-analysis. Intern Med. 2010;49(22):2423-32. doi: 10.2169/internalmedicine.49.4010. Epub 2010 Nov 15.

  PMID: 21088343 BACKGROUND

• Paine R 3rd, Standiford TJ, Dechert RE, Moss M, Martin GS, Rosenberg AL, Thannickal VJ, Burnham EL, Brown MB, Hyzy RC. A randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury. Crit Care Med. 2012 Jan;40(1):90-7. doi: 10.1097/CCM.0b013e31822d7bf0.

  PMID: 21926600 BACKGROUND

• Agrawal A, Zhuo H, Brady S, Levitt J, Steingrub J, Siegel MD, Soto G, Peterson MW, Chesnutt MS, Matthay MA, Liu KD. Pathogenetic and predictive value of biomarkers in patients with ALI and lower severity of illness: results from two clinical trials. Am J Physiol Lung Cell Mol Physiol. 2012 Oct 15;303(8):L634-9. doi: 10.1152/ajplung.00195.2012. Epub 2012 Aug 3.

  PMID: 22865551 BACKGROUND

• Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA; NHLBI ARDS Network. Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med. 2014 Aug;2(8):611-20. doi: 10.1016/S2213-2600(14)70097-9. Epub 2014 May 19.

  PMID: 24853585 BACKGROUND

• Famous KR, Delucchi K, Ware LB, Kangelaris KN, Liu KD, Thompson BT, Calfee CS; ARDS Network. Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy. Am J Respir Crit Care Med. 2017 Feb 1;195(3):331-338. doi: 10.1164/rccm.201603-0645OC.

  PMID: 27513822 BACKGROUND

• Meduri GU, Headley S, Kohler G, Stentz F, Tolley E, Umberger R, Leeper K. Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL-1 beta and IL-6 levels are consistent and efficient predictors of outcome over time. Chest. 1995 Apr;107(4):1062-73. doi: 10.1378/chest.107.4.1062.

  PMID: 7705118 BACKGROUND

• Wang CY, Calfee CS, Paul DW, Janz DR, May AK, Zhuo H, Bernard GR, Matthay MA, Ware LB, Kangelaris KN. One-year mortality and predictors of death among hospital survivors of acute respiratory distress syndrome. Intensive Care Med. 2014 Mar;40(3):388-96. doi: 10.1007/s00134-013-3186-3. Epub 2014 Jan 17.

  PMID: 24435201 BACKGROUND

• Acute Respiratory Distress Syndrome Network; Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000 May 4;342(18):1301-8. doi: 10.1056/NEJM200005043421801.

  PMID: 10793162 BACKGROUND

• Orme J Jr, Romney JS, Hopkins RO, Pope D, Chan KJ, Thomsen G, Crapo RO, Weaver LK. Pulmonary function and health-related quality of life in survivors of acute respiratory distress syndrome. Am J Respir Crit Care Med. 2003 Mar 1;167(5):690-4. doi: 10.1164/rccm.200206-542OC. Epub 2002 Dec 18.

  PMID: 12493646 BACKGROUND

• Masclans JR, Roca O, Munoz X, Pallisa E, Torres F, Rello J, Morell F. Quality of life, pulmonary function, and tomographic scan abnormalities after ARDS. Chest. 2011 Jun;139(6):1340-1346. doi: 10.1378/chest.10-2438. Epub 2011 Feb 17.

  PMID: 21330382 BACKGROUND

• Linden VB, Lidegran MK, Frisen G, Dahlgren P, Frenckner BP, Larsen F. ECMO in ARDS: a long-term follow-up study regarding pulmonary morphology and function and health-related quality of life. Acta Anaesthesiol Scand. 2009 Apr;53(4):489-95. doi: 10.1111/j.1399-6576.2008.01808.x. Epub 2009 Feb 18.

  PMID: 19226296 BACKGROUND

• Cooper AB, Ferguson ND, Hanly PJ, Meade MO, Kachura JR, Granton JT, Slutsky AS, Stewart TE. Long-term follow-up of survivors of acute lung injury: lack of effect of a ventilation strategy to prevent barotrauma. Crit Care Med. 1999 Dec;27(12):2616-21. doi: 10.1097/00003246-199912000-00002.

  PMID: 10628599 BACKGROUND

• Papazian L, Doddoli C, Chetaille B, Gernez Y, Thirion X, Roch A, Donati Y, Bonnety M, Zandotti C, Thomas P. A contributive result of open-lung biopsy improves survival in acute respiratory distress syndrome patients. Crit Care Med. 2007 Mar;35(3):755-62. doi: 10.1097/01.CCM.0000257325.88144.30.

  PMID: 17255856 BACKGROUND

• Martin C, Papazian L, Payan MJ, Saux P, Gouin F. Pulmonary fibrosis correlates with outcome in adult respiratory distress syndrome. A study in mechanically ventilated patients. Chest. 1995 Jan;107(1):196-200. doi: 10.1378/chest.107.1.196.

  PMID: 7813276 BACKGROUND

• King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigris JJ, Noble PW; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014 May 29;370(22):2083-92. doi: 10.1056/NEJMoa1402582. Epub 2014 May 18.

  PMID: 24836312 BACKGROUND

• Conte E, Gili E, Fagone E, Fruciano M, Iemmolo M, Vancheri C. Effect of pirfenidone on proliferation, TGF-beta-induced myofibroblast differentiation and fibrogenic activity of primary human lung fibroblasts. Eur J Pharm Sci. 2014 Jul 16;58:13-9. doi: 10.1016/j.ejps.2014.02.014. Epub 2014 Mar 12.

  PMID: 24613900 BACKGROUND

• Schaefer CJ, Ruhrmund DW, Pan L, Seiwert SD, Kossen K. Antifibrotic activities of pirfenidone in animal models. Eur Respir Rev. 2011 Jun;20(120):85-97. doi: 10.1183/09059180.00001111.

  PMID: 21632796 BACKGROUND

• Liu Y, Lu F, Kang L, Wang Z, Wang Y. Pirfenidone attenuates bleomycin-induced pulmonary fibrosis in mice by regulating Nrf2/Bach1 equilibrium. BMC Pulm Med. 2017 Apr 18;17(1):63. doi: 10.1186/s12890-017-0405-7.

  PMID: 28420366 BACKGROUND

• Fan E, Del Sorbo L, Goligher EC, Hodgson CL, Munshi L, Walkey AJ, Adhikari NKJ, Amato MBP, Branson R, Brower RG, Ferguson ND, Gajic O, Gattinoni L, Hess D, Mancebo J, Meade MO, McAuley DF, Pesenti A, Ranieri VM, Rubenfeld GD, Rubin E, Seckel M, Slutsky AS, Talmor D, Thompson BT, Wunsch H, Uleryk E, Brozek J, Brochard LJ; American Thoracic Society, European Society of Intensive Care Medicine, and Society of Critical Care Medicine. An Official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guideline: Mechanical Ventilation in Adult Patients with Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2017 May 1;195(9):1253-1263. doi: 10.1164/rccm.201703-0548ST.

  PMID: 28459336 BACKGROUND

• Monti G, Marzaroli M, Tucciariello MT, Ferrara B, Meroi F, Nakhnoukh C, Zambon M, Borghi G, Guarracino F, Manazza M, Ajello V, Belletti A, Biuzzi C, Plumari V, Filippini M, Cuffaro R, Racanelli G, Pontillo D, Rauch S, Oliva FM, Tescione M, Baiardo Redaelli M, Melegari G, Maj G, Navalesi P, Gerardi M, Caccioppola A, Bruni A, Ballotta A, Ferri C, Orso D, Di Benedetto V, Baldassarri R, Franceschini G, Alamami A, Pasin L, Putzu A, Romero Garcia CS, Chen YS, Noto A, Yavorovskiy A, Hajjar LA, Cortegiani A, Likhvantsev V, Konkayev A, Finco G, Sales G, Brazzi L, Paternoster G, Bellomo R, Zangrillo A, Landoni G, Di Tomasso N; PIONEER Study Group. Pirfenidone to prevent fibrosis in acute respiratory distress syndrome: The PIONEER study protocol. Contemp Clin Trials. 2025 Jun;153:107883. doi: 10.1016/j.cct.2025.107883. Epub 2025 Mar 14.

  PMID: 40090666 DERIVED

MeSH Terms

Conditions

Respiratory Distress Syndrome; Pulmonary Fibrosis

Interventions

pirfenidone

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases, Interstitial; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Giovanni Landoni, Professor

  Vita-Salute San Raffaele University

  STUDY CHAIR

Central Study Contacts

Nora Di Tomasso, MD

CONTACT

+39022643; ditomasso.nora@hsr.it

Giacomo Monti, MD

CONTACT

+39022643; monti.giacomo@hsr.it

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, Associate Professor

Study Record Dates

• First Submitted: May 25, 2021
• First Posted: October 12, 2021
• Study Start: June 1, 2022
• Primary Completion: December 1, 2025
• Study Completion: December 1, 2025
• Last Updated: August 6, 2025

Record last verified: 2025-08

Locations

IT (16); KA (1)