Clinical trial NCT05075161: Pirfenidone to Prevent Fibrosis in Ards.
Official title: Pirfenidone to Prevent Fibrosis in ARDS. A Randomized Controlled Trial - PIONEER
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Acute Respiratory Distress Syndrome (ARDS)
Keywords: ARDS
Pulmonary Fibrosis
Mechanical Ventilation
Antifibrotic drug
Intensive Care Unit
ICU discharge
Mortality
Spirometry
Quality of life
Lead sponsor: Università Vita-Salute San Raffaele
Sponsor class: OTHER
First posted: 2021-10-12
Enrollment: 130
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: The number of ventilator free days (VFD) at day 28.
timeFrame: 28 days
Secondary outcomes:
measure: ICU-free days at day 28
timeFrame: 28 days
measure: Cumulative SOFA-free point at day 28
timeFrame: 28 days
measure: Hospital length of stay.
timeFrame: 28 days or until discharge
measure: Fibroproliferative changes on high-resolution CT performed at ICU discharge
timeFrame: 28 days or until discharge
measure: Mortality at ICU/hospital discharge
timeFrame: 28 days or until discharge
measure: Quality of life assessment at follow-up (6 12 months) with SF-36 .
timeFrame: through study completion, an average of 1 year
measure: Quality of life assessment at follow-up (6 12 months) with EQ-5D score.
timeFrame: through study completion, an average of 1 year
measure: Percentage change in the spirometric values, such as FEV1 (% and L/min), FVC (% and L/min) and DLCO (%).
timeFrame: 28 days or until discharge
measure: Proportion of subjects who develop right and/or left heart dysfunction
timeFrame: 28 days or until discharge
measure: Adverse event rate
timeFrame: 28 days or until discharge
measure: Use of rescue therapies for severe hypoxaemia
timeFrame: 28 days or until discharge
measure: Broncoalveolar lavage fluid (BAL) speciments
timeFrame: 28 days or until discharge
Other outcomes:
Locations:
city: Milan
country: Italy
facility: IRCCS San Raffaele Scientific Institute
state: MI
city: Brescia
country: Italy
facility: ASST Spedali Civili di Brescia
city: Cagliari
country: Italy
facility: Ospedale San Giovanni di Dio - Azienda Ospedaliera Universitaria di Cagliari
city: Milan
country: Italy
facility: Ospedale Uboldo di Cernusco sul Naviglio
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana
city: Potenza
country: Italy
facility: A.O.R San Carlo
city: Rome
country: Italy
facility: Fondazione PTV - Policlinico Tor Vergata
city: Siena
country: Italy
facility: Azienda Ospedaliero Universitaria Senese
city: Torino
country: Italy
facility: AOU Città della Salute e della Scienza
city: Udine
country: Italy
facility: Azienda Sanitaria Universitaria Integrata di Udine
Study officials:
affiliation: Vita-Salute San Raffaele University
name: Giovanni Landoni, Professor
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.