Pirfenidone to Prevent Fibrosis in Ards.

Official title

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

Overview

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.

Interventions

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

Primary outcome measures

• The number of ventilator free days (VFD) at day 28. [Time frame: 28 days]

Secondary outcome measures (12)

• ICU-free days at day 28 [Time frame: 28 days]
• Cumulative SOFA-free point at day 28 [Time frame: 28 days]
• Hospital length of stay. [Time frame: 28 days or until discharge]
• Fibroproliferative changes on high-resolution CT performed at ICU discharge [Time frame: 28 days or until discharge]
• Mortality at ICU/hospital discharge [Time frame: 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]
• Quality of life assessment at follow-up (6 12 months) with EQ-5D score. [Time frame: 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]
• Proportion of subjects who develop right and/or left heart dysfunction [Time frame: 28 days or until discharge]
• Adverse event rate [Time frame: 28 days or until discharge]
• Use of rescue therapies for severe hypoxaemia [Time frame: 28 days or until discharge]
• Broncoalveolar lavage fluid (BAL) speciments [Time frame: 28 days or until discharge]

Eligibility criteria

Inclusion criteria

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

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)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Italy · 16 centers

• IRCCS San Raffaele Scientific Institute — Milan
• Ospedale Cesare Arrigo — Alessandria
• Ospedale Santa Maria — Bari
• ASST Spedali Civili di Brescia — Brescia
• Ospedale San Giovanni di Dio - Azienda Ospedaliera Universitaria di Cagliari — Cagliari
• Ospedale di Merano — Merano
• Ospedale Uboldo di Cernusco sul Naviglio — Milan
• Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico — Milan
• … and 8 more centers

Kazakhstan · 1 center

• Astana Medical University — Astana

Publications

• 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
• 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. d PMID 26903337
• 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
• 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
• 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
• 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
• 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
• 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

Identifiers

NCT: NCT05075161 · PIONEER · 2020-005306-25

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗