Pirfenidone to Prevent Fibrosis in Ards.

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Acute Respiratory Distress Syndrome (ARDS)

Intervention / Treatment
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* Drug: Pirfenidone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pirfenidone<br>Patients randomized to Pirfernidone Group will receive tables of 267 mg | Drug: Pirfenidone<br>* 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.<br>|
| Placebo Comparator: Placebo<br>Patients randomized to Placebo Group will receive 5 ml of Water | Drug: Placebo<br>* All drugs will be delivered by a nasogastric tube divided in 3 daily doses.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of ventilator free days (VFD) at day 28. | The primary outcome will be calculated following these rules: 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. study day 1 is the day of enrolment. if patients are on mechanical ventilation they will be classified as being on mechanical ventilation for that entire study day. to be considered liberated from mechanical ventilation, the patient will need to have at least 48 consecutive hours without mechanical ventilation. non-invasive mechanical ventilation will not be considered assistance if it is provided by face or nasal mask. 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 | 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 | 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. | 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 | 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 |  | 28 days or until discharge | 
| Quality of life assessment at follow-up (6 12 months) with SF-36 . | 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. | 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 (%). | 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 | 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 | 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 | 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 | Cell biology of pulmonary sputum or tissue | 28 days or until discharge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ARDS, Pulmonary Fibrosis, Mechanical Ventilation, Antifibrotic drug, Intensive Care Unit, ICU discharge, Mortality, Spirometry, Quality of life