Back to resultsPirfenidone to Prevent Fibrosis in Ards. (PIONEER)
Primary Purpose
Acute Respiratory Distress Syndrome (ARDS)
Status
Recruiting
Phase
Phase 3
Locations
Italy
Study Type
Interventional
Intervention
Pirfenidone
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Acute Respiratory Distress Syndrome (ARDS) focused on measuring ARDS, Pulmonary Fibrosis, Mechanical Ventilation, Antifibrotic drug, Intensive Care Unit, ICU discharge, Mortality, Spirometry, Quality of life
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)
Sites / Locations
- IRCCS San Raffaele Scientific InstituteRecruiting
- A.O.R San CarloRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Pirfenidone
Placebo
Arm Description
Patients randomized to Pirfernidone Group will receive tables of 267 mg
Patients randomized to Placebo Group will receive 5 ml of Water
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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
Hospital length of stay.
The total number of days of hospital stay or until dead
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).
Mortality at ICU/hospital 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.
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.
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.
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)
Adverse event rate
Number of patients who experience at least one adverse event and number of total adverse events
Use of rescue therapies for severe hypoxaemia
Inhaled nitric oxide, inhaled prostacyclin, prone position, high frequency oscillatory ventilation and extracorporeal membrane ventilation (ECMO)
Broncoalveolar lavage fluid (BAL) speciments
Cell biology of pulmonary sputum or tissue
Full Information
NCT ID
NCT05075161
First Posted
May 25, 2021
Last Updated
December 23, 2022
Sponsor
Università Vita-Salute San Raffaele
1. Study Identification
Unique Protocol Identification Number
NCT05075161
Brief Title
Pirfenidone to Prevent Fibrosis in Ards.
Acronym
PIONEER
Official Title
Pirfenidone to Prevent Fibrosis in ARDS. A Randomized Controlled Trial - PIONEER
Study Type
Interventional
2. Study Status
Record Verification Date
December 2022
Overall Recruitment Status
Recruiting
Study Start Date
June 1, 2022 (Actual)
Primary Completion Date
October 2024 (Anticipated)
Study Completion Date
October 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Università Vita-Salute San Raffaele
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Respiratory Distress Syndrome (ARDS)
Keywords
ARDS, Pulmonary Fibrosis, Mechanical Ventilation, Antifibrotic drug, Intensive Care Unit, ICU discharge, Mortality, Spirometry, Quality of life
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
130 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Pirfenidone
Arm Type
Experimental
Arm Description
Patients randomized to Pirfernidone Group will receive tables of 267 mg
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Patients randomized to Placebo Group will receive 5 ml of Water
Intervention Type
Drug
Intervention Name(s)
Pirfenidone
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
All drugs will be delivered by a nasogastric tube divided in 3 daily doses.
Primary Outcome Measure Information:
Title
The number of ventilator free days (VFD) at day 28.
Description
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.
Time Frame
28 days
Secondary Outcome Measure Information:
Title
ICU-free days at day 28
Description
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.
Time Frame
28 days
Title
Cumulative SOFA-free point at day 28
Description
Sequential organ failure assessment score to describe the extent of a patient's organ function and the rate of failure
Time Frame
28 days
Title
Hospital length of stay.
Description
The total number of days of hospital stay or until dead
Time Frame
28 days or until discharge
Title
Fibroproliferative changes on high-resolution CT performed at ICU discharge
Description
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).
Time Frame
28 days or until discharge
Title
Mortality at ICU/hospital discharge
Time Frame
28 days or until discharge
Title
Quality of life assessment at follow-up (6 12 months) with SF-36 .
Description
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.
Time Frame
through study completion, an average of 1 year
Title
Quality of life assessment at follow-up (6 12 months) with EQ-5D score.
Description
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.
Time Frame
through study completion, an average of 1 year
Title
Percentage change in the spirometric values, such as FEV1 (% and L/min), FVC (% and L/min) and DLCO (%).
Description
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.
Time Frame
28 days or until discharge
Title
Proportion of subjects who develop right and/or left heart dysfunction
Description
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)
Time Frame
28 days or until discharge
Title
Adverse event rate
Description
Number of patients who experience at least one adverse event and number of total adverse events
Time Frame
28 days or until discharge
Title
Use of rescue therapies for severe hypoxaemia
Description
Inhaled nitric oxide, inhaled prostacyclin, prone position, high frequency oscillatory ventilation and extracorporeal membrane ventilation (ECMO)
Time Frame
28 days or until discharge
Title
Broncoalveolar lavage fluid (BAL) speciments
Description
Cell biology of pulmonary sputum or tissue
Time Frame
28 days or until discharge
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Nora Di Tomasso, MD
Phone
+39022643
Ext
7722
Email
ditomasso.nora@hsr.it
First Name & Middle Initial & Last Name or Official Title & Degree
Giacomo Monti, MD
Phone
+39022643
Ext
2222
Email
monti.giacomo@hsr.it
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Giovanni Landoni, Professor
Organizational Affiliation
Vita-Salute San Raffaele University
Official's Role
Study Chair
Facility Information:
Facility Name
IRCCS San Raffaele Scientific Institute
City
Milan
State/Province
MI
ZIP/Postal Code
20132
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nora Di Tomasso, MD
Phone
+39022643
Ext
7722
Email
ditomasso.nora@hsr.it
Facility Name
A.O.R San Carlo
City
Potenza
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gianluca Paternoster, MD
Email
paternostergianluca@gmail.com
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28459336
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. Erratum In: Am J Respir Crit Care Med. 2017 Jun 1;195(11):1540.
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