Pirfenidone to Prevent Fibrosis in Ards. (PIONEER)

Università Vita-Salute San Raffaele

Status and phase: Enrolling; Phase 3

Conditions: Acute Respiratory Distress Syndrome (ARDS)

Treatments: Drug: Pirfenidone; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT05075161

2020-005306-25 (EudraCT Number)

PIONEER

Details and patient eligibility

About

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.

Full 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.

Enrollment: 130 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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130 participants in 2 patient groups, including a placebo group

Pirfenidone

Experimental group

Description:

Patients randomized to Pirfernidone Group will receive tables of 267 mg

Treatment:

Drug: Pirfenidone

Placebo

Placebo Comparator group

Description:

Patients randomized to Placebo Group will receive 5 ml of Water

Treatment:

Drug: Placebo