Treatment With Pirfenidone for COVID-19 Related Severe ARDS

Study Overview
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Brief Summary
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A randomized, open label, two arm, pilot trial of Pirfenidone 2,403 mg administered per nasogastric tube or orally as 801mg TID for 4 weeks in addition to Standard of Care (SoC), compared to SoC alone, in a population of COVID-19 induced severe ARDS. Patients will be randomized according to 1:1 ratio to one of the trial arms: Pirfenidone (intervention arm) or SoC (control arm).

Detailed Description
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The objective of the trial is to evaluate the safety and efficacy of treatment with Pirfenidone vs SoC in COVID-19 induced severe Acute Respiratory Distress Syndrome (ARDS) requiring mechanical ventilation. Following initial diagnosis of COVID-19, severe ARDS patient will be admitted to a dedicated intensive care unit (ICU) at Soroka University Medical Center (Day 0). Upon admission, patients will be randomized according to 1:1 ratio to one of the trial arms and receive either Pirfenidone 2,403mg administered through nasogastric tube as 801mg TID (intervention arm) plus SoC or only SoC treatment (control arm). Patients' vital signs (temperature, blood pressure, pulse rate per minute, breath rate per minute, oxygen saturation) urine output, ventilation settings, and respiratory parameters will be monitored according to SoC. Symptom will be captured daily from patients as well as adverse events (AEs) assessment and recording of the need for any supportive care during the period of ICU admission.

Official Title
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Treatment With Pirfenidone for COVID-19 Related Severe ARDS An Open Label Pilot Trial

Conditions
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Covid19, ARDS

Intervention / Treatment
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* Drug: Pirfenidone
* Other: Standard of care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women between the ages 18-80 years Diagnosis of COVID19 with severe ARDS (PaO2/FIO2 <150mmHg) Admission to the ICU and in need of mechanical ventilation Able to give informed consent according to local regulations. If the patient is unable to give written informed consent, the form will be read to them and their verbal consent will be documented. If the patient is sedated, an impartial ICU physician will approve eligibility. Exclusion Criteria: Previous use of nintedanib or pirfenidone Administration of fluvoxamine 7 days prior to admission to ICU Severe hepatic impairment (liver enzymes and bilirubin>2 of normal upper limit, at day 0) or end stage liver disease Severe renal impairment (CrCl <30 ml/min) or end stage renal disease requiring dialysis Pregnancy Participation in any other clinical trial 30 days prior to enrollment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Interventional Model Description: Following initial diagnosis of COVID-19, severe ARDS patient will be admitted to a dedicated intensive care unit (ICU) at Soroka University Medical Center (Day 0). Upon admission, patients will be randomized according to 1:1 ratio to one of the trial arms and receive either Pirfenidone 2,403mg administered through nasogastric tube as 801mg TID (intervention arm) plus SoC or SoC alone (control arm).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Standard of Care - Control<br>Standard of care (Soc) according to current guidelines and the discretion of treating physician. | Other: Standard of care<br>* Treatment with SoC as mentioned in the control arm description.<br>* Other names: Control Arm;|
| Experimental: Pirfenidone Treatment<br>In addition to SoC, Pirfenidone 2,403 mg administered orally or per nasogastric tube as 801mg TID, for 4 weeks. Pirfenidone dose will be 2,403mg daily, from day one of admission to the ICU, titrated over 3 days: Day 1 - 801mg x 1/d (801mg) Day 2 - 801mg x 2/d (1,602 mg) Day 3 - 801mg x 3/d (2,403 mg) Feeding and medication delivery will be upon the discretion of the treating physician according to tolerability. Powdered 801mg tablets will be administered through the nasogastric tube: Each tablet will be crushed and dissolved in 20cc of water. The nasogastric tube will be flushed afterwards to avoid obstruction.. If the patient is able to swallow and the nasogastric tube is removed, pirfenidone will continue to be delivered orally. | Drug: Pirfenidone<br>* Treatment with Pirfenidone as mentioned in the experimental arm description.<br>* Other names: Intervention Arm;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilation free days to day 28 (VFD28) | Measured in number of days | Up to 28 days from admission to ICU | 
| Severe adverse events (SAEs) rate | Number of SAEs divided to number of patients | Through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | Includes all cause mortality, mortality in the ICU, 28 days mortality, 60 days mortality, in-hospital mortality, and ARDS related mortality. Measured in number of days. | Through study completion, an average of 1 year | 
| ICU length of stay | Measured in number of days | Through study completion, an average of 1 year | 
| Lung compliance | Part of mechanical ventilation parameters, calculated as tidal volume divided by the difference between plateau pressure and PEEP. Daily average will be assessed until extubation. Units are mL/cmH2O. | Through study completion, an average of 1 year | 
| Tidal Volume | Part of mechanical ventilation parameters, it is the lung volume representing the volume of air displaced between normal inhalation and exhalation. Measured continuously by the ventilator, calculated and represented as area under the curve after omitting extreme values <5 and >95 percentiles. Measured in mL. | Through study completion, an average of 1 year | 
| Positive End Expiratory Pressure (PEEP) | Part of mechanical ventilation parameters, it is the pressure in the lungs above atmospheric pressure that exists at the end of expiration. It is set by the treating physicians according to the clinical situation of the patient, and will be documented daily until extubation. Measured in cmH2O. | Through study completion, an average of 1 year | 
| Driving Pressure | Part of mechanical ventilation parameters, it is the difference between plateau pressure and PEEP. Measured continuously by the ventilator, calculated and represented as area under the curve after omitting extreme values <5 and >95 percentiles. | Through study completion, an average of 1 year | 
| Quality of life questionnaire | Assessed by St George Respiratory Questionnaire (SGRQ). Scoring range from 0 to 100, with higher scored indicating more limitation. | on admission and 6 months after discharge | 
| Vital Capacity (VC) | Part of pulmonary function tests, it is the maximum amount of air a person can expel from the lungs after a maximum inhalation. Measured on a spirometer in mL. | On admission (if possible) and 6 months after discharge | 
| Forced Vital Capacity (FVC) | Part of pulmonary function tests, it is the vital capacity that results from a maximally forced expiratory effort. Measured on a spirometer in mL. | On admission (if possible) and 6 months after discharge | 
| Forced Expiratory Volume at first second (FEV1) | Part of pulmonary function tests, it is the volume of air exhaled at the end of the first second of forced expiration. Measured on a spirometer in mL. | On admission (if possible) and 6 months after discharge | 
| Diffusing Capacity for Carbon Monoxide (DLCO) | Part of pulmonary function tests, it is the extent to which oxygen passes from the air sacs of the lungs into the blood. Measured on a spirometer in mL/min/kPa. | On admission (if possible) and 6 months after discharge | 
| 6 minutes walking test | The distance covered over a time of 6 minutes, measured in meters. | 6 months after discharge from hospital | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ARDS, Pirfenidone, Covid-19