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Treatment With Pirfenidone for COVID-19 Related Severe ARDS

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ClinicalTrials.gov Identifier: NCT04653831
Recruitment Status : Recruiting
First Posted : December 4, 2020
Last Update Posted : December 4, 2020
Sponsor:
Collaborator:
Roche Pharma AG
Information provided by (Responsible Party):
Yasmeen Abu Fraiha, Soroka University Medical Center

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Covid19 ARDS Drug: Pirfenidone Other: Standard of care Not Applicable

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Treatment
Official Title: Treatment With Pirfenidone for COVID-19 Related Severe ARDS An Open Label Pilot Trial
Actual Study Start Date : November 8, 2020
Estimated Primary Completion Date : November 2021
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Pirfenidone

Arm Intervention/treatment
Standard of Care - Control
Standard of care (Soc) according to current guidelines and the discretion of treating physician.
Other: Standard of care
Treatment with SoC as mentioned in the control arm description.
Other Name: Control Arm

Experimental: Pirfenidone Treatment

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
Treatment with Pirfenidone as mentioned in the experimental arm description.
Other Name: Intervention Arm




Primary Outcome Measures :
  1. Ventilation free days to day 28 (VFD28) [ Time Frame: Up to 28 days from admission to ICU ]
    Measured in number of days

  2. Severe adverse events (SAEs) rate [ Time Frame: Through study completion, an average of 1 year ]
    Number of SAEs divided to number of patients


Secondary Outcome Measures :
  1. Mortality [ Time Frame: Through study completion, an average of 1 year ]
    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.

  2. ICU length of stay [ Time Frame: Through study completion, an average of 1 year ]
    Measured in number of days

  3. Lung compliance [ Time Frame: Through study completion, an average of 1 year ]
    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.

  4. Tidal Volume [ Time Frame: Through study completion, an average of 1 year ]
    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.

  5. Positive End Expiratory Pressure (PEEP) [ Time Frame: Through study completion, an average of 1 year ]
    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.

  6. Driving Pressure [ Time Frame: Through study completion, an average of 1 year ]
    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.

  7. Quality of life questionnaire [ Time Frame: on admission and 6 months after discharge ]
    Assessed by St George Respiratory Questionnaire (SGRQ). Scoring range from 0 to 100, with higher scored indicating more limitation.

  8. Vital Capacity (VC) [ Time Frame: On admission (if possible) and 6 months after discharge ]
    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.

  9. Forced Vital Capacity (FVC) [ Time Frame: On admission (if possible) and 6 months after discharge ]
    Part of pulmonary function tests, it is the vital capacity that results from a maximally forced expiratory effort. Measured on a spirometer in mL.

  10. Forced Expiratory Volume at first second (FEV1) [ Time Frame: On admission (if possible) and 6 months after discharge ]
    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.

  11. Diffusing Capacity for Carbon Monoxide (DLCO) [ Time Frame: On admission (if possible) and 6 months after discharge ]
    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.

  12. 6 minutes walking test [ Time Frame: 6 months after discharge from hospital ]
    The distance covered over a time of 6 minutes, measured in meters.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04653831


Contacts
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Contact: Ori Galante, MD +972507577582 ori.galante@gmail.com
Contact: Yasmeen Abu Fraiha, MD +972505607045 yasmeenaf23@gmail.com

Locations
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Israel
Soroka Medical Center Recruiting
Be'er Sheva, Israel
Contact: Yasmeen Abu Fraiha, MD       yasmeenaf23@gmail.com   
Sponsors and Collaborators
Soroka University Medical Center
Roche Pharma AG
Investigators
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Principal Investigator: Ori Galante, MD ICU physician in SMC
Additional Information:
Publications:
Chen HC, et al pirfenidone can enhance the patients' recovery from fibrotic phase of ARDS: a case report. https://doi.org/10.1016/j.chest.2019.02.130
Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Mar;43(3):304-377. doi: 10.1007/s00134-017-4683-6. Epub 2017 Jan 18.

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Responsible Party: Yasmeen Abu Fraiha, Internal Medicine resident, MD, Soroka University Medical Center
ClinicalTrials.gov Identifier: NCT04653831    
Other Study ID Numbers: SCRC20007
First Posted: December 4, 2020    Key Record Dates
Last Update Posted: December 4, 2020
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Yasmeen Abu Fraiha, Soroka University Medical Center:
Covid-19
ARDS
Pirfenidone
Additional relevant MeSH terms:
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Pirfenidone
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Anti-Inflammatory Agents
Antirheumatic Agents
Antineoplastic Agents