Therapeutic Plasma Exchange to Alleviate Hyperinflammatory Condition During Severe Covid-19 Infections (CovidEP)

Assessment of Therapeutic Plasma Exchange to Improve Respiratory Function by Alleviating Cytokine Storm During Severe Covid-19 Infections Randomised Open-label Controlled Trial

Severe Covid-19 (Coronavirus Disease 2019) infections generate major but inappropriate production of cytokines and, in some cases, generate anti-IFN (Interferon) auto-antibodies, inducing acute respiratory distress syndrom (ARDS). Therapeutic plasma exchange (TPE) have been reported to be efficient for improving the hyperinflammatory condition state and the respiratory function, which has been described in case reports or small series.

The study aims to remove cytokines during cytokine storm and anti-IFN auto-antibodies (when present) to prevent developpement of an inappropriate immune response and to improve the clinical response to reanimation treatment, in particular the respiratory parameters leading to a rapid improvement of clinical status. To that aim, the study investigates to compare a treatment using TPE plus usual treatments in intensive care unit (experimental arm) versus usual treatments in intensive care unit (routine arm) in a randomised trial.

Study Overview

• Status: Recruiting
• Conditions: Covid19; ARDS, Human; Intensive Care Units
• Intervention / Treatment: Other: Therapeutic plasma exchange : 3 sessions in 3 consecutive days (day 1 to day 3); Other: Usual treatments in intensive care unit according to the current state of knowledge

• Study Type: Interventional
• Enrollment (Anticipated): 132
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Olivier HEQUET, MD, PhD; Phone Number: +33 06 31 91 88 87; Email: olivier.hequet@efs.sante.fr
• Study Contact Backup: Name: Fabrice COGNASSE, PhD; Phone Number: +33 06 83 97 58 83; Email: fabrice.cognasse@efs.sante.fr

Study Locations

• France
  • Chalon-sur-Saône, France, 71100
    • Not yet recruiting
    • Centre Hospitalier William Morey
    • Contact: Mael HAMET, MD; Phone Number: +33 03 85 91 01 11; Email: Mael.Hamet@ch-chalon71.fr
    • Principal Investigator: Mael HAMET, MD
    • Sub-Investigator: Paul-Simon PUGLIESI, MD
  • Lyon, France, 69003
    • Not yet recruiting
    • Hôpital Edouard Herriot
    • Contact: Laurent ARGAUD, MD, PhD; Phone Number: +33 04.72.11.28.51; Email: laurent.argaud@chu-lyon.fr
    • Principal Investigator: Laurent ARGAUD, MD, PhD
  • Lyon, France, 69004
    • Recruiting
    • Hopital Croix Rousse
    • Contact: Jean Christophe RICHARD, MD, PhD; Phone Number: +33 04.26.10.92.72; Email: j-christophe.richard@chu-lyon.fr
  • Lyon, France, 69337
    • Not yet recruiting
    • Clinique de la Sauvegarde
    • Contact: Olivier DESEBBE, MD; Phone Number: +33 06.51.05.80.65; Email: oldesebbe@yahoo.com
    • Sub-Investigator: Bertrand DELANNOY, MD
  • Montelimar, France, 26216
    • Not yet recruiting
    • Groupement Hospitalier Porte de Valence - Montélimar
    • Contact: Mathieu Schoeffler, MD; Phone Number: +33 04 75 53 47 68; Email: Mathieu.SCHOEFFLER@gh-portesdeprovence.fr
    • Principal Investigator: Mathieu Schoeffler, MD
  • Paris, France, 75013
    • Not yet recruiting
    • Hôpital Pitié Salpétrière - Assistante Publique des Hôpitaux de Paris
    • Contact: Benjamin Rohaut, MD; Email: benjamin.rohaut@aphp.fr
    • Principal Investigator: Benjamin Rohaut, MD
    • Sub-Investigator: Nicolas Weiss, MD
    • Sub-Investigator: Sophie Demeret, MD
    • Sub-Investigator: Samir Saheb, MD
  • Pierre-Bénite, France, 69310
    • Not yet recruiting
    • Centre Hospitalier Lyon Sud
    • Contact: Vincent PIRIOU, MD, PhD; Phone Number: +33 04.78.86.20.70; Email: vincent.piriou@chu-lyon.fr
    • Principal Investigator: Vincent PIRIOU, MD, PhD
  • Villeurbanne, France, 69100
    • Not yet recruiting
    • Medipole Villeurbanne
    • Contact: Quoc-Viet LE, MD; Phone Number: +33 04 87 65 00 00; Email: qvle@scprea.fr
    • Principal Investigator: Quoc-Viet LE, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age > 18 years
• Hospitalized for COVID-19 confirmed by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) or scanner
• Patients with PaO2/FiO2 between 100 and 200 mmHg requiring non invasive ventilation or high flow oxygen
• At least two biological results suggesting a cytokine storm or hyperinflammatory condition state among : C-reactive protéine (CRP)>50mg/L, Procalcitonin (PCT)>1µg/L, Fibrinogen>5g/L, D-dimer >1000ng/mL, Ferritin > 800ng/mL during the last 72 hours.
• Treatment with corticosteroids (at least 2 intakes of dexamethasone 6 mg or equivalent with another form of corticosteroids)
• Patient affiliated to a social security or similar scheme
• Information and written consent from the patient or if not possible from a confident person

Exclusion Criteria:

• Ventilated intubated patients
• Patient with advanced cancer and without curative possibility
• Bacterial or viral (HIV) infection explaining the worsening (the main reason)
• Body Mass Index > 40
• Impossibility to put a central venous catheter according to investigator's judgement
• Severe hemodynamic instability with mean arterial pressure < 65 mmHg (whatever the noradrenaline dosage used)
• Immunoglobulin A (IgA) deficiency with anti-IgA antibodies
• Inclusion in another study that could interact with the Covidep study (investigator's judgement)
• Patient under legal protection measure
• Pregnant or breastfeeding women
• In case of allergy to amotosalen (psoralens) or AI-FFP (Amotosalen Inactivated Fresh Frozen Plasma) , use Se-FFP (Secured Fresh Frozen Plasma)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: TPE + usual treatments in intensive care unit according to the current state of knowledge.; TPE + usual treatments in intensive care unit according to the current state of knowledge : 3 TPE sessions i.e. one per day during 3 consecutive days on day 1-3 (day 0 = inclusion Visit date)) + usual treatments in intensive care unit. Usual treatments of patients in intensive care unit with hyperinflammatory condition due to Covid-19 infection consist in supporting respiratory function, oxygen supplementation, non invasive ventilation, invasive ventilation, antibiotic, vasopressive support and corticosteroids (in absence of bacterial secondary infection)	Other: Therapeutic plasma exchange : 3 sessions in 3 consecutive days (day 1 to day 3); Therapeutic plasma exchange (TPE) ; 3 sessions in 3 consecutive days (Day 1 to Day 3) in intensive care unit in addition to usual treatments. Plasma removed is replaced by thawed fresh frozen plasma. Plasma blood volume exchanged : 1.2 Apheresis type: centrifugation; Other: Usual treatments in intensive care unit according to the current state of knowledge; Usual treatments of patients in intensive care unit with hyperinflammatory condition due to Covid-19 infection consist in supporting respiratory function, oxygen supplementation, non invasive ventilation, invasive ventilation, antibiotic, vasopressive support and corticosteroids (in absence of bacterial secondary infection)
ACTIVE_COMPARATOR: Usual treatments in intensive care unit according to the current state of knowledge; Usual treatments of patients in intensive care unit with hyperinflammatory condition due to Covid-19 infection consist in supporting respiratory function, oxygen supplementation, non invasive ventilation, invasive ventilation, antibiotic, vasopressive support and corticosteroids (in absence of bacterial secondary infection)	Other: Usual treatments in intensive care unit according to the current state of knowledge; Usual treatments of patients in intensive care unit with hyperinflammatory condition due to Covid-19 infection consist in supporting respiratory function, oxygen supplementation, non invasive ventilation, invasive ventilation, antibiotic, vasopressive support and corticosteroids (in absence of bacterial secondary infection)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Use of intubation and invasive ventilation (IV) between Day 0 (Inclusion Visit) and Day 10	Proportion of patients requiring intubation between Day 0 and Day 10. Intubation use will be measured in both arms at Day 10.	At day 10

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess the adverse events according to CTCAE v5.0	Adverse events according to CTCAE v5.0 measured throughout the study, in both groups, including tolerance to TPEs in the experimental group over the course of the study sessions.	Throughout the study : Day 1 to Day 10 and to the end of the study (Day 60 +/- 2 days)
PaO2/FIO2 (Partial Pressure of Oxygen/Fraction of Inspired Oxygen) (mmHg) at day 4 after inclusion (PaO2/FiO2 is a usual parameter for assessing evolution of ARDS)	PaO2/FIO2 (mmHg) at day 4 after inclusion. This parameter will be compared between day 4 and day 0.The change corresponds to an increase of PaO2/FIO2 ratio equal or superior than 20%. The proportion of patients with a PaO2/FiO2 change at Day 4 will be compared between both arms.	At Day 4
Percentage of patients weaned from non invasive ventilation	Percentage of patients weaned from high flow oxygen. This parameter is compared between both arms (experimental and control arms).	At day 10
Survival at day 10	Percentage of patients alive at day 10 after inclusion. This parameter is compared between both arms.	At day 10
Survival at 2 months	Percentage of patients alive at 2 months after inclusion. This parameter is compared between both arms.	At day 60 (+/- 2 days)
Percentage of patients without any increase in inflammatory parameters (analysis of C-reactive protein, Fibrinogen,D-Dimers, procalcitonin, Ferritin)	Percentage of patients without any increase in inflammatory parameters (analysis of C-reactive protein, Fibrinogen,D-Dimers, procalcitonin, Ferritin ) at day 4 compared to values at day 0. This parameter is compared between both arms.	At day 4
Variation in cytokine and chemokine levels in the cytokine storm	Percentage of patients without any increase in cytokine or chemokine levels. Leucocyte and platelet cytokine or chemokine levels in ng/ml are assessed in both arms. Analysis of the entire panel of cytokines or chemokines defines an improvement or not. Comparison between both arms.	At day 4
Percentage of patients with improved phenotype (decreased phenotype of exhausted cells) and improved function (improved proliferation)	Lymphocyte and NK (Natural Killer) labeling and analysis by flow cytometry at day 0 and day 7. Analysis of lymphocyte proliferation (after stimulation) at day 0 and day 7. Analysis of percentage of patients with improved phenotype (decreased phenotype of exhausted cells) and improved function (improved proliferation) ; this parameter is compared between both arms.	At day 7
Percentage of patients with decreased platelet activation	Phenotype of platelets and flow cytometry analysis performed before and after TPE or usual treatment. Percentage of patients with decreased platelet activation at day 4 ; this parameter is compared between both arms.	At Day 4
Percentage of patients with decreased platelet activation	Phenotype of platelets and flow cytometry analysis performed before and after TPE or usual treatment. Percentage of patients with decreased platelet activation at day 7 ; this parameter is compared between both arms.	At Day 7
Change in anti-IFN auto-antibodies type I (α and ω) level	Change in anti-IFN auto-antibodies type I (α and ω) level at day 0 and day 4.	Day 0 and Day 4

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Principal Investigator: Olivier HEQUET, MD, PhD, Hospices Civils de Lyon - Etablissement Français du Sang

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 19, 2021
• Primary Completion (ANTICIPATED): December 1, 2022
• Study Completion (ANTICIPATED): December 1, 2022

Study Registration Dates

• First Submitted: February 5, 2021
• First Submitted That Met QC Criteria: February 10, 2021
• First Posted (ACTUAL): February 12, 2021

Study Record Updates

• Last Update Posted (ACTUAL): April 21, 2021
• Last Update Submitted That Met QC Criteria: April 20, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Covid19; Cytokine storm; Therapeutic plasma exchange; Hyperinflammatory condition; Anti-IFN antibodies
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Respiratory Distress Syndrome
• Other Study ID Numbers: 69HCL20_0518; 2020-A03039-30 (OTHER: ID-RCB)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No