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

• ClinicalTrials.gov Identifier: NCT04751643
• Recruitment Status: Recruiting
• First Posted: February 12, 2021
• Last Update Posted: April 21, 2021
• Sponsor: Hospices Civils de Lyon
• Information provided by (Responsible Party): Hospices Civils de Lyon

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Intensive Care Units; ARDS, Human; Covid19	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	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 132 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Assessment of Therapeutic Plasma Exchange to Improve Respiratory Function by Alleviating Cytokine Storm During Severe Covid-19 Infections Randomised Open-label Controlled Trial
• Actual Study Start Date: April 19, 2021
• Estimated Primary Completion Date: December 2022
• Estimated Study Completion Date: December 2022

Arms and Interventions

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)

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Assess the adverse events according to CTCAE v5.0 [ Time Frame: Throughout the study : Day 1 to Day 10 and to the end of the study (Day 60 +/- 2 days) ]
   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.
2. 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) [ Time Frame: At Day 4 ]
   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.
3. Percentage of patients weaned from non invasive ventilation [ Time Frame: At day 10 ]
   Percentage of patients weaned from high flow oxygen. This parameter is compared between both arms (experimental and control arms).
4. Survival at day 10 [ Time Frame: At day 10 ]
   Percentage of patients alive at day 10 after inclusion. This parameter is compared between both arms.
5. Survival at 2 months [ Time Frame: At day 60 (+/- 2 days) ]
   Percentage of patients alive at 2 months after inclusion. This parameter is compared between both arms.
6. Percentage of patients without any increase in inflammatory parameters (analysis of C-reactive protein, Fibrinogen,D-Dimers, procalcitonin, Ferritin) [ Time Frame: At day 4 ]
   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.
7. Variation in cytokine and chemokine levels in the cytokine storm [ Time Frame: At day 4 ]
   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.
8. Percentage of patients with improved phenotype (decreased phenotype of exhausted cells) and improved function (improved proliferation) [ Time Frame: At day 7 ]
   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.
9. Percentage of patients with decreased platelet activation [ Time Frame: At Day 4 ]
   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.
10. Percentage of patients with decreased platelet activation [ Time Frame: At Day 7 ]
    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.
11. Change in anti-IFN auto-antibodies type I (α and ω) level [ Time Frame: Day 0 and Day 4 ]
    Change in anti-IFN auto-antibodies type I (α and ω) level at day 0 and day 4.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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)

Contacts and Locations

Contacts

Contact: Olivier HEQUET, MD, PhD; 06 31 91 88 87 ext +33; olivier.hequet@efs.sante.fr

Contact: Fabrice COGNASSE, PhD; 06 83 97 58 83 ext +33; fabrice.cognasse@efs.sante.fr

Locations

France

Centre Hospitalier William Morey; Not yet recruiting

Chalon-sur-Saône, France, 71100

Contact: Mael HAMET, MD 03 85 91 01 11 ext +33 Mael.Hamet@ch-chalon71.fr

Principal Investigator: Mael HAMET, MD

Sub-Investigator: Paul-Simon PUGLIESI, MD

Hôpital Edouard Herriot; Not yet recruiting

Lyon, France, 69003

Contact: Thomas RIMMELE, MD, PhD 04.72.11.02.81 ext +33 thomas.rimmele@chu-lyon.fr

Principal Investigator: Thomas RIMMELE, MD, PhD

Hôpital Edouard Herriot; Not yet recruiting

Lyon, France, 69003

Contact: Laurent ARGAUD, MD, PhD 04.72.11.28.51 ext +33 laurent.argaud@chu-lyon.fr

Contact: MD, PhD

Principal Investigator: Laurent ARGAUD, MD, PhD

Hôpital Croix Rousse; Recruiting

Lyon, France, 69004

Contact: Jean Christophe RICHARD, MD, PhD 04.26.10.92.72 ext +33 j-christophe.richard@chu-lyon.fr

Principal Investigator: Jean Christophe RICHARD, MD, PhD

Clinique de la Sauvegarde; Not yet recruiting

Lyon, France, 69337

Contact: Olivier DESEBBE, MD 06.51.05.80.65 ext +33 oldesebbe@yahoo.com

Principal Investigator: Olivier DESEBBE, MD

Sub-Investigator: Bertrand DELANNOY, MD

Groupement Hospitalier Porte de Valence - Montélimar; Not yet recruiting

Montelimar, France, 26216

Contact: Mathieu Schoeffler, MD 04 75 53 47 68 ext +33 Mathieu.SCHOEFFLER@gh-portesdeprovence.fr

Principal Investigator: Mathieu Schoeffler, MD

Hôpital Pitié Salpétrière - Assistante Publique des Hôpitaux de Paris; Not yet recruiting

Paris, France, 75013

Contact: Benjamin Rohaut, MD benjamin.rohaut@aphp.fr

Principal Investigator: Benjamin Rohaut, MD

Sub-Investigator: Nicolas Weiss, MD

Sub-Investigator: Sophie Demeret, MD

Sub-Investigator: Samir Saheb, MD

Centre Hospitalier Lyon Sud; Not yet recruiting

Pierre-Bénite, France, 69310

Contact: Vincent PIRIOU, MD, PhD 04.78.86.20.70 ext +33 vincent.piriou@chu-lyon.fr

Principal Investigator: Vincent PIRIOU, MD, PhD

Medipole Villeurbanne; Not yet recruiting

Villeurbanne, France, 69100

Contact: Quoc-Viet LE, MD 04 87 65 00 00 ext +33 qvle@scprea.fr

Principal Investigator: Quoc-Viet LE, MD

Sponsors and Collaborators

Hospices Civils de Lyon

Investigators

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

More Information

• Responsible Party: Hospices Civils de Lyon
• ClinicalTrials.gov Identifier: NCT04751643
• Other Study ID Numbers: 69HCL20_0518; 2020-A03039-30 ( Other Identifier: ID-RCB )
• First Posted: February 12, 2021
• Last Update Posted: April 21, 2021
• Last Verified: April 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Hospices Civils de Lyon:

Covid19; Therapeutic plasma exchange; Cytokine storm; Hyperinflammatory condition; Anti-IFN antibodies

Additional relevant MeSH terms:

COVID-19; Respiratory Distress Syndrome; Infections; Respiratory Tract Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders