Plasma Exchange in Covid-19 Patients With Anti-interferon Autoantibodies (EPIC)

January 6, 2022 updated by: Centre Hospitalier St Anne

Interest of Plasma Exchange in Patients With Anti-interferon Type 1 Autoantibodies With Severe COVID-19 -

COVID-19 associated mortality remains high despite the advances in therapeutics such as dexamethasone. The severity of COVID-19 results from direct viral cytotoxicity, and the inflammatory response, which is associated with a hypercoagulable state, contribute to lethal hypoxemic pneumonia. During the SARS-CoV-2 replication phase, infected cells secrete chemokines and die by activating the immune system locally. A local inflammatory loop induces tissue destruction, which activates the immune system's circulating cells, leading to another amplifying loop called the cytokine storm. In these phenomena, the integrity of the interferon pathway plays a significant role.

Specific impairment of the interferon pathway has been identified in a subset of patients and is associated with high Covid-19 severity. This subset of patients presents preexisting autoimmune disease mediated by autoantibodies directed against IFN. It represents 10.2% (101/987) of patients admitted in ICU with COVID-19 pneumonia, and the observed mortality in this subgroup is 40%.

The investigators hypothesized that plasma exchanges (PE) would eliminate these autoantibodies while acting on other mechanisms of the pathogenesis of severe COVID-19, such as cytokine storm or hypercoagulability(7).

The EPIC trial aims to demonstrate the efficacy of plasma exchange in the subpopulation of patients with anti-interferon autoantibodies and severe COVID-19 hospitalized in intensive care and on oxygen therapy, high flow or not, receiving non-ventilation or invasive ventilation, on D28 survival.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

As of 11/09/2020, 50,000,000 people have been infected with COVID-19 worldwide, and 1,200,000 people have died, mainly from acute respiratory distress syndrome (ARDS ). Only Dexamethasone has shown survival improvement in patients hospitalized with severe COVID-19 receiving oxygen or more invasive symptomatic treatment. Despite this therapeutic advance, invasive ventilation is necessary in 30% of hospitalized cases, and mortality remains high among ventilated patients (30-40%). This study suggests that it is necessary to continue searching for a treatment to reduce this mortality rate further while confirming that immunity modulation is a promising strategy.

The severity of COVID-19 results from direct viral cytotoxicity, the accompanying inflammatory response associated with a state of hypercoagulability which contributes to lethal hypoxemic pneumonitis. During the SARS-CoV-2 replication phase, infected cells secrete chemokines and die by activating the immune system locally. A local inflammatory loop induces tissue destruction, which activates the immune system's circulating cells, leading to another amplifying loop called the cytokine storm. A high concentration of pro-inflammatory interleukins characterizes this cytokine storm. It induces an endothelial dysfunction that causes activation of the coagulation system and an increase in vascular permeability. These mechanisms lead to COVID-19 pneumopathy, and the pathologic examination reveals diffuse alveolar damage associated with a significant inflammatory infiltrate and microthrombi. These lesions cause pulmonary dysfunction and refractory hypoxia, which is the cause of mortality from COVID-19.

In these phenomena, the integrity of the type 1 interferon pathway seems to play a major role and more particularly in COVID-19. Patients in whom the type I or III interferon pathway is dysfunctional are particularly susceptible to viral damage. It is now known that dysfunction of one of the interferon pathways exposes the host to a severe viral infection such as fulminant viral hepatitis or severe influenza pneumonia caused. In a study published in September in Science, Professor Jean-Laurent Casanova's team found in 10.2% (101/987) of patients with COVID-19 pneumonia neutralizing autoantibodies directed against IFN-ω (13 patients), one of 13 types of IFN-α (36), or both (52); In this study, the authors show that these autoantibodies neutralized the ability of IFN type I to block SARS-CoV-2 infection. When a patient presents one of these autoantibodies, he is exposed to an increased mortality risk compared to the healthy population. It is estimated at 40% in the affected population versus less than 10% in the rest.

Plasma exchanges (PE) are a blood purification technique that eliminates auto-antibodies in the context of autoantibodies driven pathologies, particularly in intensive care such as autoimmune myasthenia gravis or Guillain Barré syndrome. This technique makes it possible to purify the plasma containing immunoglobulins, cytokines, chemokines, coagulation factors and replace it with plasma from healthy subjects or purified human albumin. The theoretical ability to remove some of the pro-inflammatory substances, toxins, and cellular components from the sick individual quickly identified plasma exchange as a potential therapy for COVID-19. The discovery of anti-interferon autoantibodies as a significant gravity factor leads us to hypothesize that PE would be even more beneficial in this subpopulation.

To date, eight randomized clinical trials are in progress evaluating the interest of plasma exchanges in COVID-19 on clinicaltrials.gov. The inclusion criteria in these studies are broad. As plasma exchanges are an expensive therapy with limited availability, it makes their use in all patients with severe COVID-19 impossible. In this study, the investigators propose to demonstrate the efficacy of PE in the subpopulation of patients with anti-interferon autoantibodies and severe COVID-19 hospitalized in intensive care and on oxygen therapy, high flow or not, receiving invasive or non-invasive ventilation on survival to D28.

Study Type

Interventional

Enrollment (Anticipated)

50

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • France
      • Paris, France, 75014
        • Recruiting
        • GHU Paris Psychiatrie et Neurosciences
        • Contact:
          • Aurélien Mazeraud, MD PHD
        • Principal Investigator:
          • Aurélien Mazeraud

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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:

  1. SARS-CoV-2 infection proven by PCR.
  2. Positive detection of anti-interferon antibodies.
  3. Patient, family or deferred consent (emergency clause).
  4. Affiliation to a social security scheme (or exemption from affiliation). Inclusions are possible also for protected patient (under guardianship and tutornship).

Exclusion Criteria:

  1. Pregnant women, parturients and nursing mothers
  2. Minor patient
  3. Participation in another interventional trial in progress, with the objective, even secondary, of reducing mortality
  4. Indication to EPT for another associated pathology
  5. Contra-indication to EPT, known allergy to albumin 5%.
  6. Persons under court protection,
  7. Disturbance of the haemostasis balance (PT<50%, APTT>1.5 and fibrinogen <1g/L)
  8. Patient presenting a hemorrhagic diathesis (intracranial or digestive bleeding or threatening the functional prognosis)
  9. Any progressive and advanced pathology whose life expectancy is less than one month
  10. Bacterial or viral infectious disease (HIV) explaining most of the aggravation

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: Standard of Care
Standard of care including Dexamethasone
Experimental: Therapeutic plasma exchanges
Drug: Therapeutic plasma exchanges at day 1, 3 and 5 plus Standard of care including Dexamethasone
Drug: Therapeutic plasma exchange

Plasma exchange techniques reported in COVID-19 vary from study to study. No consensus exists on the use of a specific technique.

The use of a central venous catheter will be left to the discretion of investigators. If so, central venous catheter will be inserted through the internal jugular or femoral route under ultrasound control by a trained operator. After radiographic control of the position of the catheter and the absence of complications in the placement of the catheter, plasma exchanges will be carried out.

Three plasma exchanges of 1.5 plasma volume will be carried out every 48 hours on D1, D3 and D5. Plasma volume will be assessed by this equation VP = (1-Hct)x70xweight Body(measured). The substitution volume will be 5% albumin as first intervention. The use of a hemofiltration or centrifugation technique will be left to the discretion of each center.

Other Names:
  • Therapeutic plasma exchanges

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Survival at day 28
Time Frame: 28 days
Survival up to day 28
28 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Survival at day 90
Time Frame: 90 days
Survival up to day 90
90 days
WHO Covid-19 ordinal scale at day 28
Time Frame: 28 days
Ordinal Scale for Clinical Improvement from 0 (no clinical or virological evidence of infection) to 8 (death)
28 days
WHO Covid-19 ordinal scale at day 90
Time Frame: 90 days
Ordinal Scale for Clinical Improvement from 0 (no clinical or virological evidence of infection) to 8 (death)
90 days
Lung Injury score (LIS) at day 14
Time Frame: 14 days
LIS ranges between 0 and 4, 0 points - no lung injury; 4 points severe lung injury, acute respiratory distress syndrome.
14 days
Lung Injury score at day 28
Time Frame: 28 days
LIS ranges between 0 and 4, 0 points - no lung injury; 4 points severe lung injury, acute respiratory distress syndrome.
28 days
Sequential Organ Failure Assessment day 14
Time Frame: 14 days
The SOFA Score can be used to determine the level of organ dysfunction and mortality risk in ICU patients, from 0 to 24, with severity increasing the higher the score.
14 days
Sequential Organ Failure Assessment day 28
Time Frame: 28 days
The SOFA Score can be used to determine the level of organ dysfunction and mortality risk in ICU patients, from 0 to 24, with severity increasing the higher the score.
28 days
Occurence of at least one serious adverse event
Time Frame: 90 days
Grade 3 or 4 adverse events occurrence
90 days
ICU length of stay up to day 90
Time Frame: 90 days
ICU discharge date minus ICU admission date (in days)
90 days
Hospital length of stay up to day 90
Time Frame: 90 days
date of hospital discharge minus date of hospital admission
90 days
Functionnal status at day 90 according to Activities of a Daily Living score
Time Frame: 90 days
The Activities of Daily Living assesses activities of daily living. A higher score indicates better activities of daily living.
90 days
Functionnal status at day 90 according to Instrumental Activities of a Daily Living score
Time Frame: 90 days
The Instrumental Activities of Daily Living assesses instrumental activities of daily living. The score range is 0 to 8. A higher score indicates better instrumental activities of daily living.
90 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Centre Hospitalier St Anne

Investigators

  • Principal Investigator: Mazeraud Aurélien, MD, PhD, GHU Paris Psychiatrie et Neurosciences
  • Study Chair: Sharshar Tarek, MD, PhD, GHU Paris Psychiatrie et Neurosciences

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 22, 2021

Primary Completion (Anticipated)

March 22, 2022

Study Completion (Anticipated)

March 22, 2022

Study Registration Dates

First Submitted

December 22, 2021

First Submitted That Met QC Criteria

January 6, 2022

First Posted (Actual)

January 10, 2022

Study Record Updates

Last Update Posted (Actual)

January 10, 2022

Last Update Submitted That Met QC Criteria

January 6, 2022

Last Verified

January 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • D20-P060

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

These documents are shared upon request to the sponsor

IPD Sharing Time Frame

Study protocol, SAP and Data are shared upon request to the sponsor

IPD Sharing Access Criteria

request to the sponsor k.sylla@ghu-paris.fr

IPD Sharing Supporting Information Type

  • Study Protocol
  • Statistical Analysis Plan (SAP)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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