Plasma Exchange in Covid-19 Patients With Anti-interferon Autoantibodies

COVID-19 Clinical Trial

— EPIC  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05182515
• Other study ID #: D20-P060
• Status: Recruiting
• Phase: Phase 3
• Start date: December 22, 2021
• Est. completion date: March 22, 2022

Study information

• Verified date: January 2022
• Source: Centre Hospitalier St Anne
• Contact: Aurélien Mazeraud, MD, PhD
• Phone: +33145657413
• Email: a.mazeraud[@]ghu-paris.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: March 22, 2022
• Est. primary completion date: March 22, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• COVID-19

Intervention

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.

Locations

Country	Name	City	State
France	GHU Paris Psychiatrie et Neurosciences	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Centre Hospitalier St Anne

Country where clinical trial is conducted

France, 

References & Publications (16)

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* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Survival at day 28	Survival up to day 28	28 days
Secondary	Survival at day 90	Survival up to day 90	90 days
Secondary	WHO Covid-19 ordinal scale at day 28	Ordinal Scale for Clinical Improvement from 0 (no clinical or virological evidence of infection) to 8 (death)	28 days
Secondary	WHO Covid-19 ordinal scale at day 90	Ordinal Scale for Clinical Improvement from 0 (no clinical or virological evidence of infection) to 8 (death)	90 days
Secondary	Lung Injury score (LIS) at day 14	LIS ranges between 0 and 4, 0 points - no lung injury; 4 points severe lung injury, acute respiratory distress syndrome.	14 days
Secondary	Lung Injury score at day 28	LIS ranges between 0 and 4, 0 points - no lung injury; 4 points severe lung injury, acute respiratory distress syndrome.	28 days
Secondary	Sequential Organ Failure Assessment day 14	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
Secondary	Sequential Organ Failure Assessment day 28	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
Secondary	Occurence of at least one serious adverse event	Grade 3 or 4 adverse events occurrence	90 days
Secondary	ICU length of stay up to day 90	ICU discharge date minus ICU admission date (in days)	90 days
Secondary	Hospital length of stay up to day 90	date of hospital discharge minus date of hospital admission	90 days
Secondary	Functionnal status at day 90 according to Activities of a Daily Living score	The Activities of Daily Living assesses activities of daily living. A higher score indicates better activities of daily living.	90 days
Secondary	Functionnal status at day 90 according to Instrumental Activities of a Daily Living score	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