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

Sponsor

Centre Hospitalier St Anne (Other)

Overall Status

Recruiting

CT.gov ID

NCT05182515

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

16.9

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
COVID-19	Drug: Therapeutic plasma exchange	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

This study is an open-label, randomized, multicenter, concurrent, parallel-group, standard of care controlled, to evaluate the safety and efficacy of plasma exchange (PE) in patients with anti-interferon autoantibodies, intensive care admitted for severe or critical symptoms of respiratory illness caused by Coronavirus disease 2019 (COVID-19) defined as "Life-threatening" by the WHO scale, using a group-sequential adaptive design. Approximately 50 participants will be randomized 1:1 to the Investigational or Control arm. Participants randomized to the Investigational arm will receive plasma exchanges (PE) for nearly three days in addition to standard of care (SOC), while participants in the Control arm will receive SOC only. The first plasma exchange session occurs within the first 120 hours of ICU admission. Two interim analyses are planned.This study is an open-label, randomized, multicenter, concurrent, parallel-group, standard of care controlled, to evaluate the safety and efficacy of plasma exchange (PE) in patients with anti-interferon autoantibodies, intensive care admitted for severe or critical symptoms of respiratory illness caused by Coronavirus disease 2019 (COVID-19) defined as "Life-threatening" by the WHO scale, using a group-sequential adaptive design. Approximately 50 participants will be randomized 1:1 to the Investigational or Control arm. Participants randomized to the Investigational arm will receive plasma exchanges (PE) for nearly three days in addition to standard of care (SOC), while participants in the Control arm will receive SOC only. The first plasma exchange session occurs within the first 120 hours of ICU admission. Two interim analyses are planned.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Dec 22, 2021

Anticipated Primary Completion Date :

Mar 22, 2022

Anticipated Study Completion Date :

Mar 22, 2022

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Survival at day 28 [28 days]
Survival up to day 28

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GHU Paris Psychiatrie et Neurosciences	Paris		France	75014

Sponsors and Collaborators

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