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Polyvalent Immunoglobulin in COVID-19 Related ARds (ICAR)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04350580
Recruitment Status : Recruiting
First Posted : April 17, 2020
Last Update Posted : April 24, 2020
Sponsor:
Collaborators:
Groupe Hospitalier Universitaire Paris psychiatrie & neurosciences
Laboratoire français de Fractionnement et de Biotechnologies
Information provided by (Responsible Party):
Centre Hospitalier St Anne

Brief Summary:
As of 30/03/2020, 715600 people have been infected with COVID-19 worldwide and 35500 people died, essentially due to respiratory distress syndrome (ARDS) complicated in 25% of the with acute renal failure. No specific pharmacological treatment is available yet. The lung lesions are related to both the viral infection and to an intense inflammatory reaction. Because of it's action, as an immunomodulatory agent that can attenuate the inflammatory reaction and also strengthen the antiviral response, it is proposed to evaluate the effectiveness and safety of intravenous immunoglobulin administration (IGIV) in patients developing ARDS post-SARS-CoV2. IGIV modulates immunity, and this effect results in a decrease of pro-inflammatory activity, key factor in the ARDS related to the COVID-19. It should be noted that IGIV is part of the treatments in various diseases such as autoimmune and inflammatory diffuse interstitial lung diseases. In addition, they have been beneficial in the post-influenza ARDS but also have been in 3 cases of post-SARS-CoV2 ARDS. IGIV is a treatment option because it is well tolerated, especially concerning the kidney. These elements encourage a placebo-controlled trial testing the benefit of IGIV in ARDS post-SARS-CoV2.

Condition or disease Intervention/treatment Phase
Acute Respiratory Distress Syndrome COVID-19 Drug: Human immunoglobulin Drug: Placebo Phase 3

Detailed Description:
As of 30/03/2020, 715600 people have been infected with COVID-19 worldwide and 35 500 people have died, mainly from acute respiratory distress syndrome (ARDS) complicated in 25% of cases with acute renal failure. No specific pharmacological treatment is available yet. Pulmonary lesions in these patients are related to both viral infection and an inflammatory reaction. Patients admitted to intensive care have an important inflammatory response and increased plasma concentrations of IL2, IL7, IL10, GCSF, IP10, MCP1, MIP1A, and TNFα. In the blood, the number of peripheral CD4 and CD8 T cells appears to be significantly reduced, while their status is hyperactivated. This is evidenced by immunoreactive cytometrics for HLA-DR (CD4 3-47%) and CD38 (CD8 39-4%) or by an increase in the proportion of highly pro-inflammatory Th 17 CCR6+ lymphocytes. In addition, CD8 T cells would exhibit a highly cytotoxic profile characterized by high concentrations of cytotoxic granules, perforin+, granulysin+ or double positive, suggesting associated complement activation. Because of their immunomodulatory action, which can attenuate the inflammatory response; and also strengthen the anti-viral defence, it is proposed to evaluate the efficacy and safety of intravenous immunoglobulin (IGIV) administration in patients developing post-SARS-CoV2 ARDS. IGIV modifies cell function of dendritic cells, cytokine and chemokine networks and T-lymphocytes, resulting in the proliferation of regulatory T cells to regulate the activity of T lymphocytes CD4 or CD8. The action of IGIV induces an activation more particularly of lymphocytes T regulators that could modulate the effects of the lymphocyte populations described in the study by Xu et al during COVID-19. In addition, IGIV modulate humoral acquired immunity, through their effect on the idiotypic network and antibody production. They also act on innate immunity, through antigen neutralization and modulation of phagocytic cells. These effects result in a decrease in the production of pro-inflammatory cytokines and complement activation, key factors in post-SARS-CoV2 ARDS. IGIV is part of the treatment for a variety of autoimmune and inflammatory diseases. The standard IGIV as well as polyclonal IGIV significantly reduced mortality in patients with septic shock and in Kawasaki disease, which is post-viral vasculitis of the child. In addition, they would not only be beneficial in post-influenza ARDS, but also would also in 3 cases of post-SARS-CoV2 ARDS. IVIG is a treatment option because it is well tolerated, especially regarding renal function. These factors are encouraging to quickly conduct a multicentre randomized placebo-controlled trial testing the benefit of IGIV in post-SARS-CoV2 ARDS.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 138 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: The participant will be randomized to either the group of treatment with IVIG or the placebo group. Participants in the treatment group will receive infusions of polyvalent immunoglobulins for 4 consecutive days. Participants in the placebo group will receive an equivalent volume of sodium chloride 0.9% for the same duration.
Masking: Double (Participant, Care Provider)
Masking Description: The double blinding will be provided by the hospital pharmacy of each establishment with the help of opaque sleeves to mask the product packaging and should be returned to the pharmacy when empty.
Primary Purpose: Treatment
Official Title: Value of Early Treatment With Polyvalent Immunoglobulin in the Management of Acute Respiratory Distress Syndrome Associated With SARS-CoV-2 Infections
Actual Study Start Date : April 11, 2020
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : August 2020


Arm Intervention/treatment
Experimental: Intervention - IGIV
Participants in the intervention group will receive a 2g/Kg infusion of human immunoglobulin which should be started between 24 and 36 hours after the start of mechanical ventilation in 4 injections of 0.5 g/Kg over 4 consecutive days.
Drug: Human immunoglobulin
Human immunoglobulin 2g/kg over 4 days (0.5g/kg/d)
Other Name: Clairyg

Placebo Comparator: Placebo
Participants of the placebo group will receive an equivalent volume of sodium chloride 0.9% for the same duration.
Drug: Placebo
Sodium chloride 0.9% in the same volume and over the same time as the immunoglobulin
Other Name: Sodium chloride 0.9%




Primary Outcome Measures :
  1. Ventilator-free days [ Time Frame: 28 days ]
    Sum of the days the patient did not receive VM, but if death occurs before D28, the score is zero


Secondary Outcome Measures :
  1. Mortality [ Time Frame: 28 and 90 days ]
  2. Sequential Organ Failure Assessment Score [ Time Frame: Days 1, 3, 7, 14, 21 and 28 ]
    Used to determine the extent of a person's organ function or rate of failure, from 0 to 24, with severity increasing the higher the score

  3. P/F ratio [ Time Frame: Days 1, 3, 7, 14, 21 and 28 ]
    Ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2 expressed as a fraction, not a percentage)

  4. Lung compliance [ Time Frame: Days 1, 3, 7, 14, 21 and 28 ]
  5. Radiological score [ Time Frame: Days 1, 3, 7, 14, 21 and 28 ]
    Severity scoring of lung oedema on the chest radiograph

  6. Biological efficacy endpoints - C-reactive protein [ Time Frame: Days 1, 3, 7, 14, 21 and 28 ]
    Concentration in mg/L

  7. Biological efficacy endpoints - Procalcitonin [ Time Frame: Days 1, 3, 7, 14, 21 and 28 ]
    Concentration in microgram/L

  8. Immunological profile [ Time Frame: Up to 28 days ]
    Number of CD4 HLA-DR+ and CD38+, CD8 lymphocytes

  9. Number of patients using other treatments for COVID-19 related ARDS [ Time Frame: Up to 28 days ]
    Use of corticosteroids, antiretroviral, chloroquine

  10. Occurrence of deep vein thrombosis or pulmonary embolism [ Time Frame: 28 days ]
  11. Total duration of mechanical ventilation, ventilatory weaning and curarisation [ Time Frame: 28 days ]
  12. Kidney Disease: Improving Global Outcomes (KDIGO) score and need for dialysis [ Time Frame: 28 days ]
    Divided in 3 stages, with higher severity of kidney injury in higher stages

  13. Occurrence of adverse event related to immunoglobulins [ Time Frame: 28 days ]
    Kidney failure, hypersensitivity with cutaneous or hemodynamic manifestations, aseptic meningitis, hemolytic anemia, leuko-neutropenia, transfusion related acute lung injury (TRALI)

  14. Occurrence of critical illness neuromyopathy [ Time Frame: Up to 28 days ]
    Medical research council sum score on awakening

  15. Occurrence of ventilator-acquired pneumonia [ Time Frame: Up to 28 days ]
    Radiological and clinical context associated with a bacteriological sampling in culture of tracheal secretions, bronchiolar-alveolar lavage or a protected distal sampling



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  • Any patient in intensive care:

    1. Receiving invasive mechanical ventilation for less than 36 hours
    2. ARDS meeting the Berlin criteria
    3. PCR-proven SARS-CoV-2 infection
    4. Patient, family or deferred consent (emergency clause)
    5. Affiliation to a social security scheme (or exemption from affiliation)

Exclusion Criteria:

  • Allergy to polyvalent immunoglobulins
  • Pregnant woman or minor patient
  • Known IgA deficiency
  • Patient with renal failure on admission defined by a 3 times baseline creatinine or creatinine >354 micromol/L or a diuresis of less than 0.3 mL/Kg for 24 hours or anuria for 12 hours
  • Participation in another interventional trial

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04350580


Contacts
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Contact: Aurélien Mazeraud, MD, PHD 0145658902 a.mazeraud@ghu-paris.fr
Contact: Tarek Sharshar, MD, PHD 0145658902 t.sharshar@gmail.com

Locations
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France
Centre Hospitalier Sainte-Anne Recruiting
Paris, France
Contact: Aurélien Mazeraud, MD PHD         
Sponsors and Collaborators
Centre Hospitalier St Anne
Groupe Hospitalier Universitaire Paris psychiatrie & neurosciences
Laboratoire français de Fractionnement et de Biotechnologies
Investigators
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Study Chair: Tarek Sharshar, MD, PHD Centre Hospitalier Sainte Anne
Principal Investigator: Aurélien Mazeraud, MD, PHD Centre Hospitalier Sainte Anne
Publications:

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Responsible Party: Centre Hospitalier St Anne
ClinicalTrials.gov Identifier: NCT04350580    
Other Study ID Numbers: D20-P013
2020-001570-30 ( EudraCT Number )
First Posted: April 17, 2020    Key Record Dates
Last Update Posted: April 24, 2020
Last Verified: April 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Centre Hospitalier St Anne:
acute respiratory distress syndrome
COVID-19
SARS-CoV-2
Immunoglobulin
Additional relevant MeSH terms:
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Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Acute Lung Injury
Syndrome
Disease
Pathologic Processes
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Lung Injury
Immunoglobulins
Immunoglobulins, Intravenous
Antibodies
Immunologic Factors
Physiological Effects of Drugs