Polyvalent Immunoglobulin in COVID-19 Related ARds (ICAR)

• ClinicalTrials.gov Identifier: NCT04350580
• Recruitment Status: Recruiting
• First Posted: April 17, 2020
• Last Update Posted: April 24, 2020
• Sponsor: Centre Hospitalier St Anne
• Collaborators: Groupe Hospitalier Universitaire Paris psychiatrie & neurosciences; Laboratoire français de Fractionnement et de Biotechnologies
• Information provided by (Responsible Party): Centre Hospitalier St Anne

Study Description

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.

Study Design

• 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

Arms and Interventions

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%

Outcome Measures

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

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:

• 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

Contacts and Locations

Contacts

Contact: Aurélien Mazeraud, MD, PHD; 0145658902; a.mazeraud@ghu-paris.fr

Contact: Tarek Sharshar, MD, PHD; 0145658902; t.sharshar@gmail.com

Locations

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

• Study Chair: Tarek Sharshar, MD, PHD; Centre Hospitalier Sainte Anne
• Principal Investigator: Aurélien Mazeraud, MD, PHD; Centre Hospitalier Sainte Anne

More Information

Publications:

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24. Erratum in: Lancet. 2020 Jan 30;:.

Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, Tai Y, Bai C, Gao T, Song J, Xia P, Dong J, Zhao J, Wang FS. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020 Apr;8(4):420-422. doi: 10.1016/S2213-2600(20)30076-X. Epub 2020 Feb 18. Erratum in: Lancet Respir Med. 2020 Feb 25;:.

Chaigne B, Mouthon L. Mechanisms of action of intravenous immunoglobulin. Transfus Apher Sci. 2017 Feb;56(1):45-49. doi: 10.1016/j.transci.2016.12.017. Epub 2016 Dec 30. Review.

Arish N, Eldor R, Fellig Y, Bogot N, Laxer U, Izhar U, Rokach A. Lymphocytic interstitial pneumonia associated with common variable immunodeficiency resolved with intravenous immunoglobulins. Thorax. 2006 Dec;61(12):1096-7.

Oates-Whitehead RM, Baumer JH, Haines L, Love S, Maconochie IK, Gupta A, Roman K, Dua JS, Flynn I. Intravenous immunoglobulin for the treatment of Kawasaki disease in children. Cochrane Database Syst Rev. 2003;(4):CD004000. Review.

Alejandria MM, Lansang MA, Dans LF, Mantaring JB 3rd. Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock. Cochrane Database Syst Rev. 2013 Sep 16;(9):CD001090. doi: 10.1002/14651858.CD001090.pub2. Review.

• 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
• Last Update Posted: April 24, 2020
• Last Verified: April 2020

• 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:

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