Polyvalent Immunoglobulin in COVID-19 Related ARds (ICAR)

Value of Early Treatment With Polyvalent Immunoglobulin in the Management of Acute Respiratory Distress Syndrome Associated With SARS-CoV-2 Infections

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.

Study Overview

• Status: Completed
• Conditions: COVID-19; Acute Respiratory Distress Syndrome
• Intervention / Treatment: Drug: Human immunoglobulin; Drug: Placebo

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.

We hypothesize that the number of days without invasive mechanical ventilation (IMV) is 10 days in the placebo group and 15 days in the experimental group with a standard deviation of 6 days, considering a mortality of 50% and 40% in the placebo and experimental groups respectively (26, 27). The number of days without IMV in the placebo group is (50% x 10 D) + (50% x 0 D) or 5 D on average, and following the same calculation for the experimental group of (60% x 15 D) + (40% x 0 D) or 9 D.

Therefore, a mean value of 5 days without ventilation in the placebo group versus 9 in the experimental group is assumed, and the 6-day standard deviation is assumed to be stable. Given the uncertainty regarding the assumption of normality of distributions, the non-parametric Wilcoxon-Mann-Whitney test (U-test) was used for the estimation of the sample size. Considering a bilateral alpha risk of 5% and a power of 90% and an effect size of 0.6, the number of subjects to be included is 138 patients, 69 in each arm.

The primary and secondary analyses will be stratified by age categories, sex and other clinically relevant factors (comorbidities). Demographic characteristics and parameters identified at enrolment will be summarized using descriptive statistical methods.

Demographic summaries will include gender, race/ethnicity, and age. For demographic and categorical background characteristics, a Cochran-Mantel-Haenszel test will be used to compare treatment groups. For continuous demographic and baseline characteristics, a Wilcoxon test will be used to compare treatment groups.

The number of days without mechanical ventilation will be presented as a mean with standard deviation. The groups will be analyzed in terms of intention to treat and the difference between the two groups will be analyzed by a non-parametric test of comparison of means, stratified for the primary endpoint. The point estimate of the difference between treatments and the associated 95% confidence interval will be provided.

A regression model for censored data (Cox model) will explore prognostic factors. The IGIV immunological and pathological related efficacy endpoints will also be compared according to their distribution and analyzed using Student, Mann-Whitney and Fisher tests.

Other variables will be presented as means and standard deviations or medians and interquartile ranges according to their distribution and analyzed by Student, Mann-Whitney and Fisher tests.

Parameters that are measured on a time scale from randomization or start of administration will be compared between treatment groups using the Log-Rank test.

The choice of statistical tests and multivariate models (parametric or non-parametric) will be made for each variable based on observed characteristics (normality of distributions and residuals, collinearity).

The statistical analyses relating to the main objective will be carried out as intention to treat. Secondary analyses on the population per protocol may also be carried out.

All tests will be bilateral with a significance threshold of 5%. The software used will be SPSS v26 (SPSS Inc., Chicago, IL, USA). An interim analysis will be performed after 50 participants are enrolled and another after 100 inclusions.

• Study Type: Interventional
• Enrollment (Actual): 146
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Amiens, France
    • CHU Sud Amiens
  • Angers, France
    • CHU Angers
  • Angoulême, France
    • Service de réanimation polyvalente, rond point de Girac
  • Argenteuil, France
    • CH Victor Dupouy
  • Aulnay-sous-Bois, France
    • CH Aulnay
  • Beuvry, France
    • Centre Hospitalier de Béthune
  • Bobigny, France
    • Hôpital Avicenne
  • Chalons en champagne, France
    • CH Chalons En Champagne
  • Charleville-Mézières, France
    • CH-Nord-Ardennes
  • Clamart, France
    • Hôpital d'Instruction des Armées PERCY
  • Dieppe, France
    • Centre Hospitalier de Dieppe
  • Garches, France
    • Hôpital Raymond Poincaré
  • Grenoble, France
    • CHU de Grenoble
  • Jossigny, France
    • Grand hopital de l'est Francilien - site de Jossigny
  • Libourne, France
    • Hôpital Robert Boulin
  • Lille, France
    • Pôle de Médecine intensive/réanimation Hôpital Salengro, CHRU de Lille
  • Lyon, France
    • Groupement Hospitalier Edouar Herriot
  • Lyon, France
    • Hôpital de la Croix Rousse Novembre 2019
  • Massy, France
    • Hôpital Jacques Cartier
  • Montivilliers, France
    • Hopital Jacques Monod
  • Nantes, France
    • Service de Médecine Intensive-Réanimation, CHU
  • Orléans, France
    • CHR Orléans
  • Paris, France
    • Institut Mutualiste Montsouris
  • Paris, France
    • Hopital Pitie Salpetriere
  • Paris, France
    • CHU Lariboisière
  • Paris, France
    • Centre Hospitalier Sainte-Anne
  • Paris, France
    • CHU Saint Antoine
  • Paris, France
    • CHU Pitié Salpétriere Service de réanimation chirurgicale
  • Paris, France
    • Fondation Ophtalmologique Rotschild
  • Paris, France
    • Hopital Paris Saint-Joseph
  • Poitiers, France
    • CHU Poitiers
  • Reims, France
    • CHU Robert Debré
  • Saint-Germain-en-Laye, France
    • CH Poissy
  • Strasbourg, France
    • Hôpital de HAUTEPIERRE
  • Strasbourg, France
    • Groupe Hospitalier Saint Vincent
  • Tarbes, France
    • Hopital de Tarbes
  • Trévenans, France
    • Hôpital Nord Franche-Comté
  • Valenciennes, France
    • Ch Valenciennes
  • Vandœuvre-lès-Nancy, France
    • Chu Nancy - Brabois
  • Vannes, France
    • Hopital de Vannes
  • Villejuif, France
    • Institut Gustave Roussy
  • Étampes, France
    • CH Etampes

Participation Criteria

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:

• Any patient in intensive care:

  1. Receiving invasive mechanical ventilation for less than 72 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention - IGIV; Participants in the intervention group will receive a 2g/Kg infusion of human immunoglobulin which should be started before the 96th 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 Names: 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 Names: Sodium chloride 0.9%

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ventilator-free days	Sum of the days the patient did not receive VM, but if death occurs before D28, the score is zero	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Vital status at 28 and 90 days	28 and 90 days
Sequential Organ Failure Assessment Score	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	Days 1, 3, 7, 14, 21 and 28
P/F ratio	Ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2 expressed as a fraction, not a percentage)	Days 1, 3, 7, 14, 21 and 28
Lung compliance	Measure of lung compliance	Days 1, 3, 7, 14, 21 and 28
Radiological score	Severity scoring of lung oedema on the chest radiograph	Days 1, 3, 7, 14, 21 and 28
Biological efficacy endpoints - C-reactive protein	Concentration in mg/L	Days 1, 3, 7, 14, 21 and 28
Biological efficacy endpoints - Procalcitonin	Concentration in microgram/L	Days 1, 3, 7, 14, 21 and 28
Immunological profile	Number of CD4 HLA-DR+ and CD38+, CD8 lymphocytes	Up to 28 days
Number of patients using other treatments for COVID-19 related ARDS	Use of corticosteroids, antiretroviral, chloroquine	Up to 28 days
Occurrence of deep vein thrombosis or pulmonary embolism	Diagnosis of deep vein thrombosis or pulmonary embolism through imaging exam (eg ultrasound and CT scan)	28 days
Total duration of mechanical ventilation, ventilatory weaning and curarisation	Total time of mechanical ventilation, weaning and use of neuromuscular blockade	28 days
Kidney Disease: Improving Global Outcomes (KDIGO) score and need for dialysis	Divided in 3 stages, with higher severity of kidney injury in higher stages	28 days
Occurrence of adverse event related to immunoglobulins	Kidney failure, hypersensitivity with cutaneous or hemodynamic manifestations, aseptic meningitis, hemolytic anemia, leuko-neutropenia, transfusion related acute lung injury (TRALI)	28 days
Occurrence of critical illness neuromyopathy	Medical research council sum score on awakening	Up to 28 days
Occurrence of ventilator-acquired pneumonia	Radiological and clinical context associated with a bacteriological sampling in culture of tracheal secretions, bronchiolar-alveolar lavage or a protected distal sampling	Up to 28 days

Collaborators and Investigators

• Sponsor: Centre Hospitalier St Anne
• Collaborators: Laboratoire français de Fractionnement et de Biotechnologies; Groupe Hospitalier Universitaire Paris psychiatrie & neurosciences
• Investigators: Study Chair: Tarek Sharshar, MD, PHD, Centre hospitalier Sainte Anne; Principal Investigator: Aurélien Mazeraud, MD, PHD, Centre hospitalier Sainte Anne

Publications and helpful links

General 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. No abstract available. Erratum In: Lancet Respir Med. 2020 Feb 25;:
• 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;2013(9):CD001090. doi: 10.1002/14651858.CD001090.pub2.
• 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.
• 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. doi: 10.1136/thx.2004.029819.
• 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;2003(4):CD004000. doi: 10.1002/14651858.CD004000.
• Mazeraud A, Jamme M, Mancusi RL, Latroche C, Megarbane B, Siami S, Zarka J, Moneger G, Santoli F, Argaud L, Chillet P, Muller G, Bruel C, Asfar P, Beloncle F, Reignier J, Vinsonneau C, Schimpf C, Amour J, Goulenok C, Lemaitre C, Rohaut B, Mateu P, De Rudnicki S, Mourvillier B, Declercq PL, Schwebel C, Stoclin A, Garnier M, Madeux B, Gaudry S, Bailly K, Lamer C, Aegerter P, Rieu C, Sylla K, Lucas B, Sharshar T. Intravenous immunoglobulins in patients with COVID-19-associated moderate-to-severe acute respiratory distress syndrome (ICAR): multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2022 Feb;10(2):158-166. doi: 10.1016/S2213-2600(21)00440-9. Epub 2021 Nov 11.
• Mazeraud A, Goncalves B, Aegerter P, Mancusi L, Rieu C, Bozza F, Sylla K, Siami S, Sharshar T. Effect of early treatment with polyvalent immunoglobulin on acute respiratory distress syndrome associated with SARS-CoV-2 infections (ICAR trial): study protocol for a randomized controlled trial. Trials. 2021 Feb 28;22(1):170. doi: 10.1186/s13063-021-05118-7.

Study record dates

Study Major Dates

• Study Start (Actual): April 11, 2020
• Primary Completion (Actual): November 20, 2020
• Study Completion (Actual): February 20, 2021

Study Registration Dates

• First Submitted: April 8, 2020
• First Submitted That Met QC Criteria: April 14, 2020
• First Posted (Actual): April 17, 2020

Study Record Updates

• Last Update Posted (Actual): August 19, 2021
• Last Update Submitted That Met QC Criteria: August 14, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: SARS-CoV-2; COVID-19; Immunoglobulin; acute respiratory distress syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; COVID-19; Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Physiological Effects of Drugs; Immunologic Factors; Antibodies; Immunoglobulins; Immunoglobulins, Intravenous
• Other Study ID Numbers: D20-P013; 2020-001570-30 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• 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