Polyvalent Immunoglobulin in COVID-19 Related ARds (ICAR)

• ClinicalTrials.gov Identifier: NCT04350580
• Recruitment Status: Completed
• First Posted: April 17, 2020
• Last Update Posted: June 8, 2021
• 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.

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 146 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
• Actual Primary Completion Date: November 20, 2020
• Actual Study Completion Date: March 15, 2021

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 ]
   Vital status at 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 ]
   Measure of lung compliance
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 ]
    Diagnosis of deep vein thrombosis or pulmonary embolism through imaging exam (eg ultrasound and CT scan)
11. Total duration of mechanical ventilation, ventilatory weaning and curarisation [ Time Frame: 28 days ]
    Total time of mechanical ventilation, weaning and use of neuromuscular blockade
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

Locations

France

CHU Sud Amiens

Amiens, France

CHU Angers

Angers, France

Service de réanimation polyvalente, rond point de Girac

Angoulême, France

CH Aulnay

Aulnay-sous-Bois, France

Centre hospitalier de Béthune

Beuvry, France

Hopital Avicenne

Bobigny, France

CH Chalons en champagne

Chalons en champagne, France

CH-Nord-Ardennes

Charleville-Mézières, France

Hopital d'instruction des armées Percy

Clamart, France

Centre Hospitalier de Dieppe

Dieppe, France

Hôpital Raymond Poincaré

Garches, France

CHU de Grenoble

Grenoble, France

Grand hopital de l'est Francilien - site de Jossigny

Jossigny, France

Hopital Robert Boulin

Libourne, France

Pôle de Médecine intensive/réanimation Hôpital Salengro, CHRU de Lille

Lille, France

Groupement Hospitalier Edouar Herriot

Lyon, France

Hôpital de la Croix Rousse Novembre 2019

Lyon, France

Hopital Jacques Cartier

Massy, France

Hopital Jacques Monod

Montivilliers, France

Service de Médecine Intensive-Réanimation, CHU

Nantes, France

CHR Orléans

Orléans, France

Centre Hospitalier Sainte-Anne

Paris, France

CHU Lariboisiere

Paris, France

CHU Pitié Salpétriere Service de réanimation chirurgicale

Paris, France

CHU Saint Antoine

Paris, France

Fondation ophtalmologique Rotschild

Paris, France

Hôpital Paris Saint-Joseph

Paris, France

Hôpital Pitié Salpêtrière

Paris, France

Institut Mutualiste Montsouris

Paris, France

CHU Robert Débré

Reims, France

CH Poissy

Saint-Germain-en-Laye, France

Groupe hospitalier Saint Vincent

Strasbourg, France

Hôpital de Hautepierre

Strasbourg, France

Hopital de Tarbes

Tarbes, France

Hôpital Nord Franche-Comté

Trévenans, France

CH Valenciennes

Valenciennes, France

Chu Nancy - Brabois

Vandœuvre-lès-Nancy, France

Hopital de Vannes

Vannes, France

Institut Gustave Roussy

Villejuif, France

CH Etampes

Étampes, France

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Mazeraud A, Gonçalves 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.

• 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: June 8, 2021
• Last Verified: September 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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