Polyvalent Immunoglobulin in COVID-19 Related ARds

COVID-19 Clinical Trial

— ICAR  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04350580
• Other study ID #: D20-P013
• Secondary ID: 2020-001570-30
• Status: Completed
• Phase: Phase 3
• Start date: April 11, 2020
• Est. completion date: February 20, 2021

Study information

• Verified date: August 2021
• Source: Centre Hospitalier St Anne
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 146
• Est. completion date: February 20, 2021
• Est. primary completion date: November 20, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Lung Injury
• Acute Respiratory Distress Syndrome
• COVID-19
• Respiratory Distress Syndrome, Adult
• Respiratory Distress Syndrome, Newborn
• Syndrome

Intervention

Drug:
• Human immunoglobulin
Human immunoglobulin 2g/kg over 4 days (0.5g/kg/d)
• Placebo
Sodium chloride 0.9% in the same volume and over the same time as the immunoglobulin

Locations

Country	Name	City	State
France	CHU Sud Amiens	Amiens
France	CHU Angers	Angers
France	Service de réanimation polyvalente, rond point de Girac	Angoulême
France	CH Victor Dupouy	Argenteuil
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	CH Etampes	Étampes
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 Poitiers	Poitiers
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

Sponsors (3)

Lead Sponsor	Collaborator
Centre Hospitalier St Anne	Groupe Hospitalier Universitaire Paris psychiatrie & neurosciences, Laboratoire français de Fractionnement et de Biotechnologies

Country where clinical trial is conducted

France, 

References & Publications (6)

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. — View Citation

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. — View Citation

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. — View Citation

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;:. — View Citation

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. — View Citation

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;:. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Mortality	Vital status at 28 and 90 days	28 and 90 days
Secondary	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
Secondary	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
Secondary	Lung compliance	Measure of lung compliance	Days 1, 3, 7, 14, 21 and 28
Secondary	Radiological score	Severity scoring of lung oedema on the chest radiograph	Days 1, 3, 7, 14, 21 and 28
Secondary	Biological efficacy endpoints - C-reactive protein	Concentration in mg/L	Days 1, 3, 7, 14, 21 and 28
Secondary	Biological efficacy endpoints - Procalcitonin	Concentration in microgram/L	Days 1, 3, 7, 14, 21 and 28
Secondary	Immunological profile	Number of CD4 HLA-DR+ and CD38+, CD8 lymphocytes	Up to 28 days
Secondary	Number of patients using other treatments for COVID-19 related ARDS	Use of corticosteroids, antiretroviral, chloroquine	Up to 28 days
Secondary	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
Secondary	Total duration of mechanical ventilation, ventilatory weaning and curarisation	Total time of mechanical ventilation, weaning and use of neuromuscular blockade	28 days
Secondary	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
Secondary	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
Secondary	Occurrence of critical illness neuromyopathy	Medical research council sum score on awakening	Up to 28 days
Secondary	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