Clinical trial NCT04350580: Polyvalent Immunoglobulin in COVID-19 Related ARds
Official title: Value of Early Treatment With Polyvalent Immunoglobulin in the Management of Acute Respiratory Distress Syndrome Associated With SARS-CoV-2 Infections
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Respiratory Distress Syndrome
COVID-19
Keywords: acute respiratory distress syndrome
COVID-19
SARS-CoV-2
Immunoglobulin
Lead sponsor: Centre Hospitalier St Anne
Sponsor class: OTHER
Collaborators: name: Groupe Hospitalier Universitaire Paris psychiatrie & neurosciences
name: Laboratoire français de Fractionnement et de Biotechnologies
First posted: 2020-04-17
Enrollment: 146
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Ventilator-free days
timeFrame: 28 days
Secondary outcomes:
measure: Mortality
timeFrame: 28 and 90 days
measure: Sequential Organ Failure Assessment Score
timeFrame: Days 1, 3, 7, 14, 21 and 28
measure: P/F ratio
timeFrame: Days 1, 3, 7, 14, 21 and 28
measure: Lung compliance
timeFrame: Days 1, 3, 7, 14, 21 and 28
measure: Radiological score
timeFrame: Days 1, 3, 7, 14, 21 and 28
measure: Biological efficacy endpoints - C-reactive protein
timeFrame: Days 1, 3, 7, 14, 21 and 28
measure: Biological efficacy endpoints - Procalcitonin
timeFrame: Days 1, 3, 7, 14, 21 and 28
measure: Immunological profile
timeFrame: Up to 28 days
measure: Number of patients using other treatments for COVID-19 related ARDS
timeFrame: Up to 28 days
measure: Occurrence of deep vein thrombosis or pulmonary embolism
timeFrame: 28 days
measure: Total duration of mechanical ventilation, ventilatory weaning and curarisation
timeFrame: 28 days
measure: Kidney Disease: Improving Global Outcomes (KDIGO) score and need for dialysis
timeFrame: 28 days
measure: Occurrence of adverse event related to immunoglobulins
timeFrame: 28 days
measure: Occurrence of critical illness neuromyopathy
timeFrame: Up to 28 days
measure: Occurrence of ventilator-acquired pneumonia
timeFrame: Up to 28 days
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU Sud Amiens
city: Angers
country: France
facility: CHU Angers
city: Angoulême
country: France
facility: Service de réanimation polyvalente, rond point de Girac
city: Argenteuil
country: France
facility: CH Victor Dupouy
city: Aulnay-sous-Bois
country: France
facility: CH Aulnay
city: Beuvry
country: France
facility: Centre hospitalier de Béthune
city: Bobigny
country: France
facility: Hopital Avicenne
city: Chalons en champagne
country: France
facility: CH Chalons en champagne
city: Charleville-Mézières
country: France
facility: CH-Nord-Ardennes
city: Clamart
country: France
facility: Hopital d'instruction des armées Percy
city: Dieppe
country: France
facility: Centre Hospitalier de Dieppe
city: Garches
country: France
facility: Hôpital Raymond Poincaré
city: Grenoble
country: France
facility: CHU de Grenoble
city: Jossigny
country: France
facility: Grand hopital de l'est Francilien - site de Jossigny
city: Libourne
country: France
facility: Hopital Robert Boulin
city: Lille
country: France
facility: Pôle de Médecine intensive/réanimation Hôpital Salengro, CHRU de Lille
city: Lyon
country: France
facility: Groupement Hospitalier Edouar Herriot
city: Lyon
country: France
facility: Hôpital de la Croix Rousse Novembre 2019
city: Massy
country: France
facility: Hopital Jacques Cartier
city: Montivilliers
country: France
facility: Hopital Jacques Monod
city: Nantes
country: France
facility: Service de Médecine Intensive-Réanimation, CHU
city: Orléans
country: France
facility: CHR Orléans
city: Paris
country: France
facility: Centre Hospitalier Sainte-Anne
city: Paris
country: France
facility: CHU Lariboisiere
city: Paris
country: France
facility: CHU Pitié Salpétriere Service de réanimation chirurgicale
city: Paris
country: France
facility: CHU Saint Antoine
city: Paris
country: France
facility: Fondation ophtalmologique Rotschild
city: Paris
country: France
facility: Hôpital Paris Saint-Joseph
city: Paris
country: France
facility: Hôpital Pitié Salpêtrière
city: Paris
country: France
facility: Institut Mutualiste Montsouris
city: Poitiers
country: France
facility: CHU Poitiers
city: Reims
country: France
facility: CHU Robert Débré
city: Saint-Germain-en-Laye
country: France
facility: CH Poissy
city: Strasbourg
country: France
facility: Groupe hospitalier Saint Vincent
city: Strasbourg
country: France
facility: Hôpital de Hautepierre
city: Tarbes
country: France
facility: Hopital de Tarbes
city: Trévenans
country: France
facility: Hôpital Nord Franche-Comté
city: Valenciennes
country: France
facility: CH Valenciennes
city: Vandœuvre-lès-Nancy
country: France
facility: Chu Nancy - Brabois
city: Vannes
country: France
facility: Hopital de Vannes
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Étampes
country: France
facility: CH Etampes
Study officials:
affiliation: Centre Hospitalier Sainte Anne
name: Tarek Sharshar, MD, PHD
role: STUDY_CHAIR
affiliation: Centre Hospitalier Sainte Anne
name: Aurélien Mazeraud, MD, PHD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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. No abstract available.
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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. doi: 10.1136/thx.2004.029819.
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;2003(4):CD004000. doi: 10.1002/14651858.CD004000.
citation: 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.
citation: 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.
citation: 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.