Study Results
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Basic Information
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COMPLETED
PHASE3
146 participants
INTERVENTIONAL
2020-04-11
2021-02-20
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
DOUBLE
Study Groups
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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.
Human immunoglobulin
Human immunoglobulin 2g/kg over 4 days (0.5g/kg/d)
Placebo
Participants of the placebo group will receive an equivalent volume of sodium chloride 0.9% for the same duration.
Placebo
Sodium chloride 0.9% in the same volume and over the same time as the immunoglobulin
Interventions
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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
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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
* 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
18 Years
ALL
No
Sponsors
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Groupe Hospitalier Universitaire Paris psychiatrie & neurosciences
UNKNOWN
Laboratoire français de Fractionnement et de Biotechnologies
INDUSTRY
Centre Hospitalier St Anne
OTHER
Responsible Party
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Principal Investigators
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Tarek Sharshar, MD, PHD
Role: STUDY_CHAIR
Centre Hospitalier Sainte Anne
Aurélien Mazeraud, MD, PHD
Role: PRINCIPAL_INVESTIGATOR
Centre Hospitalier Sainte Anne
Locations
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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-Nord-Ardennes
Charleville-Mézières, , France
CH Chalons en champagne
Châlons-en-Champagne, , 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, , France
Countries
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References
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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.
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.
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.
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.
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.
Provided Documents
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Document Type: Statistical Analysis Plan
Other Identifiers
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2020-001570-30
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
D20-P013
Identifier Type: -
Identifier Source: org_study_id
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