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Clinical Trial
. 2022 Feb;10(2):158-166.
doi: 10.1016/S2213-2600(21)00440-9. Epub 2021 Nov 11.

Intravenous immunoglobulins in patients with COVID-19-associated moderate-to-severe acute respiratory distress syndrome (ICAR): multicentre, double-blind, placebo-controlled, phase 3 trial

Aurélien Mazeraud  1 , Matthieu Jamme  2 , Rossella Letizia Mancusi  3 , Claire Latroche  4 , Bruno Megarbane  5 , Shidasp Siami  6 , Jonathan Zarka  7 , Guy Moneger  8 , Francesco Santoli  9 , Laurent Argaud  10 , Patrick Chillet  11 , Gregoire Muller  12 , Cedric Bruel  13 , Pierre Asfar  14 , Francois Beloncle  14 , Jean Reignier  15 , Christophe Vinsonneau  16 , Caroline Schimpf  17 , Julien Amour  18 , Cyril Goulenok  19 , Caroline Lemaitre  20 , Benjamin Rohaut  21 , Philippe Mateu  22 , Stephane De Rudnicki  23 , Bruno Mourvillier  24 , Pierre-Louis Declercq  25 , Carole Schwebel  26 , Annabelle Stoclin  27 , Marc Garnier  28 , Benjamin Madeux  29 , Stéphane Gaudry  30 , Karine Bailly  31 , Christian Lamer  32 , Philippe Aegerter  33 , Christine Rieu  17 , Khaoussou Sylla  3 , Bruno Lucas  34 , Tarek Sharshar  35
Affiliations
Clinical Trial

Intravenous immunoglobulins in patients with COVID-19-associated moderate-to-severe acute respiratory distress syndrome (ICAR): multicentre, double-blind, placebo-controlled, phase 3 trial

Aurélien Mazeraud et al. Lancet Respir Med. 2022 Feb.

Abstract

Background: Acute respiratory distress syndrome (ARDS) is a major complication of COVID-19 and is associated with high mortality and morbidity. We aimed to assess whether intravenous immunoglobulins (IVIG) could improve outcomes by reducing inflammation-mediated lung injury.

Methods: In this multicentre, double-blind, placebo-controlled trial, done at 43 centres in France, we randomly assigned patients (1:1) receiving invasive mechanical ventilation for up to 72 h with PCR confirmed COVID-19 and associated moderate-to-severe ARDS to receive either IVIG (2 g/kg over 4 days) or placebo. Random assignment was done with a web-based system and was stratified according to the participating centre and the duration of invasive mechanical ventilation before inclusion in the trial (<12 h, 12-24 h, and >24-72 h), and treatment was administered within the first 96 h of invasive mechanical ventilation. To minimise the risk of adverse events, the IVIG administration was divided into four perfusions of 0·5 g/kg each administered over at least 8 hours. Patients in the placebo group received an equivalent volume of sodium chloride 0·9% (10 mL/kg) over the same period. The primary outcome was the number of ventilation-free days by day 28, assessed according to the intention-to-treat principle. This trial was registered on ClinicalTrials.gov, NCT04350580.

Findings: Between April 3, and October 20, 2020, 146 patients (43 [29%] women) were eligible for inclusion and randomly assigned: 69 (47%) patients to the IVIG group and 77 (53%) to the placebo group. The intention-to-treat analysis showed no statistical difference in the median number of ventilation-free days at day 28 between the IVIG group (0·0 [IQR 0·0-8·0]) and the placebo group (0·0 [0·0-6·0]; difference estimate 0·0 [0·0-0·0]; p=0·21). Serious adverse events were more frequent in the IVIG group (78 events in 22 [32%] patients) than in the placebo group (47 events in 15 [20%] patients; p=0·089).

Interpretation: In patients with COVID-19 who received invasive mechanical ventilation for moderate-to-severe ARDS, IVIG did not improve clinical outcomes at day 28 and tended to be associated with an increased frequency of serious adverse events, although not significant. The effect of IVIGs on earlier disease stages of COVID-19 should be assessed in future trials.

Funding: Programme Hospitalier de Recherche Clinique.

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Conflict of interest statement

Declaration of interests We declare no competing interests.

Figures

Figure 1
Figure 1
Trial profile FiO2=fraction of inspired oxygen. IVIG=intravenous immunoglobulin. IMV=invasive mechanical ventilation. PaO2=partial pressure of arterial oxygen in mm Hg.
Figure 2
Figure 2
Cumulative distribution of ventilation-free days (A), and Kaplan-Meier curves of patients who were extubated (B), and probability of survival (C) IVIG=intravenous immunoglobulin.
Figure 3
Figure 3
Forest plot of the subgroup analysis of ventilator-free days Mean difference is reported for the main outcome of ventilation-free days at day 28 for all the patients and for invasive mechanical ventilation time at randomisation, age, survival at day 7, body-mass index, corticosteroid administration, and in the per-protocol population. All subgroup analyses were prespecified except the analysis of patients receiving corticosteroids, which was not prespecified in the initial protocol. BMI=body-mass index.
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