TY - JOUR

T1 - Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC)

T2 - a double-blind, placebo-controlled, phase 3, randomised trial

AU - Polizzotto, Mark N.

AU - Nordwall, Jacqueline

AU - Babiker, Abdel G.

AU - Phillips, Andrew

AU - Vock, David M.

AU - Eriobu, Nnakelu

AU - Kwaghe, Vivian

AU - Paredes, Roger

AU - Mateu, Lourdes

AU - Ramachandruni, Srikanth

AU - Narang, Rajeev

AU - Jain, Mamta K.

AU - Lazarte, Susana M.

AU - Baker, Jason V.

AU - Frosch, Anne E.P.

AU - Poulakou, Garyfallia

AU - Syrigos, Konstantinos N.

AU - Arnoczy, Gretchen S.

AU - McBride, Natalie A.

AU - Robinson, Philip A.

AU - Sarafian, Farjad

AU - Bhagani, Sanjay

AU - Taha, Hassan S.

AU - Benfield, Thomas

AU - Liu, Sean T.H.

AU - Antoniadou, Anastasia

AU - Jensen, Jens Ulrik Stæhr

AU - Kalomenidis, Ioannis

AU - Susilo, Adityo

AU - Hariadi, Prasetyo

AU - Jensen MD, Tomas O.

AU - Morales-Rull, Jose Luis

AU - Helleberg, Marie

AU - Meegada, Sreenath

AU - Johansen, Isik S.

AU - Canario, Daniel

AU - Fernández-Cruz, Eduardo

AU - Metallidis, Simeon

AU - Shah, Amish

AU - Sakurai, Aki

AU - Koulouris, Nikolaos G.

AU - Trotman, Robin

AU - Weintrob, Amy C.

AU - Podlekareva, Daria

AU - Hadi, Usman

AU - Lloyd, Kathryn M.

AU - Røge, Birgit Thorup

AU - Saito, Sho

AU - Muñoz, Jose

AU - Lundgren, Jens D.

AU - The ITAC (INSIGHT 013) Study Group

N1 - Publisher Copyright: © 2022 Elsevier Ltd

PY - 2022

Y1 - 2022

N2 - Background: Passive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited. Methods: In this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of anti-spike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581. Findings: From Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1·06 (95% CI 0·77–1·45; p=0·72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18·6% vs 9·5% for placebo; p=0·002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0·98, 95% CI 0·66–1·46; p=0·91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2·21, 95% CI 1·14–4·29); for patients who were antibody negative, the OR was 0·51 (0·29–0·90; pinteraction=0·001). Interpretation: When administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry. Funding: US National Institutes of Health.

AB - Background: Passive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited. Methods: In this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of anti-spike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581. Findings: From Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1·06 (95% CI 0·77–1·45; p=0·72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18·6% vs 9·5% for placebo; p=0·002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0·98, 95% CI 0·66–1·46; p=0·91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2·21, 95% CI 1·14–4·29); for patients who were antibody negative, the OR was 0·51 (0·29–0·90; pinteraction=0·001). Interpretation: When administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry. Funding: US National Institutes of Health.

U2 - 10.1016/S0140-6736(22)00101-5

DO - 10.1016/S0140-6736(22)00101-5

M3 - Journal article

C2 - 35093205

AN - SCOPUS:85123885568

VL - 399

SP - 530

EP - 540

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 10324

ER -