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Randomized Controlled Trial
. 2022 May;22(5):622-635.
doi: 10.1016/S1473-3099(21)00751-9. Epub 2021 Dec 23.

Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial

ACTIV-3/Therapeutics for Inpatients with COVID-19 (TICO) Study Group
Collaborators
Randomized Controlled Trial

Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial

ACTIV-3/Therapeutics for Inpatients with COVID-19 (TICO) Study Group. Lancet Infect Dis. 2022 May.

Abstract

Background: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19.

Methods: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978.

Findings: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90.

Interpretation: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19.

Funding: US National Institutes of Health and Operation Warp Speed.

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Conflict of interest statement

Declaration of interests WHS reports grants from National Heart, Lung and Blood Institute (NHLBI) during the conduct of the study and personal fees from Aerpio Pharmaceuticals outside of the submitted work. US reports grants from NIH, Cytodin, and Regeneron outside of the submitted work. RLG reports personal fees from GSK Pharmaceuticals during the conduct of the study, and personal fees and non-financial support from Gilead Sciences and personal fees from Johnson & Johnson and Roivant Sciences, outside of the submitted work. TWR reports grants from NHLBI of the NIH during the conduct of the study and personal fees from Cumberland Pharmaceuticals and Sanofi outside of the submitted work. JDC reports grants from NIH outside the submitted work. IDP reports grants from NIH during the conduct of the study, and grants from Janssen Pharmaceuticals, NIH, and US Centers for Disease Control and Prevention (CDC), research funding support from Regeneron and Asahi Kasei Pharma, and grants from Intermountain Research and Medical Foundation outside the submitted work. AJR reports personal fees from Merck outside of the submitted work. MNG reports research funding support from Regeneron outside of the submitted work. BWT reports salary support from INSIGHT during the conduct of the study, and grants from NIH, Agency for Healthcare Research and Quality, CDC, Veterans Affairs Health Services Research and Development, grants and personal fees from Zambon pharmaceuticals, and personal fees and research funding support from Genentech outside of the submitted work. MKJ reports payment to their employer for clinical trial activities from Regeneron Pharmaceuticals, Gilead Sciences, Janssen Pharmaceuticals, and Merck, and payments for advisory board meetings from Gilead Sciences outside of the submitted work. AK reports grants from United Therapeutics, Johnson & Johnson, 4D Medical, Lung LLC, and Reata Pharmaceuticals outside of the submitted work. MAM reports grants from Roche/Genentec and personal fees from Pliant Therapeutics, Novartis, Johnson & Johnson, and Citius Pharmaceuticals outside of the submitted work. AAG reports grants from NIH during the conduct of the study and grants from AbbVie and Faron Pharmaceuticals outside of the submitted work. SMB reports grants from CDC during the conduct of the study and personal fees from Hamilton, payment to their employer for service on a trial steering committee from Faron and Sedana; grants from Janssen, NIH, and US Department of Defense; and book royalties from Oxford University and Brigham Young University outside of the submitted work. SP reports grants to their university from the University of Minnesota during the conduct of the study, and other grants to their university from University of Minnesota, European and Developing Countries Clinical Trials Partnership, UK Research and Innovation (UKRI), Academy of Medical Sciences, ViiV Healthcare, UK Medical Research Council (MRC), and Gilead Sciences outside of the submitted work. HFG reports grants from Swiss National Science Foundation, NIH, Swiss HIV Cohort Study, and Yvonne Jacob Foundation; unrestricted grants from Gilead Sciences; and personal fees from Merck, Gilead Sciences and ViiV, for being an advisor, consultant, or DSMB member, outside of the submitted work. SS reports grants from NIH during the conduct of the study. HC reports being a Gilead employee. RG reports being a full-time employee of Vir Biotechnology and owned stock in Vir Biotechnology during the conduct of the study. SO reports being an employee of GlaxoSmithKline Pharmaceuticals. DM reports support from Brii Biosciences during the conduct of the study. AGB reports grants from University of Minnesota during the conduct of the study and grants from MRC and UKRI outside of the submitted work. BTT reports receiving consulting fees from Bayer, Novartis, and Thetis outside the submitted work. JDN reports grants from NIAID NIH during the conduct of the study. All other members of the writing committee declare no competing interests.

Figures

Figure 1
Figure 1
Study profile *One patient who was randomly assigned to the placebo group was enrolled at a site not using the BRII-196 plus BRII-198 agent. This patient was not included in the placebo group for comparisons with BRII-196 plus BRII-198. †Day 5 outcomes were used for the early futility assessment. ‡Day 90 outcome of sustained clinical recovery was the primary efficacy outcome; patients lost to follow-up were censored.
Figure 2
Figure 2
Distribution of patients on the pulmonary ordinal scale (A) and the pulmonary-plus ordinal scale (B) on day 5 The sotrovimab group and the BRII-196 plus BRII-198 group were each compared with the placebo group. ECMO=extracorporeal membrane oxygenation. NIHSS=National Institutes of Health Stroke Scale. *One patient in the common placebo group was enrolled at a site that was not enrolling patients into the BRII-196 plus BRII-198 group of the trial; this patient was not included in the placebo group for comparison with BRII-196 plus BRII-198.
Figure 3
Figure 3
Time to sustained clinical recovery up to day 90 for sotrovimab versus placebo (A) and BRII-196 plus BRII-198 versus placebo (B) The rate ratios were calculated with Fine-Gray models to account for the competing risk of death and stratified according to trial pharmacy. Reasons for censoring included death before sustained recovery was reached (11 patients in the sotrovimab and placebo groups and 13 in the BRII-196 plus BRII-198 group), loss to follow-up (five patients in the sotrovimab and BRII-196 plus BRII-198 groups and nine in the placebo group), and not reaching sustained recovery by day 90 (six patients in the sotrovimab group, three in the BRII-196 plus BRII-198 group, and seven in the placebo group) .
Figure 4
Figure 4
Subgroup analysis for time to sustained recovery up to day 90 (A) and the composite safety outcome at day 90 (B) by antibody status and antigen levels at baseline These analyses tested for heterogeneity of treatment effects for sotrovimab and BRII-196 plus BRII-198 by baseline measurements of endogenous neutralising antibodies against the SARS-CoV-2 receptor binding domain and concentrations of SARS-CoV-2 nucleocapsid antigens. Antibody and antigen measurements were done on plasma collected before study drug infusion. Samples with >30% binding inhibition against the SARS-CoV-2 receptor binding domain on the GenScript SARS-CoV-2 Surrogate Virus Neutralization Test assay were classified as positive for endogenous neutralising antibodies. Nucleocapsid antigen concentration >1450 pg/mL on a Quanterix assay, which was approximately the median value in the trial population, was considered a high antigen concentration.
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