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Bamlanivimab reduces nasopharyngeal SARS-CoV-2 RNA levels but not symptom duration in non-hospitalized adults with COVID-19: A Phase 2 Randomized Clinical Trial

IMPORTANCE: The antiviral activity and efficacy of anti-SARS-CoV-2 monoclonal antibody (mAb) therapies to accelerate recovery from COVID-19 is important to define. OBJECTIVE: To determine safety and efficacy of the mAb bamlanivimab to reduce nasopharyngeal (NP) SARS-CoV-2 RNA levels and symptom dura...

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Autores principales: Chew, Kara W., Moser, Carlee, Daar, Eric S., Wohl, David A., Li, Jonathan Z., Coombs, Robert, Ritz, Justin, Giganti, Mark, Javan, Arzhang Cyrus, Li, Yijia, Malvestutto, Carlos, Klekotka, Paul, Price, Karen, Nirula, Ajay, Fischer, William, Bala, Veenu, Ribeiro, Ruy M., Perelson, Alan S., Fletcher, Courtney V., Eron, Joseph J., Currier, Judith S., Hughes, Michael D., Smith, Davey M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8722620/
https://www.ncbi.nlm.nih.gov/pubmed/34981077
http://dx.doi.org/10.1101/2021.12.17.21268009
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author Chew, Kara W.
Moser, Carlee
Daar, Eric S.
Wohl, David A.
Li, Jonathan Z.
Coombs, Robert
Ritz, Justin
Giganti, Mark
Javan, Arzhang Cyrus
Li, Yijia
Malvestutto, Carlos
Klekotka, Paul
Price, Karen
Nirula, Ajay
Fischer, William
Bala, Veenu
Ribeiro, Ruy M.
Perelson, Alan S.
Fletcher, Courtney V.
Eron, Joseph J.
Currier, Judith S.
Hughes, Michael D.
Smith, Davey M.
author_facet Chew, Kara W.
Moser, Carlee
Daar, Eric S.
Wohl, David A.
Li, Jonathan Z.
Coombs, Robert
Ritz, Justin
Giganti, Mark
Javan, Arzhang Cyrus
Li, Yijia
Malvestutto, Carlos
Klekotka, Paul
Price, Karen
Nirula, Ajay
Fischer, William
Bala, Veenu
Ribeiro, Ruy M.
Perelson, Alan S.
Fletcher, Courtney V.
Eron, Joseph J.
Currier, Judith S.
Hughes, Michael D.
Smith, Davey M.
author_sort Chew, Kara W.
collection PubMed
description IMPORTANCE: The antiviral activity and efficacy of anti-SARS-CoV-2 monoclonal antibody (mAb) therapies to accelerate recovery from COVID-19 is important to define. OBJECTIVE: To determine safety and efficacy of the mAb bamlanivimab to reduce nasopharyngeal (NP) SARS-CoV-2 RNA levels and symptom duration. DESIGN: ACTIV-2/A5401 is a randomized, blinded, placebo-controlled platform trial. Two dose cohorts were enrolled between August 19 and November 17, 2020 for phase 2 evaluation: in the first, participants were randomized 1:1 to bamlanivimab 7000 mg versus placebo, and in the second to bamlanivimab 700 mg versus placebo. Randomization was stratified by time from symptom onset (≤ or >5 days) and risk of progression to severe COVID-19 (“higher” vs “lower”). SETTING: Multicenter trial conducted at U.S. sites. PARTICIPANTS: Non-hospitalized adults ≥18 years of age with positive SARS-CoV-2 antigen or nucleic acid test within 7 days, ≤10 days of COVID-19 symptoms, and with oxygen saturation ≥92% within 48 hours prior to study entry. INTERVENTION: Single infusion of bamlanivimab (7000 or 700 mg) or placebo. MAIN OUTCOMES AND MEASURES: Detection of NP SARS-CoV-2 RNA at days 3, 7, 14, 21, and 28, time to improvement of all of 13 targeted COVID-19 symptoms by daily self-assessment through day 28, and grade 3 or higher treatment emergent adverse events (TEAEs) through day 28. Secondary measures included quantitative NP SARS-CoV-2 RNA, all-cause hospitalizations and deaths (composite), area under the curve of symptom scores from day 0 through day 28, plasma bamlanivimab concentrations, plasma and serum inflammatory biomarkers, and safety through week 24. RESULTS: Ninety-four participants were enrolled to the 7000 mg cohort and 223 to the 700 mg cohort and initiated study intervention. The proportion meeting protocol criteria for “higher” risk for COVID-19 progression was 42% and 51% for the 7000 and 700 mg cohort, respectively. Median time from symptom onset at study entry for both cohorts was 6 days. There was no difference in the proportion with undetectable NP SARS-CoV-2 RNA at any post-treatment timepoints (risk ratio compared to placebo, 0.82–1.05 for 7000 mg dose [overall p=0.88] and 0.81–1.21 for 700 mg dose [overall p=0.49]), time to symptom improvement (median of 21 vs 18.5 days, p=0.97, for 7000 mg bamlanivimab vs placebo and 24 vs 20.5 days, p=0.08, for 700 mg bamlanivimab vs placebo), or grade 3+ TEAEs with either dose compared to placebo. Median NP SARS-CoV-2 RNA levels were lower at day 3 and C-reactive protein, ferritin, and fibrinogen levels significantly reduced at days 7 and 14 for bamlanivimab 700 mg compared to placebo, with similar trends observed for bamlanivimab 7000 mg. Viral decay modeling supported more rapid decay with bamlanivimab compared to placebo. CONCLUSIONS AND RELEVANCE: Treatment with bamlanivimab 7000 mg and 700 mg was safe and compared to placebo led to more rapid reductions in NP SARS-CoV-2 RNA and inflammatory biomarkers, but did not decrease time to symptom improvement. The clinical utility of mAbs for outcomes other than hospitalizations and deaths is uncertain. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04518410
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spelling pubmed-87226202022-01-04 Bamlanivimab reduces nasopharyngeal SARS-CoV-2 RNA levels but not symptom duration in non-hospitalized adults with COVID-19: A Phase 2 Randomized Clinical Trial Chew, Kara W. Moser, Carlee Daar, Eric S. Wohl, David A. Li, Jonathan Z. Coombs, Robert Ritz, Justin Giganti, Mark Javan, Arzhang Cyrus Li, Yijia Malvestutto, Carlos Klekotka, Paul Price, Karen Nirula, Ajay Fischer, William Bala, Veenu Ribeiro, Ruy M. Perelson, Alan S. Fletcher, Courtney V. Eron, Joseph J. Currier, Judith S. Hughes, Michael D. Smith, Davey M. medRxiv Article IMPORTANCE: The antiviral activity and efficacy of anti-SARS-CoV-2 monoclonal antibody (mAb) therapies to accelerate recovery from COVID-19 is important to define. OBJECTIVE: To determine safety and efficacy of the mAb bamlanivimab to reduce nasopharyngeal (NP) SARS-CoV-2 RNA levels and symptom duration. DESIGN: ACTIV-2/A5401 is a randomized, blinded, placebo-controlled platform trial. Two dose cohorts were enrolled between August 19 and November 17, 2020 for phase 2 evaluation: in the first, participants were randomized 1:1 to bamlanivimab 7000 mg versus placebo, and in the second to bamlanivimab 700 mg versus placebo. Randomization was stratified by time from symptom onset (≤ or >5 days) and risk of progression to severe COVID-19 (“higher” vs “lower”). SETTING: Multicenter trial conducted at U.S. sites. PARTICIPANTS: Non-hospitalized adults ≥18 years of age with positive SARS-CoV-2 antigen or nucleic acid test within 7 days, ≤10 days of COVID-19 symptoms, and with oxygen saturation ≥92% within 48 hours prior to study entry. INTERVENTION: Single infusion of bamlanivimab (7000 or 700 mg) or placebo. MAIN OUTCOMES AND MEASURES: Detection of NP SARS-CoV-2 RNA at days 3, 7, 14, 21, and 28, time to improvement of all of 13 targeted COVID-19 symptoms by daily self-assessment through day 28, and grade 3 or higher treatment emergent adverse events (TEAEs) through day 28. Secondary measures included quantitative NP SARS-CoV-2 RNA, all-cause hospitalizations and deaths (composite), area under the curve of symptom scores from day 0 through day 28, plasma bamlanivimab concentrations, plasma and serum inflammatory biomarkers, and safety through week 24. RESULTS: Ninety-four participants were enrolled to the 7000 mg cohort and 223 to the 700 mg cohort and initiated study intervention. The proportion meeting protocol criteria for “higher” risk for COVID-19 progression was 42% and 51% for the 7000 and 700 mg cohort, respectively. Median time from symptom onset at study entry for both cohorts was 6 days. There was no difference in the proportion with undetectable NP SARS-CoV-2 RNA at any post-treatment timepoints (risk ratio compared to placebo, 0.82–1.05 for 7000 mg dose [overall p=0.88] and 0.81–1.21 for 700 mg dose [overall p=0.49]), time to symptom improvement (median of 21 vs 18.5 days, p=0.97, for 7000 mg bamlanivimab vs placebo and 24 vs 20.5 days, p=0.08, for 700 mg bamlanivimab vs placebo), or grade 3+ TEAEs with either dose compared to placebo. Median NP SARS-CoV-2 RNA levels were lower at day 3 and C-reactive protein, ferritin, and fibrinogen levels significantly reduced at days 7 and 14 for bamlanivimab 700 mg compared to placebo, with similar trends observed for bamlanivimab 7000 mg. Viral decay modeling supported more rapid decay with bamlanivimab compared to placebo. CONCLUSIONS AND RELEVANCE: Treatment with bamlanivimab 7000 mg and 700 mg was safe and compared to placebo led to more rapid reductions in NP SARS-CoV-2 RNA and inflammatory biomarkers, but did not decrease time to symptom improvement. The clinical utility of mAbs for outcomes other than hospitalizations and deaths is uncertain. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04518410 Cold Spring Harbor Laboratory 2021-12-21 /pmc/articles/PMC8722620/ /pubmed/34981077 http://dx.doi.org/10.1101/2021.12.17.21268009 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Chew, Kara W.
Moser, Carlee
Daar, Eric S.
Wohl, David A.
Li, Jonathan Z.
Coombs, Robert
Ritz, Justin
Giganti, Mark
Javan, Arzhang Cyrus
Li, Yijia
Malvestutto, Carlos
Klekotka, Paul
Price, Karen
Nirula, Ajay
Fischer, William
Bala, Veenu
Ribeiro, Ruy M.
Perelson, Alan S.
Fletcher, Courtney V.
Eron, Joseph J.
Currier, Judith S.
Hughes, Michael D.
Smith, Davey M.
Bamlanivimab reduces nasopharyngeal SARS-CoV-2 RNA levels but not symptom duration in non-hospitalized adults with COVID-19: A Phase 2 Randomized Clinical Trial
title Bamlanivimab reduces nasopharyngeal SARS-CoV-2 RNA levels but not symptom duration in non-hospitalized adults with COVID-19: A Phase 2 Randomized Clinical Trial
title_full Bamlanivimab reduces nasopharyngeal SARS-CoV-2 RNA levels but not symptom duration in non-hospitalized adults with COVID-19: A Phase 2 Randomized Clinical Trial
title_fullStr Bamlanivimab reduces nasopharyngeal SARS-CoV-2 RNA levels but not symptom duration in non-hospitalized adults with COVID-19: A Phase 2 Randomized Clinical Trial
title_full_unstemmed Bamlanivimab reduces nasopharyngeal SARS-CoV-2 RNA levels but not symptom duration in non-hospitalized adults with COVID-19: A Phase 2 Randomized Clinical Trial
title_short Bamlanivimab reduces nasopharyngeal SARS-CoV-2 RNA levels but not symptom duration in non-hospitalized adults with COVID-19: A Phase 2 Randomized Clinical Trial
title_sort bamlanivimab reduces nasopharyngeal sars-cov-2 rna levels but not symptom duration in non-hospitalized adults with covid-19: a phase 2 randomized clinical trial
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8722620/
https://www.ncbi.nlm.nih.gov/pubmed/34981077
http://dx.doi.org/10.1101/2021.12.17.21268009
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