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1.
J Infect Dis ; 2022 Jul 27.
Article in English | MEDLINE | ID: covidwho-1961062

ABSTRACT

BACKGROUND: The open-label RECOVERY study reported improved survival in hospitalized, SARS-CoV-2 seronegative patients treated with casirivimab and imdevimab (CAS + IMD). METHODS: In this phase I/II/III, double-blind, placebo-controlled trial conducted prior to widespread circulation of Delta and Omicron, hospitalized COVID-19 patients were randomized (1:1:1) to 2.4 g or 8.0 g CAS + IMD or placebo, and characterized at baseline for viral load and SARS-CoV-2 serostatus. RESULTS: 1336 patients on low-flow or no supplemental (low-flow/no) oxygen were treated. The primary endpoint was met: in seronegative patients, the least-squares mean difference (CAS + IMD versus placebo) for time-weighted average change from baseline in viral load through day 7 was -0.28 log10 copies/mL (95% CI, -0.51 to -0.05; P = .0172). The primary clinical analysis of death or mechanical ventilation (death/MV) from day 6-29 in patients with high viral load had a strong positive trend but did not reach significance. CAS + IMD numerically reduced all-cause mortality in seronegative patients through day 29 (relative risk reduction, 55.6%; 95% CI, 24.2-74.0). No safety concerns were noted. CONCLUSIONS: In hospitalized COVID-19 patients on low-flow/no oxygen, CAS + IMD reduced viral load and likely improves clinical outcomes in the overall population, with the benefit driven by seronegative patients, and no harm observed in seropositive patients.

2.
BMJ Open ; 12(5): e055989, 2022 05 02.
Article in English | MEDLINE | ID: covidwho-1891827

ABSTRACT

OBJECTIVES: There is little in-depth qualitative evidence of how symptoms manifest themselves in outpatients with COVID-19 and how these in turn impact outpatients' daily lives. The objective of the study was therefore to explore the experience of outpatients with COVID-19 qualitatively, concerning the symptomatic experience and its subsequent impact on daily life. SETTING: Qualitative research study comprising virtual in-depth, open-ended interviews with outpatients and clinicians. PARTICIPANTS: Thirty US adult patients with COVID-19 were interviewed within 21 days of diagnosis. Patients were 60% female and 87% white, who had to self-report one of the following: fever, cough, shortness of breath/difficulty breathing, change/loss of taste/smell, vomiting/diarrhoea or body/muscle aches. Five independent clinicians were also interviewed about their experience treating outpatients. PRIMARY AND SECONDARY OUTCOME MEASURES: Transcripts were analysed thematically to organise symptoms and impacts of daily life into higher-order overarching categories, and subsequently propose a conceptual model. The adequacy of the sample size was assessed by conceptual saturation analysis. RESULTS: Patient-reported concepts were organised into six symptom themes (upper respiratory, lower respiratory, systemic, gastrointestinal, smell and taste, and other) and seven impact themes (activities of daily living, broad daily activities, leisure/social activities, and physical, emotional, professional and quarantine-specific impacts). Symptom type, severity, duration and time of onset varied by patient. Clinicians endorsed all patient-reported symptoms. CONCLUSIONS: The manifestation of symptoms in outpatients is heterogeneous and affects all aspects of daily life. Outpatients offered new detailed insights into their symptomatic experiences, including heterogeneous experiences of smell and taste, and the impacts that symptoms had on their daily lives. Findings of this research may be used to supplement existing knowledge of the outpatient experience of mild-to-moderate COVID-19, to further inform treatment guidelines and to provide an evidence base for evaluating potential treatment benefits.


Subject(s)
COVID-19 , Outpatients , Activities of Daily Living , Adult , Dyspnea/etiology , Female , Humans , Male , Patient Outcome Assessment , Qualitative Research
3.
Clin Infect Dis ; 2022 Feb 26.
Article in English | MEDLINE | ID: covidwho-1886374

ABSTRACT

BACKGROUND: Open-label platform trials and a prospective meta-analysis suggest efficacy of anti-IL-6R therapies in hospitalized patients with COVID-19 receiving corticosteroids. This study evaluated the efficacy and safety of sarilumab, an anti-IL-6R monoclonal antibody, in the treatment of hospitalized patients with COVID-19. METHODS: In this adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial, adults hospitalized with COVID-19 (ClinicalTrials.gov: NCT04315298) received intravenous sarilumab or placebo. The phase 3 primary analysis population included patients with critical COVID-19 receiving mechanical ventilation randomized to sarilumab 400 mg or placebo. The primary outcome was proportion of patients with ≥1-point improvement in clinical status from baseline to day 22. RESULTS: There were 457 and 1365 patients randomized and treated in phases 2 and 3, respectively. In phase 3, patients with critical COVID-19 receiving mechanical ventilation (n = 298; 28.2% on corticosteroids), the proportion with ≥1-point improvement in clinical status (alive, not receiving mechanical ventilation) at day 22 was 43.2% in sarilumab and 35.5% in placebo (risk difference +7.5%; 95% CI, -7.4 to 21.3; P = .3261), a relative risk improvement of 21.7%. In post-hoc analyses pooling phase 2 and 3 critical patients receiving mechanical ventilation, the hazard ratio for death in sarilumab versus placebo was 0.76 (95% CI, .51-1.13) overall and 0.49 (95% CI, .25-.94) in patients receiving corticosteroids at baseline. CONCLUSIONS: This study did not establish the efficacy of sarilumab in hospitalized patients with severe/critical COVID-19. Post-hoc analyses were consistent with other studies that found a benefit of sarilumab in patients receiving corticosteroids.

4.
J Patient Rep Outcomes ; 6(1): 41, 2022 May 04.
Article in English | MEDLINE | ID: covidwho-1879267

ABSTRACT

BACKGROUND: At the onset of the COVID-19 pandemic, there was limited understanding of symptom experience and disease progression. We developed and validated a fit-for-purpose disease-specific instrument to assess symptoms in patients with COVID-19 to inform endpoints in an interventional trial for non-hospitalized patients. METHODS: The initial drafting of the 23-item Symptoms Evolution of COVID-19 (SE-C19) Instrument was developed based on the Centers for Disease Control and Prevention symptom list and available published literature specific to patients with COVID-19 as of Spring 2020. The measurement principles outlined in the Food and Drug Administration (FDA) Patient-Reported Outcomes (PRO) guidance and the FDA's series of four methodological Patient-Focused Drug Development guidance documents were also considered. Following initial development, semi-structured qualitative interviews were conducted with a purposive sample of 30 non-hospitalized COVID-19 patients. Interviews involved two stages: (1) concept elicitation, to obtain information about the symptoms experienced as a result of COVID-19 in the patients' own words, and (2) cognitive debriefing, for patients to describe their understanding of the SE-C19 instructions, specific symptoms, response options, and recall period to ensure the content of the SE-C19 is relevant and comprehensive. Five clinicians treating COVID-19 outpatients were also interviewed to obtain their insights on symptoms experienced by patients and provide input on the SE-C19. RESULTS: Patients reported no issues regarding the relevance or appropriateness of the SE-C19 instructions, including the 24-h recall period. The comprehensiveness of the SE-C19 was confirmed against the conceptualization of the patient experience of symptoms developed in the qualitative research. Minor conceptual gaps were revealed to capture nuances in the experience of nasal and gustatory symptoms and systemic manifestations of sickness. Almost all items were endorsed by patients as being appropriate, well understood, and easy to respond to. The clinicians largely approved all items, response options, and recall period. CONCLUSIONS: The qualitative research provided supportive evidence of the content validity of the SE-C19 to assess the symptoms of outpatients with COVID-19, and its use in clinical trials to evaluate the benefit of treatment. Minor changes may be considered to improve conceptual clarity and ease of responding.

5.
J Infect Dis ; 225(10): 1765-1772, 2022 05 16.
Article in English | MEDLINE | ID: covidwho-1853084

ABSTRACT

BACKGROUND: REGN3048 and REGN3051 are human monoclonal antibodies (mAb) targeting the spike glycoprotein on the Middle East respiratory syndrome coronavirus (MERS-CoV), which binds to the receptor dipeptidyl peptidase-4 (DPP4) and is necessary for infection of susceptible cells. METHODS: Preclinical study: REGN3048, REGN3051 and isotype immunoglobulin G (IgG) were administered to humanized DPP4 (huDPP4) mice 1 day prior to and 1 day after infection with MERS-CoV (Jordan strain). Virus titers and lung pathology were assessed. Phase 1 study: healthy adults received the combined mAb (n = 36) or placebo (n = 12) and followed for 121 days. Six dose levels were studied. Strict safety criteria were met prior to dose escalation. RESULTS: Preclinical study: REGN3048 plus REGN3051, prophylactically or therapeutically, was substantially more effective for reducing viral titer, lung inflammation, and pathology in huDPP4 mice compared with control antibodies and to each antibody monotherapy. Phase 1 study: REGN3048 plus REGN3051 was well tolerated with no dose-limiting adverse events, deaths, serious adverse events, or infusion reactions. Each mAb displayed pharmacokinetics expected of human IgG1 antibodies; it was not immunogenic. CONCLUSIONS: REGN3048 and REGN3051 in combination were well tolerated. The clinical and preclinical data support further development for the treatment or prophylaxis of MERS-CoV infection.


Subject(s)
Coronavirus Infections , Middle East Respiratory Syndrome Coronavirus , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/prevention & control , Dipeptidyl Peptidase 4/metabolism , Humans , Immunoglobulin G , Mice , Spike Glycoprotein, Coronavirus
6.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-307247

ABSTRACT

Background: Elucidating the relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load and clinical outcomes is critical for understanding COVID-19.Methods: SARS-CoV-2 levels were analysed by quantitative real-time polymerase chain reaction (RT-qPCR) of naso- or oro-pharyngeal swab specimens collected at baseline and clinical outcomes were recorded over 60 days from 1362 COVID-19 hospitalised patients enrolled in a multi-center, randomized, placebo-controlled phase II/III trial of sarilumab for COVID-19 (NCT04315298).Findings: In post-hoc analyses, higher baseline viral load, measured by both RT-qPCR cycle threshold (Ct) and log10 copies/mL, was associated with greater supplemental oxygenation requirements and disease severity at study entry. Higher baseline viral load was associated with higher mortality, lower likelihood of improvement in clinical status and supplemental oxygenation requirements, and lower rates of hospital discharge. Viral load was not impacted by sarilumab treatment over time compared with placebo.Interpretation: These data support viral load as an important determinant of clinical outcomes in hospitalized patients with COVID-19 requiring supplemental oxygen or assisted ventilation.Trial Registration: NCT04315298Funding Statement: Supported by Regeneron Pharmaceuticals, Inc. and Sanofi. Certain aspects of this project have been funded in whole or in part with federal funds from the Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under OT number: HHSO100201700020C.Declaration of Interests: All authors are employees or employees and shareholders of Regeneron Pharmaceuticals, Inc.Ethics Approval Statement: The local institutional review board or ethics committee at each centre oversaw trial conduct and documentation. All patients provided written informed consent before participation. Ethics approval was obtained from the following ethics review boards: WCG IRB, Puyallup, WA (IRB00000533);Oregon Health & Science University, Portland, OR (MOD00027616);Institutional Review Board University of Florida, Gainesville, FL (IRB202000779);Columbia University, Human Research Protection Office and IRBs, New York, NY (IRB-AAAS9615);Johns Hopkins Medicine, Office of Human Subjects Research, IRB, Baltimore, MD (IRB00246576/CIR00058074);NYU School Of Medicine, New York, NY (I20-00351_MOD03);Northwestern University IRB, Chicago, IL (STU00212239-MOD0012);Westchester Medical Center, NY Medical College, Office of Research Administration, Valhalla, NY (IRBReg#00000428);Portland Health and Services IRB Providence – St. Johns, Portland, OR (MOD2020001024);Cornell Weill Medicine IRB, New York, NY (IRB00009419);Providence St. Joseph IRB, Renton, WA (MOD2020001029);Providence Health and Services IRB, Portland, OR (MOD2020000519);Ascension St. John Hospital, Tulsa, OK (IRB#00001980);Geisinger IRB, Danville, PA (IRB#0008345).

8.
Open forum infectious diseases ; 8(Suppl 1):S809-S810, 2021.
Article in English | EuropePMC | ID: covidwho-1564579

ABSTRACT

Background Casirivimab and imdevimab (CAS/IMDEV) is authorized for emergency use in the US for outpatients with COVID-19. We present results from patient cohorts receiving low flow or no supplemental oxygen at baseline from a phase 1/2/3, randomized, double-blinded, placebo (PBO)-controlled trial of CAS/IMDEV in hospitalized patients (pts) with COVID-19. Methods Hospitalized COVID-19 pts were randomized 1:1:1 to 2.4 g or 8.0 g of IV CAS/IMDEV (co-administered) or PBO. Primary endpoints were time-weighted average (TWA) change in viral load from baseline (Day 1) to Day 7;proportion of pts who died or went on mechanical ventilation (MV) through Day 29. Safety was evaluated through Day 57. The study was terminated early due to low enrollment (no safety concerns). Results Analysis was performed in pooled cohorts (low flow or no supplemental oxygen) as well as combined treatment doses (2.4 g and 8.0 g). The prespecified primary virologic analysis was in seronegative (seroneg) pts (combined dose group n=360;PBO n=160), where treatment with CAS/IMDEV led to a significant reduction in viral load from Day 1–7 (TWA change: LS mean (SE): -0.28 (0.12);95% CI: -0.51, -0.05;P=0.0172;Fig. 1). The primary clinical analysis had a strong positive trend, though it did not reach statistical significance (P=0.2048), and 4/6 clinical endpoints prespecified for hypothesis testing were nominally significant (Table 1). In seroneg pts, there was a 47.0% relative risk reduction (RRR) in the proportion of pts who died or went on MV from Day 1–29 (10.3% treated vs 19.4% PBO;nominal P=0.0061;Fig. 2). There was a 55.6% (6.7% treated vs 15.0% PBO;nominal P=0.0032) and 35.9% (7.3% treated vs 11.5% PBO;nominal P=0.0178) RRR in the prespecified secondary endpoint of mortality by Day 29 in seroneg pts and the overall population, respectively (Fig. 2). No harm was seen in seropositive patients, and no safety events of concern were identified. Figure 1: TWA daily viral load decreased from baseline (Day 1) in seronegative patients receiving low flow or no supplemental oxygen Table 1. Primary virologic and clinical endpoints Figure 2: Clinical outcomes in hospitalized patients receiving low flow or no supplemental oxygen* Conclusion Co-administration of CAS/IMDEV led to a significant reduction in viral load in hospitalized, seroneg pts requiring low flow or no supplemental oxygen. In seroneg pts and the overall population, treatment also demonstrated clinically meaningful, nominally significant reductions in 28-day mortality and proportion of pts dying or requiring MV. Disclosures Eleftherios Mylonakis, MD, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Chemic labs/KODA therapeutics (Grant/Research Support)Cidara (Grant/Research Support)Leidos Biomedical Research Inc/NCI (Grant/Research Support)NIH/NIAID (Grant/Research Support)NIH/NIGMS (Grant/Research Support)Pfizer (Grant/Research Support)Regeneron (Grant/Research Support)SciClone Pharmaceuticals (Grant/Research Support) Selin Somersan-Karakaya, MD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Sumathi Sivapalasingam, MD, BARDA (Other Financial or Material Support, HHSO100201700020C)Excision BioTherapeutics (Employee)Regeneron Pharmaceuticals, Inc. (Shareholder, Other Financial or Material Support, Royalties, patents planned, issued or pending, former employee) Shazia Ali, PharmD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Yiping Sun, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Rafia Bhore, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Jingning Mei, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Jutta Miller, BS, RN, BARDA (Other Financial or Ma erial Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Lisa Cupelli, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee) Andrea T. Hooper, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Pfizer, Inc. (Shareholder, Other Financial or Material Support, Former employee)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder, Royalties, patents planned, issued or pending) Jennifer D. Hamilton, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder, Royalties, patents planned, issued or pending) Cynthia Pan, BPharm, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Viet Pham, BS, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Yuming Zhao, MS, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Romana Hosain, MD, MPH, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Adnan Mahmood, MD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) John D. Davis, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Kenneth C. Turner, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder, Royalties, patents planned, issued or pending) Yunji Kim, PharmD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Amanda Cook, BS, Dip Reg Aff, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Jason C. Wells, MD, BARDA (Other Financial or Material Support, HHSO100201700020C) Bari Kowal, MS, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Yuhwen Soo, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) A. Thomas DiCioccio, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Gregory P. Geba, MD, DrPH, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Shareholder) Neil Stahl, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder, Royalties, patents planned, issued or pending) Leah Lipsich, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Ned Braunstein, MD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Gary Herman, MD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder, Royalties, patents planned, issued or pending) George D. Yancopoulos, MD, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder, Royalties, patents planned, issued or pending) David M. Weinreich, MD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder)

9.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-296043

ABSTRACT

ABSTRACT Background Hospitalized patients with Covid-19 experience high mortality rates, ranging from 10-30%. Casirivimab and imdevimab (REGEN-COV ® ) is authorized in various jurisdictions for use in outpatients with Covid-19 and in post-exposure prophylaxis. The UK-based platform RECOVERY study reported improved survival in hospitalized seronegative patients treated with REGEN-COV, but in most of the world, anti-spike monoclonal antibody therapy is currently not approved for use in hospitalized patients. Methods In this phase 1/2/3 double-blind placebo-controlled trial, patients on low-flow or no supplemental oxygen hospitalized with Covid-19 were randomized (1:1:1) to 2.4 g or 8.0 g REGEN-COV or placebo and characterized at baseline for viral load and SARS-CoV-2 endogenous immune response. Results 1336 patients on low-flow or no supplemental oxygen were treated. The primary endpoint was met: in seronegative patients, the LS mean difference (REGEN-COV vs. placebo) for TWA change from baseline viral load was −0.28 log 10 copies/mL (95% CI: −0.51, −0.05;P=0.0172). The primary clinical analysis of death or mechanical ventilation from day 6-29 in patients with high-viral load had a strong positive trend but did not reach significance. REGEN-COV reduced all-cause mortality in seronegative patients through day 29 (RRR, 55.6%;95% CI: 24.2%, 74%). No safety concerns were noted overall nor in seropositive patients. Conclusions In hospitalized patients with Covid-19 on low-flow or no oxygen, REGEN-COV treatment reduced viral load and the risk of death or mechanical ventilation as well as all-cause mortality in the overall population, with the benefit driven by seronegative patients and no harm observed in seropositive patients. ( ClinicalTrials.gov number, NCT04426695 .)

10.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-294514

ABSTRACT

Summary Monoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. As rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of minor virus variants in SARS-COV-2 isolates found in COVID-19 patients or identified from preclinical in vitro and in vivo studies. This study demonstrates that a combination of non-competing antibodies, REGEN-COV, not only provides full coverage against current variants of concern/interest but also protects against emergence of new such variants and their potential seeding into the population in a clinical setting.

11.
J Infect Dis ; 224(11): 1830-1838, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1545972

ABSTRACT

BACKGROUND: Elucidating the relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load and clinical outcomes is critical for understanding coronavirus disease 2019 (COVID-19). METHODS: The SARS-CoV-2 levels were analyzed by quantitative real-time polymerase chain reaction (RT-qPCR) of nasopharyngeal or oropharyngeal swab specimens collected at baseline, and clinical outcomes were recorded over 60 days from 1362 COVID-19 hospitalized patients enrolled in a multicenter, randomized, placebo-controlled phase 2/3 trial of sarilumab for COVID-19 (ClinicalTrials.gov NCT04315298). RESULTS: In post hoc analyses, higher baseline viral load, measured by both RT-qPCR cycle threshold and log10 copies/mL, was associated with greater supplemental oxygenation requirements and disease severity at study entry. Higher baseline viral load was associated with higher mortality, lower likelihood of improvement in clinical status and supplemental oxygenation requirements, and lower rates of hospital discharge. Viral load was not impacted by sarilumab treatment over time versus placebo. CONCLUSIONS: These data support viral load as an important determinant of clinical outcomes in hospitalized patients with COVID-19 requiring supplemental oxygen or assisted ventilation.


Subject(s)
COVID-19 , Viral Load , COVID-19/diagnosis , COVID-19/mortality , Humans , Nasopharynx/virology , Oropharynx/virology , Respiration, Artificial , SARS-CoV-2
12.
N Engl J Med ; 385(23): e81, 2021 12 02.
Article in English | MEDLINE | ID: covidwho-1442848

ABSTRACT

BACKGROUND: In the phase 1-2 portion of an adaptive trial, REGEN-COV, a combination of the monoclonal antibodies casirivimab and imdevimab, reduced the viral load and number of medical visits in patients with coronavirus disease 2019 (Covid-19). REGEN-COV has activity in vitro against current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern. METHODS: In the phase 3 portion of an adaptive trial, we randomly assigned outpatients with Covid-19 and risk factors for severe disease to receive various doses of intravenous REGEN-COV or placebo. Patients were followed through day 29. A prespecified hierarchical analysis was used to assess the end points of hospitalization or death and the time to resolution of symptoms. Safety was also evaluated. RESULTS: Covid-19-related hospitalization or death from any cause occurred in 18 of 1355 patients in the REGEN-COV 2400-mg group (1.3%) and in 62 of 1341 patients in the placebo group who underwent randomization concurrently (4.6%) (relative risk reduction [1 minus the relative risk], 71.3%; P<0.001); these outcomes occurred in 7 of 736 patients in the REGEN-COV 1200-mg group (1.0%) and in 24 of 748 patients in the placebo group who underwent randomization concurrently (3.2%) (relative risk reduction, 70.4%; P = 0.002). The median time to resolution of symptoms was 4 days shorter with each REGEN-COV dose than with placebo (10 days vs. 14 days; P<0.001 for both comparisons). REGEN-COV was efficacious across various subgroups, including patients who were SARS-CoV-2 serum antibody-positive at baseline. Both REGEN-COV doses reduced viral load faster than placebo; the least-squares mean difference in viral load from baseline through day 7 was -0.71 log10 copies per milliliter (95% confidence interval [CI], -0.90 to -0.53) in the 1200-mg group and -0.86 log10 copies per milliliter (95% CI, -1.00 to -0.72) in the 2400-mg group. Serious adverse events occurred more frequently in the placebo group (4.0%) than in the 1200-mg group (1.1%) and the 2400-mg group (1.3%); infusion-related reactions of grade 2 or higher occurred in less than 0.3% of the patients in all groups. CONCLUSIONS: REGEN-COV reduced the risk of Covid-19-related hospitalization or death from any cause, and it resolved symptoms and reduced the SARS-CoV-2 viral load more rapidly than placebo. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04425629.).


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Neutralizing/administration & dosage , Antiviral Agents/administration & dosage , COVID-19/drug therapy , Adolescent , Adult , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Neutralizing/pharmacology , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , COVID-19/mortality , Dose-Response Relationship, Drug , Double-Blind Method , Drug Combinations , Female , Hospitalization/statistics & numerical data , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Pregnancy , Pregnancy Complications, Infectious/drug therapy , Proportional Hazards Models , Viral Load/drug effects , Young Adult
13.
Cell ; 184(15): 3949-3961.e11, 2021 07 22.
Article in English | MEDLINE | ID: covidwho-1252550

ABSTRACT

Monoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. Because rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment-induced emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of virus variants in SARS-COV-2 isolates found in COVID-19 patients treated with the two-antibody combination REGEN-COV, as well as in preclinical in vitro studies using single, dual, or triple antibody combinations, and in hamster in vivo studies using REGEN-COV or single monoclonal antibody treatments. Our study demonstrates that the combination of non-competing antibodies in REGEN-COV provides protection against all current SARS-CoV-2 variants of concern/interest and also protects against emergence of new variants and their potential seeding into the population in a clinical setting.


Subject(s)
Antibodies, Monoclonal/immunology , COVID-19/immunology , COVID-19/prevention & control , Mutation/genetics , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Animals , COVID-19/virology , Chlorocebus aethiops , Cricetinae , Cryoelectron Microscopy , Hospitalization , Humans , Lung/pathology , Lung/virology , Male , Neutralization Tests , Vero Cells , Viral Load
14.
Adv Ther ; 38(6): 3185-3202, 2021 06.
Article in English | MEDLINE | ID: covidwho-1220185

ABSTRACT

INTRODUCTION: Identifying risk factors for progression to severe COVID-19 requiring urgent medical visits and hospitalizations (UMVs) among patients initially diagnosed in the outpatient setting may help inform patient management. The objective of this study was to estimate the incidence of and risk factors for COVID-19-related UMVs after outpatient COVID-19 diagnosis or positive SARS-CoV-2 test. METHODS: Data for this retrospective cohort study were from the Optum® de-identified COVID-19 Electronic Health Record database from June 1 to December 9, 2020. Adults with first COVID-19 diagnosis or positive SARS-CoV-2 test in outpatient settings were identified. Cumulative incidence function analysis stratified by risk factors was used to estimate the 30-day incidence of COVID-19-related UMVs. Competing risk regression models were used to derive adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) for factors associated with UMVs. RESULTS: Among 206,741 patients [58.8% female, 77.5% non-Hispanic Caucasian, mean (SD) age: 46.7 (17.8) years], the 30-day incidence was 9.4% (95% CI 9.3-9.6) for COVID-19-related emergency room (ER)/urgent care (UC)/hospitalizations and 3.8% (95% CI 3.7-3.9) for COVID-19-related hospitalizations. Likelihood of hospitalization increased with age and body mass index, with age the strongest risk factor (aHR 5.61; 95% CI 4.90-6.32 for patients ≥ 85 years). Increased likelihood of hospitalization was observed for first presentation in the ER/UC vs. non-ER/UC outpatient settings (aHR 2.35; 95% CI 2.22-2.47) and prior all-cause hospitalization (aHR 1.90; 95% CI 1.79-2.00). Clinical risk factors of hospitalizations included pregnancy, uncontrolled diabetes, chronic obstructive pulmonary disease, chronic kidney disease, and autoimmune disease. A study limitation is that data on COVID-19 severity and symptoms were not captured. CONCLUSION: Predictors of COVID-19-related UMVs include older age, obesity, and several comorbidities. These findings may inform patient management and resource allocation following outpatient COVID-19 diagnosis.


Subject(s)
COVID-19 , Adult , Aged , Aged, 80 and over , COVID-19 Testing , Female , Hospitalization , Humans , Male , Middle Aged , Outpatients , Retrospective Studies , SARS-CoV-2
15.
N Engl J Med ; 384(3): 238-251, 2021 01 21.
Article in English | MEDLINE | ID: covidwho-983927

ABSTRACT

BACKGROUND: Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads. METHODS: In this ongoing, double-blind, phase 1-3 trial involving nonhospitalized patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGN-COV2, or 8.0 g of REGN-COV2 and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody-positive or serum antibody-negative). Key end points included the time-weighted average change in viral load from baseline (day 1) through day 7 and the percentage of patients with at least one Covid-19-related medically attended visit through day 29. Safety was assessed in all patients. RESULTS: Data from 275 patients are reported. The least-squares mean difference (combined REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was -0.56 log10 copies per milliliter (95% confidence interval [CI], -1.02 to -0.11) among patients who were serum antibody-negative at baseline and -0.41 log10 copies per milliliter (95% CI, -0.71 to -0.10) in the overall trial population. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody-negative at baseline, the corresponding percentages were 15% and 6% (difference, -9 percentage points; 95% CI, -29 to 11). The percentages of patients with hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in the combined REGN-COV2 dose groups and the placebo group. CONCLUSIONS: In this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.).


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Neutralizing/therapeutic use , COVID-19/drug therapy , Immunologic Factors/therapeutic use , SARS-CoV-2/isolation & purification , Viral Load/drug effects , Adult , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Neutralizing/adverse effects , COVID-19/diagnosis , COVID-19/virology , Double-Blind Method , Drug Combinations , Female , Humans , Immunologic Factors/adverse effects , Least-Squares Analysis , Male , Middle Aged , Outpatients , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2/genetics
16.
Science ; 369(6506): 1010-1014, 2020 08 21.
Article in English | MEDLINE | ID: covidwho-599036

ABSTRACT

Neutralizing antibodies have become an important tool in treating infectious diseases. Recently, two separate approaches yielded successful antibody treatments for Ebola-one from genetically humanized mice and the other from a human survivor. Here, we describe parallel efforts using both humanized mice and convalescent patients to generate antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, which yielded a large collection of fully human antibodies that were characterized for binding, neutralization, and three-dimensional structure. On the basis of these criteria, we selected pairs of highly potent individual antibodies that simultaneously bind the receptor binding domain of the spike protein, thereby providing ideal partners for a therapeutic antibody cocktail that aims to decrease the potential for virus escape mutants that might arise in response to selective pressure from a single-antibody treatment.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Pneumonia, Viral/immunology , Spike Glycoprotein, Coronavirus/immunology , Adolescent , Adult , Angiotensin-Converting Enzyme 2 , Animals , Antibodies, Neutralizing/chemistry , Antibodies, Viral/chemistry , Antibody Affinity , Antibody-Dependent Cell Cytotoxicity , Betacoronavirus/chemistry , Binding Sites, Antibody , Broadly Neutralizing Antibodies/chemistry , Broadly Neutralizing Antibodies/immunology , COVID-19 , Cell Line , Coronavirus Infections/therapy , Cytophagocytosis , Epitopes , Humans , Immunization, Passive , Mice , Middle Aged , Models, Molecular , Neutralization Tests , Pandemics , Peptidyl-Dipeptidase A/metabolism , Protein Interaction Domains and Motifs , Receptors, Coronavirus , Receptors, Virus/metabolism , SARS Virus/immunology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Young Adult
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