Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial | Global Health | JAMA | JAMA Network
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Figure 1.  Patient Enrollment and Treatment Assignment of the BLAZE-1 Trial of Bamlanivimab for Mild to Moderate COVID-19
Patient Enrollment and Treatment Assignment of the BLAZE-1 Trial of Bamlanivimab for Mild to Moderate COVID-19

SARS-CoV-2 indicates severe acute respiratory syndrome coronavirus 2.

aStratified by duration since symptom onset to randomization (≤8 days vs >8 days).

bIncluded in the adverse event analysis.

cHad data on at least 1 postbaseline viral load.

dThree patients were excluded from the efficacy analysis because they did not have data on at least 1 postbaseline viral load. However, these patients were included in the safety analysis because they did receive the intervention as randomized.

eFour patients were excluded from the efficacy analysis because they did not have data on at least 1 postbaseline viral load. However, these patients were included in the safety analysis because they did receive the intervention as randomized.

fHad data on viral load for both baseline and at day 11.

Figure 2.  Change in Log Viral Load and in Viral Load Cycle Threshold Over Time With Bamlanivimab Monotherapy and Bamlanivimab and Etesevimab Combination Therapy
Change in Log Viral Load and in Viral Load Cycle Threshold Over Time With Bamlanivimab Monotherapy and Bamlanivimab and Etesevimab Combination Therapy

Randomization and infusion occurred on day 1. A, The middle line represents the median change from baseline for log viral load; the boxes represent the interquartile range; the squares inside each box represent the mean; the whiskers extend to the highest and lowest values within 1.5 x the interquartile range of the nearer quartile; and the dots represent observed values outside that range. B, The cycle threshold is defined as the number of cycles required for the fluorescent signal of the polymerase chain reaction assay to cross the threshold (ie, exceeds background level). Cycle threshold levels are inversely proportional to the number of copies of the virus and thus serve to estimate viral load. Virus is presumed to be undetectable beyond approximately 40 cycle thresholds. SARS-CoV-2 indicates severe acute respiratory syndrome coronavirus 2.

Table 1.  Patient Demographics and Baseline Clinical Characteristics
Patient Demographics and Baseline Clinical Characteristics
Table 2.  Outcomes for Primary and Prespecified Secondary End Points
Outcomes for Primary and Prespecified Secondary End Points
Table 3.  Adverse Events
Adverse Events
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    5 Comments for this article
    EXPAND ALL
    Expanding Combinations Will Improve Efficacy
    Jianshe Yang, PhD, MM | Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
    This paper reports that bamlanivimab alone had limited capacity to neutralize antispike antigens without a significant difference from placebo when treating outpatients with mild to moderate coronavirus disease 2019 [1]. The effect was improved when bamlanivimab was combined with f etesevimab, another distinct mAbextracted from the convalescent serum of a COVID-19 patient from China. Single use of etesevimab had outcomes similar to those of Bamlanivimab [2].

    We have written that mAbs hold great promise against COVID-19 [3] and speculate that SARS-CoV-2 has a  diversity of antigens that put it beyond the neutralizing capacity of single specific mAbs. Polyclonal mAbs
    for combination infusion might improve efficacy. But the cross-interaction among these different mAbs in a co-system must be demonstrated. Current studies, at most, have developed the two-mAb combinations. Further trials of three or more mAbs should be performed, especially with mAbs originating from diverse patient sources given that the varying infectious capacity of SARS-CoV-2 in patients by gender, age, BMI, race and other comorbidities.

    References

    1. Gottlieb RL, Nirula A, Chen P, et al. Effect of Bamlanivimab as monotherapy or in combination with Etesevimab on viral load in patients with mild to moderate COVID-19. JAMA,2021 doi:10.1001/jama.2021.0202
    2. Shi R, Shan C, Duan X, et al. A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2.  Nature. 2020;584(7819):120-124
    3. Jianshe Yang. mAbs may be the most promising candidate to bat SARS-CoV-2: a comment on “Bridging the Gap at Warp Speed-Delivering Options for Preventing and Treating Covid-19”. N Engl J Med 2020; 383:1899-1901

    Contributed by Professor JS Yang, PhD; Chengyou Jia, PhD, Professor Zhongwei Lv, MD, both in Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China.
    E-mail: yangjs@impcas.ac.cn
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Monoclonal antibodies to SARS-CoV-2 to treat mild to moderate COVID-19 outpatients?
    Job Harenberg, Professor of Medicine | Heidelberg University, Germany
    Therapeutic perspectives for the treatment of SARS-CoV-2-induced COVID-19 disease receive a future-oriented perspective through the use of monoclonal antibodies. The authors have described its possible early early use to prevent rapid development of illness from local to septic viral infection.

    Since patients are usually hospitalized with severe symptoms, the limited efficacy of monoclonal antibodies may be explained by their use in relatively advanced stages of COVID-19. Mild or moderate symptoms of COVID-19 are more frequent in patients before hospitalization. The logistical challenges of treatment of outpatients are enormous but would be worthwhile and attractive for pilot projects.

    Contributed
    by emeritus Professor Job Harenberg, MD, Heidelberg University, Germany
    E-mail: j.harenberg@doasense.de
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Bamlanivimab versus Etesivimab
    Sardar Babar, MD | Singing River Hospital system
    I find it interesting that the 700 mg Bamlanivimab group showed statistically significant decreases in clinically meaningful parameters such as resolution and decrease in symptoms at day 11, whereas higher doses did not. This dose also came close to achieving statistical significance in reduction in hospitalization. This raises the question of whether the Etesevimab alone would have produced similar results to the combination.
    A trial of Etesivimab versus Bamlanivimab is called for.
    CONFLICT OF INTEREST: None Reported
    Appropriate Placebo Group?
    Pieter Cohen, MD | Harvard Medical School
    The authors report that the monoclonal combination therapy led to a statistically significant decrease in several outcomes including in COVID-19 related emergency department visits and hospitalization compared to placebo. However, this comparison may be flawed.

    As the authors describe, “patients who received bamlanivimab monotherapy or placebo were enrolled first (June 17-August 21, 2020) followed by patients who received bamlanivimab and etesevimab or placebo (August 22-September 3, 2020)” However, the outcomes of patients receiving combination therapy appear to have been compared to the outcomes of all patients receiving placebo, not just those randomized between August 22-September 3, 2020. />
    Several studies have suggested that the severity of COVID-19 has been decreasing during the course of the pandemic in the United States [1,2].  Therefore, comparing combination therapy to patients who received placebo during an earlier period of the pandemic may overestimate its effectiveness. Could the authors provide a comparison – including statistical analysis – between patients receiving combination therapy vs those receiving placebo treatment only during the comparable dates (i.e., August 22-September 3, 2020)?

    References

    1. Asch DA, Sheils NE, Islam MN, Chen Y, Werner RM, Buresh J, Doshi JA. Variation in US Hospital Mortality Rates for Patients Admitted With COVID-19 During the First 6 Months of the Pandemic. JAMA internal medicine. 2020 Dec 22.
    2. Anesi GL, Jablonski J, Harhay MO, Atkins JH, Bajaj J, Baston C, Brennan PJ, Candeloro CL, Catalano LM, Cereda MF, Chandler JM. Characteristics, Outcomes, and Trends of Patients With COVID-19–Related Critical Illness at a Learning Health System in the United States. Annals of internal medicine. 2021 Jan 19.
    CONFLICT OF INTEREST: Dr. Cohen reports receiving compensation from UptoDate for co-authoring a chapter on the outpatient management of COVID-19.
    READ MORE
    Historical vs. Randomized Controls for Bamlanivimab-Etesevimab in BLAZE-1
    Jolanta Piszczek, BSc Pharm, Pharm D, MSc | Vancouver Island Health Authority
    In the interim analysis of BLAZE-1, Chen et al report that 143 patients were randomized to receive placebo, and 309 received one of the three doses of bamlanivimab monotherapy. [1] These participants were randomized between June 17 and August 21, 2020. On August 21, as per the history of changes log on clinicaltrials.gov for BLAZE-1 (NCT04427501), the combination arm of bamlanivimab-etesevimab was added, and patients were recruited into this arm from August 22 to September 2, 2020.

    In the final analysis of BLAZE-1 [2], the number of patients who received the combination therapy between August 22 and
    September 2 was reported as N=112, but the number of patients who received placebo was N=156, meaning that only an additional 13 patients received placebo after August 21, 2020.

    Based on these numbers, the 112 patients who received combination therapy were evaluated not through a randomized trial methodology, but rather mainly by comparing them with historical controls. These therapies were given sequentially and the result favoring bamlanivimab-etesevimab over placebo is subject to the same bias present in non-randomized studies, including non-contemporaneous bias that is essential to control for in a rapidly evolving pandemic.

    While the final analysis of BLAZE-1 is thought-provoking, it does not provide the high standard of evidence afforded by a randomized controlled trial.

    References

    1. Chen P, Nirula A, Heller B, et al; for the BLAZE-1 Investigators. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19.  N Engl J Med. Published online October 28, 2020. doi:10.1056/NEJMoa2029849

    2. Gottlieb RL, Nirula A, Chen P, et al. Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2021;325(7):632–644. doi:10.1001/jama.2021.0202
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Original Investigation
    January 21, 2021

    Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial

    Author Affiliations
    • 1Baylor University Medical Center and Baylor Scott and White Research Institute, Dallas, Texas
    • 2Eli Lilly and Company, Indianapolis, Indiana
    • 3Department of Medicine, Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California
    • 4Vitalink Research, Union, South Carolina
    • 5Long Beach Clinical Trials, Long Beach, California
    • 6Imperial Health, Lake Charles, Louisiana
    • 7Cook County Health, Chicago, Illinois
    • 8Indago Research, Hialeah, Florida
    • 9Las Vegas Medical Research Center, Las Vegas, Nevada
    • 10Feinberg School of Medicine, Northwestern University, Chicago, Illinois
    • 11Franciscan Health, Greenwood, Indiana
    • 12Georgetown University, Washington, DC
    JAMA. 2021;325(7):632-644. doi:10.1001/jama.2021.0202
    Key Points

    Questions  What is the effect of early treatment with antispike neutralizing antibodies on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load in outpatients with mild to moderate coronavirus disease 2019 (COVID-19)?

    Findings  In the phase 2 portion of a randomized phase 2/3 clinical trial with 577 patients, there was no significant difference in change in viral load with 3 different doses of bamlanivimab monotherapy compared with placebo; treatment with a combination of bamlanivimab and etesevimab significantly decreased SARS-CoV-2 log viral load at day 11 compared with placebo (between-group difference, –0.57 [95% CI, –1.00 to –0.14], P = .01).

    Meaning  Treatment with bamlanivimab and etesevimab combination therapy, but not bamlanivimab monotherapy, resulted in a reduction in SARS-CoV-2 log viral load at day 11 in patients with mild to moderate COVID-19.

    Abstract

    Importance  Coronavirus disease 2019 (COVID-19) continues to spread rapidly worldwide. Neutralizing antibodies are a potential treatment for COVID-19.

    Objective  To determine the effect of bamlanivimab monotherapy and combination therapy with bamlanivimab and etesevimab on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load in mild to moderate COVID-19.

    Design, Setting, and Participants  The BLAZE-1 study is a randomized phase 2/3 trial at 49 US centers including ambulatory patients (N = 613) who tested positive for SARS-CoV-2 infection and had 1 or more mild to moderate symptoms. Patients who received bamlanivimab monotherapy or placebo were enrolled first (June 17-August 21, 2020) followed by patients who received bamlanivimab and etesevimab or placebo (August 22-September 3). These are the final analyses and represent findings through October 6, 2020.

    Interventions  Patients were randomized to receive a single infusion of bamlanivimab (700 mg [n = 101], 2800 mg [n = 107], or 7000 mg [n = 101]), the combination treatment (2800 mg of bamlanivimab and 2800 mg of etesevimab [n = 112]), or placebo (n = 156).

    Main Outcomes and Measures  The primary end point was change in SARS-CoV-2 log viral load at day 11 (±4 days). Nine prespecified secondary outcome measures were evaluated with comparisons between each treatment group and placebo, and included 3 other measures of viral load, 5 on symptoms, and 1 measure of clinical outcome (the proportion of patients with a COVID-19–related hospitalization, an emergency department [ED] visit, or death at day 29).

    Results  Among the 577 patients who were randomized and received an infusion (mean age, 44.7 [SD, 15.7] years; 315 [54.6%] women), 533 (92.4%) completed the efficacy evaluation period (day 29). The change in log viral load from baseline at day 11 was –3.72 for 700 mg, –4.08 for 2800 mg, –3.49 for 7000 mg, –4.37 for combination treatment, and –3.80 for placebo. Compared with placebo, the differences in the change in log viral load at day 11 were 0.09 (95% CI, –0.35 to 0.52; P = .69) for 700 mg, –0.27 (95% CI, –0.71 to 0.16; P = .21) for 2800 mg, 0.31 (95% CI, –0.13 to 0.76; P = .16) for 7000 mg, and –0.57 (95% CI, –1.00 to –0.14; P = .01) for combination treatment. Among the secondary outcome measures, differences between each treatment group vs the placebo group were statistically significant for 10 of 84 end points. The proportion of patients with COVID-19–related hospitalizations or ED visits was 5.8% (9 events) for placebo, 1.0% (1 event) for 700 mg, 1.9% (2 events) for 2800 mg, 2.0% (2 events) for 7000 mg, and 0.9% (1 event) for combination treatment. Immediate hypersensitivity reactions were reported in 9 patients (6 bamlanivimab, 2 combination treatment, and 1 placebo). No deaths occurred during the study treatment.

    Conclusions and Relevance  Among nonhospitalized patients with mild to moderate COVID-19 illness, treatment with bamlanivimab and etesevimab, compared with placebo, was associated with a statistically significant reduction in SARS-CoV-2 viral load at day 11; no significant difference in viral load reduction was observed for bamlanivimab monotherapy. Further ongoing clinical trials will focus on assessing the clinical benefit of antispike neutralizing antibodies in patients with COVID-19 as a primary end point.

    Trial Registration  ClinicalTrials.gov Identifier: NCT04427501

    Introduction

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread rapidly worldwide, fueling the coronavirus disease 2019 (COVID-19) global pandemic. Patients infected with the virus display a wide range of symptoms including cough, fever, malaise, myalgias, gastrointestinal symptoms, ageusia, and anosmia; some individuals progress to acute respiratory distress syndrome and death. Severe illness typically occurs approximately 1 week after the onset of symptoms and can rapidly progress from mild symptoms.1 The risk factors for severe COVID-19 include being male, older age, and having cardiovascular disease, lung disease, hypertension, diabetes, or obesity.2,3

    Currently, only remdesivir (a viral RNA–dependent RNA polymerase inhibitor) has been approved by the US Food and Drug Administration for COVID-19 treatment, although steroids are now recommended by many professional societies, including the World Health Organization, as the primary treatment.4-6 However, convalescent plasma and neutralizing monoclonal antibodies, a class of therapeutics that have exhibited efficacy in other viral infections and show promise in the reduction of SARS-CoV-2 viral load, have been granted Emergency Use Authorization.7-12

    Bamlanivimab (also known as LY3819253 or LY-CoV555) and etesevimab (LY3832479 or LY-CoV016) are potent antispike neutralizing monoclonal antibodies that were derived from 2 separate patients who recovered from COVID-19 in North America and China, respectively.13,14 In preclinical experiments, etesevimab was shown to bind a different epitope from bamlanivimab and to neutralize resistant variants with mutations in the epitope bound by bamlanivimab (eTable 1 in Supplement 1). Combining these 2 neutralizing monoclonal antibodies in clinical use may enhance viral load reduction and decrease treatment-emergent resistant variants.15

    Interim results from the Blocking Viral Attachment and Cell Entry with SARS-CoV-2 Neutralizing Antibodies (BLAZE-1) trial with data for the 3 monotherapy doses of the neutralizing antibody bamlanivimab have been published.9 The current report presents the final data set for patients randomized to the 4 treatment groups and the placebo group in the initial portion of the trial, including findings for the bamlanivimab and etesevimab combination group, the 3 bamlanivimab monotherapy groups, and the placebo group.

    Methods
    Study Design

    This clinical trial is an ongoing, multipart, phase 2/3, randomized, double-blind, placebo-controlled, single-infusion study including patients with recently diagnosed mild or moderate COVID-19 in the outpatient setting.9 The original and final protocol for the phase 2 trial, including the original and final statistical analysis plan, appear in Supplement 2. The trial complied with the Declaration of Helsinki, the International Conference on Harmonization Guidelines for Good Clinical Practice, and applicable local regulations. The protocol was reviewed and approved by the ethics committees of all participating centers, and patients provided written informed consent before study entry.

    Patients

    All patients were aged 18 years or older, tested positive for SARS-CoV-2 infection, had 1 or more mild to moderate symptoms, and presented within 3 days of their first positive test result for SARS-CoV-2 (either direct antigen or reverse transcriptase–polymerase chain reaction). Mild to moderate COVID-19 was defined per US Food and Drug Administration guidance and included symptoms such as fever, cough, sore throat, malaise, headache, muscle pain, gastrointestinal symptoms, and shortness of breath with exertion. Investigators reviewed symptoms, risk factors, and other noninvasive inclusion and exclusion criteria prior to enrollment (the full list of inclusion and exclusion criteria appears in the clinical protocol in Supplement 2). Patient-reported race and ethnicity categories were collected as part of the demographic characteristics.

    Randomization and Intervention

    This study evaluated the effect of bamlanivimab monotherapy and combination therapy with bamlanivimab and etesevimab on change in viral load during treatment of mild to moderate COVID-19. All participants were centrally randomized to each study intervention using an interactive web response system (Figure 1). Before the study was initiated, the log-in information and directions for the interactive web response system was provided to each of the 49 US study sites.

    Randomization was stratified by patients’ duration of symptoms (≤8 days vs >8 days) because symptom duration has an effect on prognosis.9 The treatment was administered within 3 days of the first positive SARS-CoV-2 test sample collection. Each patient in the trial received a single, 1-hour, intravenous infusion of placebo, bamlanivimab, or bamlanivimab and etesevimab. This final analysis includes results for the 5 treatment groups: placebo, 700 mg of bamlanivimab, 2800 mg of bamlanivimab, 7000 mg of bamlanivimab, and a combination treatment with 2800 mg of bamlanivimab and 2800 mg of etesevimab.

    Patients who received bamlanivimab monotherapy or placebo were enrolled first (June 17-August 21, 2020) followed by patients who received bamlanivimab and etesevimab or placebo (August 22-September 3, 2020). The analysis was triggered on October 6, 2020, when the last patient randomized to treatment with bamlanivimab and etesevimab reached day 29 and includes all virological and symptom data available at that database lock. A previous report summarized earlier interim results of the 3 monotherapy doses of LY-CoV555 (bamlanivimab) vs placebo.9 The interim analysis was triggered on September 5, 2020.

    Primary and Secondary Outcomes

    The primary outcome characterized the effect of bamlanivimab monotherapy and combination therapy with bamlanivimab and etesevimab compared with placebo on SARS-CoV-2 log viral load from baseline to day 11 (±4 days). Viral load was measured by nasopharyngeal swab followed by quantitative reverse transcriptase–polymerase chain reaction at a central laboratory. Derivation of the viral load measure is described in §6.10 of the statistical analysis plan (Supplement 2).

    A total of 9 prespecified secondary outcome measures were evaluated. Three focused on viral load (time to viral clearance; proportion of patients with viral clearance at days 7, 11, 15, and 22; and viral load area under the curve [AUC] at day 29), 5 focused on symptoms (change in symptom score at days 7, 11, 15, and 22; time to symptom improvement; time to symptom resolution; and the proportion of patients showing symptom improvement or resolution at days 7, 11, 15, and 22), and 1 focused on clinical outcomes (the proportion of patients with a COVID-19–related hospitalization, emergency department visit, or death) at day 29.

    A questionnaire was used to assess symptom severity. The total symptom score (range, 0-24) was achieved by rating 8 symptom domains (cough, shortness of breath, feeling feverish, fatigue, body aches and pain, sore throat, chills, headache) from none or absent (score of 0) to severe (score of 3) and combining them to provide an overall score (excluding loss of appetite, taste, and smell).9

    Adverse events or serious adverse events also were evaluated. The subgroup analyses for participants enrolled with shorter (≤8 days) and longer (>8 days) duration of symptoms prior to randomization were prespecified and performed, but because the subgroup with a symtom duration of longer than 8 days was only approximately 8% of the participants, the results of these analyses are not reported.

    Exploratory Outcomes

    The total symptom score AUC from day 0 to day 11 and from day 0 to day 29 were analyzed using a linear model, which contained treatment as a fixed effect and baseline severity as a covariate. To assess the prevalence of resistance variants, nasopharyngeal samples were obtained at study enrollment (baseline sample), and then subsequent sampling was done at days 3, 7, 11, 15, 22, and 29. A treatment-emergent variant was determined by comparing the sequencing results from each study participant’s baseline sample with the posttreatment samples. For instances in which a baseline next-generation sequencing result was not available (n = 37/448), the baseline status for these variants was imputed to the reference sequence of BetaCoV/Wuhan/IPBCAMS-WH-04/2019. Additional information about the methods used to detect resistance variants appears in the eMethods in Supplement 1.

    Sample Size

    A viral dynamic model was used to simulate viral loads over time for participants treated with bamlanivimab monotherapy, the bamlanivimab and etesevimab combination treatment, and placebo. This simulated population and Monte Carlo methods were used to estimate the statistical power associated with the comparison of change from baseline to day 11 (±4 days) in SARS-CoV-2 viral load between the treatment groups and the placebo group (additional details appear in §5.2 of the statistical analysis plan in Supplement 2).

    Given these assumptions, a sample size of 100 participants per group was estimated to provide 91% power to test the superiority of bamlanivimab monotherapy or the bamlanivimab and etesevimab combination treatment vs placebo for the effect on viral load, as measured by change from baseline to day 11 (±4 days) at the 2-sided α level of .05.

    Statistical Analyses

    The SARS-CoV-2 viral load data were evaluated using a log base 10 scale. The treatment effects were compared using 2-sided tests with an α level of .05. Significance testing for the primary end point was performed using mixed-model repeated-measure analysis at the 2-sided .05 level. When the mixed-model repeated-measure analysis was used, it included: (1) treatment group, (2) stratification factor of duration since symptom onset to randomization (≤8 days vs >8 days), (3) baseline value in the model, (4) visit day (ie, 1, 3, 7, and 11), and (5) the treatment × visit interaction as fixed factors.

    For the primary end point, the stratification factor of duration since symptom onset to randomization was not used in the model to avoid collinearity with baseline viral load. The Fisher exact test was used for the comparison of binary variables across treatment groups. Continuous outcome variables with a single time point were analyzed using analysis of covariance with (1) treatment group, (2) stratification factor of duration since symptom onset to randomization (≤8 days vs >8 days), and (3) baseline value in the model.

    A post hoc analysis was performed evaluating COVID-19–related deterioration for patients aged 65 years or older or those with a body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 35 or greater. COVID-19–related deterioration was defined as a patient experiencing a COVID-19–related hospitalization, an emergency department visit, or death.

    Adjustments for multiple testing were not conducted for this study; therefore, the findings should be interpreted as exploratory. The full statistical analysis methods appear in §6.1 of the statistical analysis plan in Supplement 2. The statistical analyses were performed using Enterprise Guide 7.1 for SAS version 9.4 (SAS Institute Inc).

    Results
    Patient Demographics and Clinical Characteristics

    At the time of the database lock (October 6, 2020), 577 patients had been randomized and had received an infusion of neutralizing monoclonal antibodies or placebo (Figure 1). There were 101 patients assigned to 700 mg of bamlanivimab, 107 patients assigned to 2800 mg of bamlanivimab, 101 patients assigned to 7000 mg of bamlanivimab, 112 patients assigned to combination therapy (2800 mg of bamlanivimab and 2800 mg of etesevimab), and 156 patients assigned to placebo. Patients in the bamlanivimab monotherapy groups, the bamlanivimab and etesevimab combination therapy group, and the placebo group were generally well balanced at the time of enrollment (Table 1).

    The mean age of patients was 44.7 years (SD, 15.7 years). A total of 315 patients (54.6%) were female, 245 patients (42.5%) identified as Hispanic, and 387 patients (67.1%) had at least 1 risk factor for severe COVID-19 (aged ≥55 years, BMI ≥30, or ≥1 relevant comorbidity such as hypertension). Patients were randomized and received study infusions within a median of 4 days of symptom onset. At the time of randomization, 449 patients (77.8%) had mild symptoms. On the day of the infusion, the observed mean polymerase chain reaction cycle threshold value (a measure of viral load) was 23.7 (SD, 7.4), demonstrating a high viral burden in the population. There were 533 patients (92.4%) who completed the efficacy evaluation period (day 29).

    Primary Outcome

    The change in log viral load from baseline to day 11 was –3.72 for the 700 mg group, –4.08 for the 2800 mg group, –3.49 for the 7000 mg group, –4.37 for the combination therapy group, and –3.80 for the placebo group. Compared with the placebo group, the change from baseline to day 11 in log viral load was not significantly different for any of the monotherapy groups (0.09 [95% CI, –0.35 to 0.52], P = .69 for the 700 mg group; –0.27 [95% CI, –0.71 to 0.16], P = .21 for the 2800 mg group; and 0.31 [95% CI, –0.13 to 0.76], P = .16 for the 7000 mg group), but the change was statistically significantly different for the combination therapy group (–0.57 [95% CI, –1.00 to –0.14], P = .01; Figure 2 and Table 2).

    Secondary Outcomes

    Among the secondary outcome measures, differences between each treatment group vs the placebo group were statistically significant for 10 of 84 end points. The change from baseline to day 29 in viral load AUC was not significantly different for the 700 mg (difference, –6.25 [95% CI, –13.21 to 0.71]; P = .08) and 7000 mg monotherapy dose groups (difference, –5.38 [95% CI, –12.36 to 1.61]; P = .13), but the change was statistically significantly different for the 2800 mg dose group (difference, –9.50 [95% CI, –16.32 to –2.68]; P = .006) and for the combination treatment group (difference, –17.91 [95% CI, –25.25 to –10.58]; P < .001). However, viral clearance (defined as 2 consecutive negative test results for SARS-CoV-2) did not differ among any of the treatment groups at any time point (Table 2).

    Compared with the placebo group, the change in mean total symptom score from baseline to day 11 was statistically significantly different for the 700 mg monotherapy group (mean difference, –0.78 [95% CI, –1.37 to –0.20]; P = .009) and for the combination group (mean difference, –0.60 [95% CI, –1.18 to –0.03]; P = .04), but the change was not significantly different for the 2800 mg monotherapy group (mean difference, –0.32 [95% CI, –0.91 to 0.26]; P = .27) or for the 7000 mg group (mean difference, –0.45 [95% CI, –1.04 to 0.13]; P = .13).

    Compared with the placebo group, the change in symptom improvement from baseline to day 11 was statistically significantly different for the 700 mg group (difference, 16.0% [95% CI, 3.6% to 28.4%]; P = .02) and the 7000 mg group (difference, 15.0% [95% CI, 2.6% to 27.4%]; P = .02), but the change was not significant for the 2800 mg group (difference, 1.4% [95% CI, –10.8% to 13.7%]; P = .90) and the combination treatment group (difference, 9.8% [95% CI, –2.5% to 22.0%]; P = .13). Compared with the placebo group, the change in symptom resolution from baseline to day 11 was statistically significantly different for the 700 mg group (difference, 13.7% [95% CI, 1.2% to 26.1%]; P = .04), but the change was not significant for the 2800 mg group (difference, 3.3% [95% CI, –8.7% to 15.4%]; P = .61), the 7000 mg group (difference, 6.7% [95% CI, –5.6% to 19.1%]; P = .30), or the combination group (difference, 9.0% [95% CI, –3.1% to 21.1%]; P = .16).

    The proportion of patients with COVID-19–related hospitalizations or emergency department visits at day 29 was 1.0% (1 event/101 patients) in the 700 mg group, 1.9% (2 events/107 patients) in the 2800 mg group, 2.0% (2 events/101 patients) in the 7000 mg group, 0.9% (1 event/112 patients) in the combination therapy group, and 5.8% (9 events/156 patients) in the placebo group. The difference vs placebo was –4.8% (95% CI, –8.9% to –0.6%; P = .09) for the 700 mg group, –3.9% (95% CI, –8.4% to 0.6%; P = .21) for the 2800 mg group, –3.8% (95% CI, –8.3% to –0.8%; P = .21) for the 7000 mg group, and –4.9% (95% CI, –8.9% to –0.8%; P = .049) for the combination group (Table 2).

    The results from additional secondary end points (including time to viral clearance, symptom resolution, and symptom improvement) appear in eFigures 1, 2, and 3 in Supplement 1.

    Post Hoc Analyses

    Among patients aged 65 years or older or with a BMI of 35 or greater, those who received bamlanivimab monotherapy had a lower hospitalization rate (2.7% [1/37 patients] in the 700 mg group and a difference of –10.8% [95% CI, –21.4% to –0.1%]; 3.3% [1/30 patients] in the 2800 mg group and a difference of –10.1% [95% CI, –21.4% to 1.2%]; and 5.9% [2/34 patients] in the 7000 mg group and a difference of –7.6% [95% CI, –19.8% to 4.6%]) as well as those who received combination therapy (0% [0/31 patients] in the bamlanivimab and etesevimab group and a difference of –13.5% [95% CI, –22.7% to –4.2%]; P = .04) compared with those who received placebo (13.5% [7/52 patients]; eTable 2 in Supplement 1). Only 1 patient in the study (in the placebo group) was admitted to the intensive care unit. Additional post hoc analyses appear in the eResults and eFigure 4 in Supplement 1.

    Exploratory Outcomes

    Total symptom score AUC from baseline to day 11 was assessed in an exploratory analysis. Compared with placebo, the difference in mean change in total symptom score AUC from baseline to day 11 was –8.28 (95% CI, –14.04 to –2.53; P = .005) for the 700 mg group, –6.59 (95% CI, –12.46 to –0.72; P = .03) for the 2800 mg group, –8.09 (95% CI, –14.05 to –2.13; P = .008) for the 7000 mg group, and –8.63 (95% CI, –14.39 to –2.88; P = .003) for the combination therapy group (eTable 2 in Supplement 1).

    In an exploratory analysis to assess the ability of bamlanivimab and etesevimab to reduce the levels of treatment-emergent bamlanivimab-resistant variants, the frequency of these variants in baseline samples across cohorts in the study population was low (0.4% [2/523 patients]) and is similar to the global prevalence of these variants.

    Putative treatment-emergent bamlanivimab-resistant variants were detected in 7.1% of patients (7/98) in the 700 mg group, in 9.8% of patients (10/102) in the 2800 mg group, in 11.3% of patients (11/97) in the 7000 mg group, in 1% of patients (1/102) in the bamlanivimab and etesevimab combination group, and in 4.8% of patients (7/145) in the placebo group (eTable 2 in Supplement 1). The patient with a treatment-emergent bamlanivimab-resistant variant in the combination group had a single sample with an S494P spike variant on day 11 at an allele fraction of 0.198 and a viral load of 3.64 (N1 cycle threshold of approximately 32). This variant was transient in nature and was not detected in subsequent samples through study day 25. The bamlanivimab monotherapy groups had a higher frequency of patients who had a variant detected at more than 1 time point during the viral time course (4.1% for the 700 mg group, 5.9% for the 2800 mg group, and 7.2% for the 7000 mg group) than the placebo group or the bamlanivimab and etesevimab combination group (both 0%).

    Adverse Events

    Serious adverse events unrelated to SARS-CoV-2 infection or considered related to the study drug by the investigator occurred in 0% (0/309) of patients in the bamlanivimab monotherapy groups, in 0.9% (1/112) of patients in the bamlanivimab and etesevimab combination group, and in 0.6% (1/156) of patients in the placebo group (Table 3). The serious adverse event observed in the combination group was a urinary tract infection that was deemed unrelated to the study drug. The serious adverse event observed in the placebo group was upper abdominal pain and was deemed unrelated to the study drug.

    The most frequently reported adverse events were nausea (3.0% for the 700 mg group, 3.7% for the 2800 mg group, 5.0% for the 7000 mg group, 3.6% for the combination therapy group, and 3.8% for the placebo group) and diarrhea (1.0%, 1.9%, 5.9%, 0.9%, and 4.5%, respectively). Immediate hypersensitivity reactions that could have been infusion related were reported in 9 patients (6 in the bamlanivimab monotherapy groups, 2 in the bamlanivimab and etesevimab group, and 1 in the placebo group). Most reactions occurred during infusion and were reported as mild in severity and not dose related. There were no changes in vital signs and symptoms included pruritus, flushing, rash, and facial swelling. The infusions were completed in all instances.

    Discussion

    In this phase 2/3 clinical trial that evaluated the efficacy and adverse effects of bamlanivimab monotherapy and bamlanivimab and etesevimab combination therapy in outpatients with recently diagnosed mild to moderate COVID-19, the primary end point, mean change from baseline in log viral load at day 11, was not significantly different for the bamlanivimab monotherapy groups compared with the placebo group, but was significantly different for the bamlanivimab and etesevimab combination therapy group compared with the placebo group.

    Among the secondary outcomes, there were no consistent differences between the monotherapy groups or the combination therapy group vs placebo for the other measures of viral load or clinical symptom scores. The proportion of patients with COVID-19–related hospitalizations or emergency department visits was numerically lower for the monotherapy groups and the combination therapy group compared with the placebo group, but the difference was only significant for the combination group. Additional study is needed to understand whether the greater reduction of viral load shown by combination therapy would eventually translate to clinical benefit compared with monotherapy.

    Consistent with the literature,16-19 the post hoc analyses indicated that hospitalization rates were higher in placebo-treated patients with the comorbidities of advanced age (≥65 years) or morbid obesity (BMI ≥35) (13.5%), although no hospitalizations were observed in this high-risk subgroup in the combination therapy group. These preliminary data are hypothesis generating and suggest the need for further study to determine whether patients with these risk factors should be prioritized for this particular treatment.

    In the exploratory analysis of ongoing viral sequencing, putative bamlanivimab-resistant variants were observed in all treatment groups, including placebo. Even though the combination group had the largest reductions in viral load, the monotherapy groups all performed comparably with the combination group on several clinical end points (eg, mean total symptom score and hospitalization rate). Therefore, the clinical significance of the resistant variants remains unclear.

    Currently, only remdesivir is approved by the US Food and Drug Administration for the treatment of patients with COVID-19 who are seriously ill, although corticosteroids are generally considered the treatment of choice in this population and baricitinib recently received Emergency Use Authorization. COVID-19 convalescent plasma is available for use in hospitalized patients through Emergency Use Authorization; although, efficacy has not been established definitively and it is still considered investigational.7,20 Recently, the 700 mg dose of bamlanivimab has been authorized for emergency use in the US and Canada for the treatment of outpatients with mild to moderate COVID-19. Additional studies, including the ongoing subsequent portions of this trial in high-risk patients, are needed to fully elucidate the clinical benefit of therapeutic monoclonal antibodies for COVID-19.

    Limitations

    This study had several limitations. First, the trial was originally designed as a safety and biomarker study.

    Second, the patient population was small, which made detecting clinically meaningful differences between treatment groups more difficult.

    Third, only 1 combination dose was chosen for this study. Because the antiviral activity of etesevimab monotherapy or different combination doses was not investigated, it is difficult to determine whether the greater reduction in viral load observed in the combination group was due to additive or synergistic effects vs differential efficacy of etesevimab.

    Fourth, the primary end point at day 11 may have been too late in the immune response to optimally detect treatment effects. All patients, including those who received placebo, demonstrated substantial viral reduction by day 11. An earlier time point like day 3 or day 7 could possibly have been more appropriate to measure viral load.

    Fifth, the full genotypic and phenotypic analysis of the trial is still ongoing, and the resistance data presented here are limited to the sample sequences that were available at the time of this analysis.

    Conclusions

    Among nonhospitalized patients with mild to moderate COVID-19 illness, treatment with bamlanivimab and etesevimab, compared with placebo, was associated with a statistically significant reduction in SARS-CoV-2 viral load at day 11; no significant difference in viral load reduction was observed for bamlanivimab monotherapy. Further ongoing clinical trials will focus on assessing the clinical benefit of antispike neutralizing antibodies in patients with COVID-19 as a primary end point.

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    Article Information

    Corresponding Author: Daniel M. Skovronsky, MD, PhD, Eli Lilly and Company, 893 Delaware St, Indianapolis, IN 46225 (skovronsky_daniel@lilly.com).

    Accepted for Publication: January 8, 2021.

    Published Online: January 21, 2021. doi:10.1001/jama.2021.0202

    Author Contributions: Drs Gottlieb and Nirula had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Gottlieb and Nirula made equal contributions and are co–first authors.

    Concept and design: Nirula, Huhn, Adams, Van Naarden, Custer, Durante, Sabo, Klekotka, Shen, Skovronsky.

    Acquisition, analysis, or interpretation of data: Gottlieb, Nirula, Chen, Boscia, Heller, Morris, Huhn, Cardona, Mocherla, Stosor, Shawa, Kumar, Adams, Van Naarden, Custer, Durante, Oakley, Schade, Holzer, Ebert, Higgs, Kallewaard, Patel, Klekotka, Shen, Skovronsky.

    Drafting of the manuscript: Gottlieb, Nirula, Adams, Oakley, Holzer, Sabo, Patel, Klekotka, Shen, Skovronsky.

    Critical revision of the manuscript for important intellectual content: Gottlieb, Nirula, Chen, Boscia, Heller, Morris, Huhn, Cardona, Mocherla, Stosor, Shawa, Kumar, Adams, Van Naarden, Custer, Durante, Oakley, Schade, Holzer, Ebert, Higgs, Kallewaard, Sabo, Patel, Klekotka, Shen, Skovronsky.

    Statistical analysis: Cardona, Adams, Durante, Higgs, Shen.

    Obtained funding: Sabo.

    Administrative, technical, or material support: Gottlieb, Morris, Huhn, Mocherla, Kumar, Adams, Oakley, Schade, Ebert, Kallewaard, Sabo, Patel, Klekotka.

    Supervision: Gottlieb, Nirula, Huhn, Adams, Van Naarden, Custer, Sabo, Klekotka, Shen, Skovronsky.

    Conflict of Interest Disclosures: Dr Gottlieb reported receiving personal fees and nonfinancial support (medication for another trial) from Gilead Sciences; and serving on an advisory board for Sentinel. Drs Nirula and Adams, Mr Van Naarden, Dr Custer, Mr Durante, and Drs Oakley, Schade, Holzer, Ebert, Higgs, Kallewaard, Sabo, Patel, Klekotka, Shen, and Skovronsky are all employees and shareholders of Eli Lilly and Company. Dr Chen reported receiving consulting fees from Eli Lilly and Company. Dr Boscia reported receiving honoraria for serving on the GlaxoSmithKline speakers bureau. Dr Huhn reported receiving grants and personal fees from Gilead, Viiv, and Janssen; receiving grants from Proteus and Bristol-Myers Squibb; and receiving personal fees from TheraTechnologies. Dr Kumar reported receiving grants and consulting fees from GlaxoSmithKline, Amgen, TheraTechnologies, Merck, and Gilead Sciences; and owning stock in GlaxoSmithKline, Johnson & Johnson, Merck, Gilead Sciences, and Pfizer. No other disclosures were reported.

    Funding/Support: This trial was sponsored and funded by Eli Lilly and Company.

    Role of the Funder/Sponsor: Eli Lilly and Company was responsible for the design of the clinical trial; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript. Eli Lilly and Company did not have the right to veto publication or to control the decision regarding to which journal the paper was submitted. All final content decisions were made by the authors.

    Data Sharing Statement: See Supplement 3.

    Additional Contributions: We thank David McIlwain, PhD, medical writer and employee of Eli Lilly and Company, for writing and editorial support. The names of those who assisted in this program, including investigators and support staff, are listed in Supplement 1. In addition, we thank the patients and the network of mobile home health research nurses, whose contribution was vital to this project.

    Additional Information: Bamlanivimab emerged from the collaboration between Eli Lilly and Company and AbCellera Biologics to create antibody therapies for the prevention and treatment of COVID-19. Eli Lilly and Company developed the antibody after it was discovered by AbCellera Biologics and scientists at the National Institute of Allergy and Infectious Diseases Vaccine Research Center. Etesevimab emerged from the collaboration among Eli Lilly and Company, Junshi Biosciences, and the Institute of Microbiology of the Chinese Academy of Sciences.

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