Oct 28, 2020 9 mins, 53 secs

In this ongoing phase 2 trial involving outpatients with recently diagnosed mild or moderate Covid-19, we randomly assigned 452 patients to receive a single intravenous infusion of neutralizing antibody LY-CoV555 in one of three doses (700 mg, 2800 mg, or 7000 mg) or placebo and evaluated the quantitative virologic end points and clinical outcomes.

At the time of the interim analysis, the observed mean decrease from baseline in the log viral load for the entire population was −3.81, for an elimination of more than 99.97% of viral RNA.

For patients who received the 2800-mg dose of LY-CoV555, the difference from placebo in the decrease from baseline was −0.53 (95% confidence interval [CI], −0.98 to −0.08; P=0.02), for a viral load that was lower by a factor of 3.4.

Smaller differences from placebo in the change from baseline were observed among the patients who received the 700-mg dose (−0.20; 95% CI, −0.66 to 0.25; P=0.38) or the 7000-mg dose (0.09; 95% CI, −0.37 to 0.55; P=0.70).

On days 2 to 6, the patients who received LY-CoV555 had a slightly lower severity of symptoms than those who received placebo.

The percentage of patients who had a Covid-19–related hospitalization or visit to an emergency department was 1.6% in the LY-CoV555 group and 6.3% in the placebo group.

In this interim analysis of a phase 2 trial, one of three doses of neutralizing antibody LY-CoV555 appeared to accelerate the natural decline in viral load over time, whereas the other doses had not by day 11.

Several treatment options have been explored for hospitalized patients with Covid-19 (e.g., antimalarial drugs,4 antiviral agents,5-7 immunomodulators,8-12 glucocorticoids,13,14 and convalescent plasma15,16) with varying results.

Preclinical studies of neutralizing-antibody treatments for SARS-CoV-2 infection in several animal models have shown promising results, with marked reductions in viral loads in the upper and lower respiratory tracts.17 SARS-CoV-2 gains entry into cells through binding of its spike protein to receptors for angiotensin-converting enzyme 2 on target cells.18 LY-CoV555 (also known as LY3819253), a potent antispike neutralizing monoclonal antibody that binds with high affinity to the receptor-binding domain of SARS-CoV-2, was derived from convalescent plasma obtained from a patient with Covid-19.

Here, we report interim results from the Blocking Viral Attachment and Cell Entry with SARS-CoV-2 Neutralizing Antibodies (BLAZE-1) trial, an ongoing phase 2 trial to evaluate the efficacy and safety of LY-CoV555 in patients with recently diagnosed mild or moderate Covid-19 in the outpatient setting.

(A full list of the inclusion and exclusion criteria is provided in the protocol, available with the full text of this article at NEJM.org.) Each patient received a single intravenous infusion of LY-CoV555 or placebo monotherapy over approximately 1 hour.

Although the trial contains additional treatment groups, here we focus on the interim analysis of results from only four of these groups: LY-CoV555 at doses of 700 mg, 2800 mg, and 7000 mg and placebo.

The doses of LY-CoV555 that were evaluated in this trial were based on pharmacologic modeling that predicted that the 700-mg dose would be efficacious.

The use of these doses was supported by safety data from a phase 1 trial of LY-CoV555 involving hospitalized patients.

The primary outcome was the change from baseline in the SARS-CoV-2 viral load at day 11 (±4 days) after positive results on testing.

To determine the sample size, we used a dynamic model to simulate viral load over time in patients treated with LY-CoV555 or placebo.

This simulated population was used to estimate the statistical power and comparisons in the change from baseline in viral load.

(Details are provided in Section 5.2 in the statistical analysis plan, which is included in the protocol document.) All the patients who had undergone randomization and who had received either LY-CoV555 or placebo were included in the primary analysis if their viral-load measures were available both at baseline and at least once after baseline.

From June 17 through August 21, 2020, a total of 467 patients underwent randomization to receive either LY-CoV555 (317 patients) or placebo (150 patients), and the patients in the LY-CoV555 group were assigned to one of three dose subgroups.

Of the patients who had undergone randomization, 452 met the criteria for inclusion in the primary analysis (309 in the LY-CoV555 group and 143 in the placebo group).

LY-CoV555 was administered to these patients in doses of 700 mg (101 patients), 2800 mg (107 patients), or 7000 mg (101 patients) (Figure 1).

After undergoing randomization, patients received an infusion of LY-CoV555 or placebo within a median of 4 days after the onset of symptoms; at the time of randomization, more than 80% of the patients had only mild symptoms.

By day 11, the majority of patients had a substantial trend toward viral clearance, including those in the placebo group.

For patients who received the 2800-mg dose of LY-CoV555, the difference from placebo in the decrease from baseline was −0.53 (95% confidence interval [CI], −0.98 to −0.08; P=0.02), for a lower viral load by a factor of 3.4 (Table 2).

However, smaller differences from placebo in the decrease from baseline were observed among the patients who received the 700-mg dose (−0.20; 95% CI, −0.66 to 0.25; P=0.38) and the 7000-mg dose (0.09; 95% CI, −0.37 to 0.55; P=0.70).

On day 3, among the patients who received the 2800-mg dose of LY-CoV555, the observed difference from placebo in the decrease from baseline in the mean log viral load was −0.64 (95% CI, −1.11 to −0.17) (Table 2).

The other two doses of LY-CoV555 showed similar improvements in viral clearance at day 3, with a difference from placebo in the change from baseline of −0.42 (95% CI, −0.89 to 0.06) for the 700-mg dose and −0.42 (95% CI, −0.90 to 0.06) for the 7000-mg dose.

The difference from placebo in the change from baseline for the pooled doses of LY-CoV555 was −0.49 (95% CI, −0.87 to −0.11).

Panel A shows the SARS-CoV-2 viral load (as measured by the cycle threshold on reverse-transcriptase–polymerase-chain-reaction assay) for all the patients who received either LY-CoV555 or placebo and for whom viral-load data were available at the time of the interim analysis.

Panel B shows the cumulative probability that patients in each trial group would have the indicated cycle threshold of viral load on day 7.

Figure 2A presents the absolute viral load among hospitalized patients (pooled across randomization strata) as well as a box plot of viral loads among nonhospitalized patients.

On day 7, all the available measures of viral load among hospitalized patients were higher than the median values among the nonhospitalized patients.

Figure 2B shows the cumulative probability that patients in each trial group would have the indicated cycle threshold of viral load on day 7.

At day 29, the percentage of patients who were hospitalized with Covid-19 was 1.6% (5 of 309 patients) in the LY-CoV555 group and 6.3% (9 of 143 patients) in the placebo group (Table 3).

The percentage of patients according to the LY-CoV555 dose who were hospitalized was similar to the overall percentage, with 1.0% (1 of 101) in the 700-mg subgroup, 1.9% (2 of 107) in the 2800-mg subgroup, and 2.0% (2 of 101) in the 7000-mg subgroup.

In a post hoc analysis examining hospitalization among patients who were 65 years of age or older and among those with a BMI of 35 or more, the percentage who were hospitalized was 4% (4 of 95) in the LY-CoV555 group and 15% (7 of 48) in the placebo group.

Shown is the difference in the change from baseline (delta value) in symptom scores between the LY-CoV555 group and the placebo group from day 2 to day 11.

To assess the effect of treatment on Covid-19 symptoms, we compared the change from baseline in symptom scores between the LY-CoV555 group and the placebo group (Figure 3 and Fig. S1 in the Supplementary Appendix).

From day 2 to day 6, the change in the symptom score from baseline was better in the LY-CoV555 group than in the placebo group, with values of −0.79 (95% CI, −1.35 to −0.24) on day 2, −0.57 (95% CI, −1.12 to −0.01) on day 3, −1.04 (95% CI, −1.60 to −0.49) on day 4, −0.73 (95% CI, −1.28 to −0.17) on day 5, and −0.79 (95% CI, −1.35 to −0.23) on day 6.

The change from baseline in the symptom score continued to be better in the LY-CoV555 group than in the placebo group from day 7 to day 11, although by these time points most of the patients in the two groups had fully recovered or had only very mild symptoms.

Serious adverse events occurred in none of the 309 patients in LY-CoV555 group and in 0.7% (1 of 143 patients) in the placebo group (Table 4).

The percentage of patients who had an adverse event during treatment was 22.3% (69 of 309) in the LY-CoV555 group and 24.5% (35 of 143) in the placebo group.

Diarrhea was reported in 3.2% of the patients (10 of 309) in the LY-CoV555 group and in 4.9% (7 of 143) in the placebo group; vomiting was reported in 1.6% (5 of 309) and 2.8% (4 of 143), respectively.

Infusion-related reactions were reported in 2.3% of the patients (7 of 309) in the LY-CoV555 group and in 1.4% (2 of 143) in the placebo group.

Such variants were present with an allele fraction of more than 20% in at least one sample at any time point in 8.2% of the patients in the LY-CoV555 group (6.3% in the 700-mg subgroup, 8.4% in the 2800-mg subgroup, and 9.9% in the 7000-mg subgroup) and in 6.1% of those in the placebo group.

In this preplanned interim analysis of the BLAZE-1 trial, we examined the efficacy of LY-CoV555 in the treatment of mild or moderate Covid-19.

Among the patients who received LY-CoV555, the viral load at day 11 (the primary outcome) was lower than that in the placebo group only among those who received the 2800-mg dose.

However, a decreased viral load at day 11 did not appear to be a clinically meaningful end point, since the viral load was substantially reduced from baseline for the majority of patients, including those in the placebo group, a finding that was consistent with the natural course of the disease.20,21 However, the evaluation of the effect of LY-CoV555 therapy on patients’ symptoms at earlier time points during treatment (e.g., on day 3) showed a possible treatment effect, with no substantial differences observed among the three doses.

An unanticipated observation in this trial was that patients with a higher viral load on day 7 had a higher rate of hospitalization than those with better clearance of viral RNA on day 7, a finding that was consistent with the delayed viral clearance that was observed in patients with more severe disease.20,22,23 On day 7, no hospitalized patient had a viral load that was below the median value of the population.

To examine the potential of LY-CoV555 to improve Covid-19 clinical outcomes, we evaluated the effect of LY-CoV555 therapy on the frequency of hospitalization, an important outcome given the association between hospitalization and subsequent mortality in patients with Covid-19.23,24 On day 29, the percentage of patients who were hospitalized was 1.6% in the LY-CoV555 group and 6.3% in the placebo group.

In a post hoc analysis that was focused on high-risk subgroups (an age of ≥65 years or a BMI of ≥35), the percentage of hospitalization was 4.2% in the LY-CoV555 group and 14.6% in the placebo group.

Although the differences in the effects of the three doses of LY-CoV555 were not clear, the 2800-mg dose was the only one to show evidence of accelerated viral clearance.

The safety profile of patients who received LY-CoV555 was similar to that of placebo-treated patients.

In this interim analysis, the patients who received LY-CoV555 had fewer hospitalizations and a lower symptom burden than those who received placebo, with the most pronounced effects observed in high-risk cohorts.

If these results are confirmed in additional analyses in this trial, LY-CoV555 could become a useful treatment for emergency use in patients with recently diagnosed Covid-19.

Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial.

Dexamethasone in hospitalized patients with Covid-19 — preliminary report.

Effect of convalescent plasma on mortality among hospitalized patients with COVID-19: initial three-month experience.

Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.

Change from Baseline in Viral Load

Panel A shows the SARS-CoV-2 viral load (as measured by the cycle threshold on reverse-transcriptase–polymerase-chain-reaction assay) for all the patients who received either LY-CoV555 or placebo and for whom viral-load data were available at the time of the interim analysis

Panel B shows the cumulative probability that patients in each trial group would have the indicated cycle threshold of viral load on day 7

Shown is the difference in the change from baseline (delta value) in symptom scores between the LY-CoV555 group and the placebo group from day 2 to day 11


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