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SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19


Patients

Enrollment and test design. Characteristics of patients at baseline.

From June 17 to August 21, 2020, a total of 467 patients randomized to receive either LY-CoV555 (317 patients) or placebo (150 patients), and assigned patients in the LY-CoV555 group to one of three dose subgroups had gone . Of the patients undergoing randomization, 452 met inclusion criteria (309 in the LY-CoV555 group and 143 in the placebo group) in the primary analysis. LY-CoV555 was given to these patients in doses of 700 mg (101 patients), 2800 mg (107 patients), or 7000 mg (101 patients).Figure 1). The two test groups were well balanced in relation to risk factors at the time of enrollment (Table 1). Approximately 70% of patients had at least one risk factor – age 65 years or older, with a body-mass index (BMI, kilogram divided by the square of height in 35 kg m) or at least one relevant concomitant. Sickness – For severe Kovid-19. After undergoing randomization, patients received an infusion of LY-CoV555 or placebo in the middle of 4 days after the onset of symptoms; At the time of randomization, more than 80% of the patients had only mild symptoms. The value of a 23-day PCR cycle threshold (CT) of observed mean influenza days (equivalent to approximately 2.5 million RNA equivalents) matches the expectation that a recently diagnosed population will have a higher viral burden. The conversion from CT value to viral load is described in Section 6.10 of the statistical analysis scheme.

primary outcome

Change in viral load from baseline.

By day 11, most patients had a substantial trend toward viral withdrawal, including those in the placebo group. The observed decrease from baseline in log viral load for the entire population was .83.81 (baseline mean, 6.36; day 11 mean, 2.56); This value is associated with more than 4300 factor deficiencies of the SARS-CoV-2 burden for elimination of more than 99.97% of viral RNA. For patients receiving a 2800-mg dose of LY-CoV555, the difference from baseline to placebo was bas0.53 (95% confidence interval) [CI],, 0.98 to 80.08; P = 0.02 for low viral load by a factor of 3.4).Table 2). However, small differences from placebo to baseline reduction were seen in patients who received the 700-mg dose (% 0.20; 95% CI, .60.66 to 0.25; P = 0.38) and the 7000-mg dose (0.09; 95) . % CI, CI0.37 to 0.55; P = 0.70).

Secondary viral results

On day 3, in patients receiving a 2800-mg dose of LY-CoV555, the observed difference from placebo in baseline reduction in mean log viral load was .0.64 (95% CI, −1.11 to −0.17).Table 2). The other two doses of LY-CoV555 showed a similar improvement in viral clearance on day 3, with a difference in change from baseline of −0.42 (95% CI, −0.89 to 0.06) for a dose of 700 mg and −0.42. For doses of 7000 mg (95% CI, .0.90 to 0.06). The difference from placebo to baseline for the deposited dose of LY-CoV555 was 0.11 (from 0.49 (95% CI, −0.87) to 0.11).

Explanatory measures of viral clearance

SARS-CoV-2 viral load in all patients and according to the test group on day 7.

Panel A shows SARS-CoV-2 viral load (as measured by cycle threshold) for all patients who received LY-CoV555 or placebo and for whom viral-load data were interim. Available at time of analysis. Box plots indicate patients who were not hospitalized, and red squares indicate those who were hospitalized. Such hospital contacts were found to be associated with a higher viral load on day 7. The boxes represent interquartile ranges, with the horizontal line in each box representing the median and the whiskers showing the minimum and maximum values ​​(except for the outliers that were greater than 1.5 times the values ​​indicated at each end of the box). Panel B shows the cumulative probability that patients in each test group will have a cycle threshold indicating viral load on day 7.

In the pooled test population, an association was observed between the incidence of slower viral clearance and greater hospitalization. Figure 2a Presents full viral load between hospitalized patients (accumulated across randomization) as well as a box plot of viral load among nonpatients. On day 7, all available measures of viral load among hospitalized patients were higher than average values ​​among non-moderate patients. In patients with a high viral load on day 7, the frequency of hospitalization was 12% (7 of 56 patients), with a CT value less than 27.5 (3 of 340 patients) compared with a frequency of 0.9%. ) Among people with low viral load. (The SARS-CoV-2 N1 gene primer determines a Ct value that is equivalent to approximately 570,000 nucleic acid-based amplification tests per milliliter with the use of the Food and Drug Administration’s SARS-CoV-2 reference panel.) Subsequently. . The difference was not estimated and emerged from post hoc exploratory analysis, it is unclear whether this would apply to other populations. Figure 2b The cumulative probability indicates that patients in each test group will have a cycle threshold indicating viral load on day 7.

Kovid-19-Related Hospitalization

admitted to hospital.

On the 29th day, the percentage of patients hospitalized with Kovid-19 in the LY-CoV555 group was 1.6% (out of 309 patients) and 6.3% (9 out of 143 patients) in the placebo group (Table 3). The percentage of patients according to hospitalized LY-CoV555 dose was similar to the total percentage, 1.0% (1 of 101) in the 700-mg subgroup, 1.9% (2 of 107) in the 2800-mg group. And 2.0% (2 of 101) in a subgroup of 7000 mg. A post hoc analysis examined hospitalization in patients who were 65 years of age or older and had a BMI of 35 or more, who were hospitalized, with 4% (95%) in the LY-CoV555 group 4) was and 15% (48 of 7) in the placebo group. In the trial only 1 patient (in the placebo group) was admitted to an intensive care unit.

Symptom score

Symptoms from day 2 to day 11.

Shown is the change in baseline (delta value) in symptom scores between 2 to day 11. between the LY-CoV555 group and the placebo group. Symptom scores range from 0 to 24 and include eight domains, each classified on a scale of 0 (no symptoms) to 3 (severe symptoms). The bars represent 95% confidence intervals. Details about symptom-scoring methods are given in Supplementary appendix.

To assess the effect of treatment on Kovid-19 symptoms, we compared baseline changes in symptom scores between the LY-CoV555 group and the placebo group (Figure 3 And figs. S1 in Supplementary appendix). Symptom scores ranged from 0 to 24 and included eight domains that were categorized from 0 (no symptoms) to 3 (severe symptoms). From day 2 to day 6, the change in symptom score from baseline was better in the LY-CoV555 group than in the placebo group, with values ​​of .70.79 (95% CI, −1.35 to −0.24) on day 2 – 0.57 (95 % CI, −1.12 to) 0.01) on day 3, .041.04 (95% CI, CI1.60 to .40.49) on day 4, .70.73 (95% CI, −1.28 to −0.17) on day 5, and and0 .79 (95% CI, .31.35 to 30.23) on day 6. 6. Changes from baseline in symptom scores for days 7 to day 11 in the LY-CoV555 group continued to be better than the placebo group, although this suggests time Most of the patients in the two groups recovered completely or had very mild symptoms.

Security

Adverse events.

Serious adverse events occurred in any of the 309 patients in the LY-CoV555 group and in the placebo group in 0.7% (1 of 143 patients).Table 4). The percentage of patients with an adverse event during treatment was 22.3% (69 out of 309) in the LY-CoV555 group and 24.5% (35 of 143) in the placebo group. Diarrhea was reported in 3.2% of 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 out of 309) and 2.8% (4 out of 143) respectively. The most frequent adverse event in the LY-CoV555 group was nausea (3.9%), while diarrhea (4.9%) was the most frequent adverse event in the placebo group. Infusion-related reactions were reported in 2.3% of patients (7 of 309) in the LY-CoV555 group and 1.4% (2 of 143) in the infusion group. Most of these incidents – including pruritus, flushing, rash, and facial swelling – occurred during the infusion and were reported as mild in severity. No changes in vital signs were observed during these reactions, and infusion was completed in all instances. In some patients, antihistamines were administered to help resolve symptoms.

We used standard methods to sequence all viral samples to determine resistance-related treatment failure potential. Accordingly, we assessed the prevalence of variants with resistance to LY-CoV555, estimated in preclin studies. Such variants were present in 8.2% of patients in the LY-CoV555 group at any one time with an allele fraction of more than 20% (6.3% in the 700-mg subgroup, 8.4% in the 2800 mg subgroup, and 7000- 9.9% in the milligram subgroup) and 6.1% in the placebo group. The clinical significance of the presence of these variants is not known.



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