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SARS-CoV-2 neutralizing antibody LY-CoV555 in Covid-19 outpatients



patient

Admission and trial design. Patient characteristics at baseline.

From June 17, 2020 to August 21, 2020, a total of 467 patients received LY-CoV555 random assignment (317 cases) or placebo (150 cases), and patients in the LY-CoV555 group were assigned to three doses One of the subgroups. Among the randomized patients, 452 met the criteria for inclusion in the main analysis (309 in the LY-CoV555 group and 143 in the placebo group). The dose of LY-CoV555 is 700 mg (101 patients), 2800 mg (107 patients) or 7000 mg (101 patients) (figure 1). At the time of entry, the two experimental groups maintained a good balance of risk factors (Table 1). Nearly 70% of patients have at least one risk factor-65 years of age or older, body mass index (BMI, weight in kilograms divided by height in meters squared) of 35 or higher, or at least one A related co-existing disease-severe Covid-19. After randomization, patients received LY-CoV555 or placebo infusion within a median of 4 days after the onset of symptoms. At the time of randomization, more than 80% of patients had only mild symptoms. The average PCR cycle threshold (Ct) value observed on the day of infusion was 23.9 (approximately 2.5 million RNA equivalents), which was in line with expectations, that is, the population diagnosed recently will have a higher viral burden. The conversion from Ct value to viral load is described in section 6.10 of the statistical analysis plan.

Main result

The baseline change from viral load.

By day 11, most patients, including the placebo group, had a clear trend of virus clearance. The observed mean reduction in the log viral load of the entire population relative to the baseline is −3.81 (baseline mean 6.36; day 11 mean 2.56); this value corresponds to a 4300 reduction in the burden of SARS-CoV-2 Times, thereby eliminating more than 99.97% of viral RNA.For patients receiving a dose of 2800 mg LY-CoV555, compared with placebo, the difference in reduction from baseline was -0.53 (95% confidence interval) [CI], -0.98 to -0.08; P = 0.02), the viral load decreased by 3.4 (Table 2). However, among 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), the difference from baseline in decline was greater than that of placebo. small. %CI, -0.37 to 0.55; P = 0.70).

Secondary viral results

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

Exploratory measures for virus removal

The SARS-CoV-2 viral load of all patients and the test group on day 7 showed.

Group A shows the SARS-CoV-2 viral load (measured by the circulation threshold determined by reverse transcriptase-polymerase chain reaction) of all patients who received LY-CoV555 or placebo and the viral load data was in the interim analysis Available. The box diagram represents patients who have not been hospitalized, and the red square represents patients who have been hospitalized. It was found that this hospital contact was related to the high viral load on the 7th day. The box represents the interquartile range, the horizontal line in each box represents the median, and the whiskers represent the minimum and maximum values ​​(excluding outliers greater than 1.5) multiplied by the values ​​represented by each end of the box). Group B shows the cumulative probability that the patients in each test group have the indicated viral load cycle threshold on day 7.

In the pooled trial population, an association was observed between slower virus clearance and more hospitalization events. Figure 2A The absolute viral load of hospitalized patients (across random stratification) and a box plot of the viral load of non-hospitalized patients are given. On day 7, all available viral load measurements in hospitalized patients were higher than the median value for non-inpatients. Among patients with a higher viral load on day 7, the frequency of hospitalization was 12% (7 of 56 patients) in patients with a Ct value below 27.5, and the frequency was 0.9% (3 of 340 patients). Name)) in those with a low viral load. (The SARS-CoV-2 N1 gene primers used the SARS-CoV-2 reference group of the US Food and Drug Administration, and the Ct value determined was equivalent to about 570,000 nucleic acid-based amplification tests per milliliter.) The exploratory analysis did not follow. This difference is expected, and it is not clear whether this difference applies to other populations. Figure 2B The cumulative probability of patients in each test group having the indicated viral load cycle threshold on day 7 is shown.

Covid-19-related hospitalization

Hospitalization.

On day 29, the percentage of patients hospitalized for Covid-19 in the LY-CoV555 group was 1.6% (5 out of 309 patients), compared to 6.3% in the placebo group (9 out of 143 patients) (table 3). The percentage of patients hospitalized under the LY-CoV555 dose was similar to the overall percentage, 1.0% in the 700 mg subgroup (1 out of 101) and 1.9% in the 2800 mg subgroup (2 out of 107), And 2.0% in the 7000 mg subgroup (2 out of 101). In the post-hoc analysis, the hospitalization rate for patients over 65 years old and patients with BMI over 35 was 4% (4% of 95%) in the LY-CoV555 group, and 15% (7 of 48) A) in the placebo group. Only one patient (placebo group) was admitted to the intensive care unit in this trial.

Symptom score

Symptom score from day 2 to day 11.

It shows the difference between the symptom score and the baseline (δ value) between the LY-CoV555 group and the placebo group from day 2 to day 11. The symptom score ranges from 0 to 24, including 8 domains, and each domain is scored on a scale from 0 (no symptoms) to 3 (severe symptoms). 𝙸 indicates the 95% confidence interval. For details on the symptom scoring method, see the appendix.

In order to assess the effect of treatment on Covid-19 symptoms, we compared the changes in symptom scores from baseline between the LY-CoV555 group and the placebo group (image 3 And Figure S1 in the Supplementary Appendix). The symptom score ranges from 0 to 24, including 8 domains from 0 (no symptoms) to 3 (severe symptoms). From day 2 to day 6, the change in symptom score of the LY-CoV555 group from baseline was better than that of the placebo group, and the value on day 2 was -0.79 (95% CI, -1.35 to -0.24)-day 3 It was 0.57 (95% CI, -1.12 to -0.01), -1.04 (95% CI, -1.60 to -0.49) on day 4, and -0.73 (95% CI, -1.28 to -0.17) on day 5. On day 6 it was -0.79 (95% CI, from -1.35 to -0.23). From day 7 to day 11, the symptom score of the LY-CoV555 group continued to change better than the placebo group from baseline. At these points in time, most patients in the two groups had fully recovered or had very mild symptoms.

Safety

Adverse events.

There were no serious adverse events in the 309 patients in the LY-CoV555 group, and 0.7% (1 of 143 patients) in the placebo group had serious adverse events (Table 4). The percentage of patients with adverse events during treatment in the LY-CoV555 group was 22.3% (69 out of 309 patients) and 24.5% in the placebo group (35 out of 143 patients). Diarrhea occurred in 3.2% of patients in the LY-CoV555 group (10 out of 309 patients) and 4.9% in the placebo group (7 out of 143). Vomiting rates were 1.6% (5 out of 309) and 2.8% (4 out of 143). The most common adverse event in the LY-CoV555 group was nausea (3.9%), while diarrhea (4.9%) was the most common adverse event in the placebo group. 2.3% of patients in the LY-CoV555 group (7 of 309) and 1.4% of the placebo group (2 of 143) had infusion-related reactions. Most of these events-including itching, flushing, rash and facial swelling-occurred during the infusion and were reported to be mild. No changes in vital signs were found during these reactions, and the infusion was completed in all cases. In some patients, taking antihistamines can help relieve symptoms.

We use standard methods to sequence all virus samples to determine the likelihood of treatment failure related to resistance. Therefore, we assessed the prevalence of LY-CoV555-resistant variants predicted in preclinical studies. 8.2% of patients in the LY-CoV555 group had at least one sample with an allele score of more than 20% for this type of variant at any point in time (6.3% for the 700-mg subgroup, 2800-mg subgroup, at 7000 mg 9.9% in the subgroup) and 6.1% in the placebo group. The clinical importance of the existence of these variants is unclear.


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