Randomized Controlled Trial
Study population and setting
This interim study from the BLAZE-1 trial involved outpatients with mild symptomatic COVID-19. Patients were randomized to 1 placebo group and three treatment groups (700 mg, 2800 mg, 7000 mg doses) of LY-CoV555 neutralizing antibody (developed by Eli Lilly). Patients at 41 US centers received a one-time intravenous infusion of placebo or LY-CoV555. Inclusion required a positive SARS-CoV-2 nasopharyngeal RT-PCR assay and at least one mild or moderate COVID-19 symptom, such as fever, cough, or sore throat. Exclusion criteria were hospitalization, history of prior SARS-CoV-2 infection, SpO2 ≤93% on room air, requirement of supplementation oxygen, hemodynamic instability requiring vasopressors, serious co-morbidity requiring surgery, allergy to formulation, and pregnancy. The primary outcome was change in nasopharyngeal viral load from baseline to day 11. Secondary outcomes included safety assessments, symptom score (8 domains graded from 0 (none) to 3 (severe symptoms)), time to SARS-CoV-2 clearance, and proportion of patients who experienced COVID-19 related hospitalization, ER visit, or death. This interim analysis was prompted on September 5, 2020, when the last patient randomized to LY-CoV555 had reached day 11.
Summary of Main Findings
This analysis included US 452 outpatients recruited from 41 centers between June 17 and August 21, 2020. The median age of participants was 45 years, the median BMI was 29 kg/m2, most participants had one or more COVID-19 risk factors, and the median duration of symptoms was 4 days. In intention-to-treat analysis, the 2800-mg dose of LY-CoV555 significantly decreased mean log viral load from baseline to day 11 compared to placebo (-4.00 vs. -3.47, p=0.02), but these differences were not significant for 700-mg (-3.67 vs. -3.47, p=0.38) or 7000-mg (-3.38 vs. -3.47, p=0.70) doses. At day 29, COVID-19 related hospitalizations for placebo, 700-mg, 2800-mg, and 7000-mg groups were 6.3%, 1.0%, 1.9%, and 2.0% (combined LY-CoV555 1.6%), respectively. Posthoc analyses showed percentages of hospitalizations for high-risk groups (BMI ≥ 35, age ≥ 65) at 4.2% for the combined LY-CoV555 group and 14.6% for placebo. Symptom severity score was significantly lower in patients receiving LY-CoV555 (in combined dose analysis) compared to placebo for days 2 to 6 (−0.79, 95% CI: −1.35 to −0.24; −0.57, 95% CI: −1.12 to −0.01; −1.04, 95% CI: −1.60 to −0.49; −0.73, 95% CI: −1.28 to −0.17; −0.79, 95% CI: −1.35 to −0.23; respectively). Adverse effects were comparable between treatment and placebo group (22.3% vs. 24.5%), with nausea (3.9%) as the most common adverse effect in the LY-CoV555 group.
The design was double-blind and placebo-controlled conducted in the outpatient setting among participants with a short duration of symptoms (those most likely to benefit from antibody infusion). Median time from symptom onset to treatment was relatively short at 4 days, permitting analysis of the effect of early intervention. There was a low rate of drop-off between randomization (467 patients) to primary analysis (452 patients). LY-CoV555 had a safety profile comparable to placebo with no serious adverse effects.
The main endpoint was reduction in viral load at day 11, but the authors mention that this is not a clinically meaningful endpoint as most patients with mild COVID-19 have recovered by day 11. The data does not exhibit a dose-dependent relationship between LY-CoV555 treatment and viral load, as only the intermediate dose (2800-mg) was shown to significantly improve viral load. Multiple secondary outcomes, including viral load on multiple days, symptom score, adverse effects, hospitalization, ER visit, and mortality were measured, and the analyses were not corrected for multiple comparisons. Finally, analyses were adjusted for baseline value of endpoint and duration from symptom onset to randomization (≤8 days vs. >8 days) but did not adjust for additional demographic or clinical characteristics.
This study is the first to assess usage of neutralizing antibody for outpatients, who typically have milder COVID-19 symptoms. This study suggests that this treatment may result in earlier symptom improvement, greater reduction in nasopharyngeal viral load, and reduced hospitalization.
This review was posted on: 19 February 2021