A total of 354 ambulatory patients from the U.S., aged ≥ 12 years were evaluated in this portion of the phase 3, BLAZE-1 trial (J2X-MC-PYAB). The primary results of BLAZE-1 have been reported previously [13]. The primary objective of the study was to evaluate PHVL (PHVL was defined as a log viral load > 5.27, corresponding to a mean PCR cycle-threshold value of < 27.5 on day 7) in patients treated with low dose (350/700 mg) BAM + ETE compared to placebo. Secondary objectives included effects on SARS-CoV-2 viral load, clinical status, and symptom resolution in BAM + ETE and placebo groups. The rationale for the BAM + ETE dose selection was partly based on positive results in the BLAZE-4 study [11] supporting the potential efficacy of low-dose BAM + ETE for mild-to-moderate COVID-19 in patients without risk factors for severe disease (i.e., age > 65 years and/or obesity). Patients were infused with a total dose volume of 200 ml over at least 8 min and monitored for at least 60 min after completion of the infusion. Patients assigned to placebo treatment received 200 ml 0.9% sodium chloride injection. Each participant received a single dose of study intervention, and patients were followed for 85 days post-treatment.

Separately, a total of 300 ambulatory patients ≥ 12 years of age were treated with 5- or 3-min IV push of low-dose (350/700 mg) BAM + ETE in an addendum to the BLAZE-1 study. The primary objective was to evaluate the safety and clinical status after a single dose of BAM + ETE IV push during an 85-day post-treatment follow-up.

Inclusion and exclusion criteria are consistent with other reported results of the BLAZE-1 study [8]. In brief, at the time of screening, patients were ≥ 12 years of age and satisfied at least one high-risk criterion had one or more mild or moderate COVID-19 symptoms based on FDA guidance [14], were not currently hospitalized, and had a positive SARS-CoV-2 PCR test ≤ 3 days prior to the start of drug infusion. For ethical reasons, once the clinical efficacy of BAM + ETE at higher doses was established, enrollment into the placebo arm was stopped in this trial to ensure that patients were not deprived of potential treatment benefits.

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 all patients or legally authorized representatives gave written informed consent prior to study entry.

PHVL was defined as a viral load greater than 5.27 on day 7 as validated by Dougan et al. [9]. The proportion of patients with PHVL was summarized and compared to placebo.

Viral load change from baseline (CFB) was calculated as the value at the visit of interest minus the baseline value. The baseline was defined as the last non-missing assessment recorded on or prior to the date of study drug infusion. Viral RNA was collected from nasopharyngeal swabs of patients. The proportion of patients experiencing COVID-19 hospitalization (defined as ≥ 24 h of acute care) or death from any cause by day 29 was compared for the treatment arm to all high-risk placebo patients. To increase the power of the analysis of this outcome measure, patients from the previous phase 3 BLAZE-1 placebo arm (N = 776) (these patients were from the corresponding placebo group for the phase 3 high-risk population, who were administered BAM + ETE 2800 mg + 2800 mg and the BAM + ETE 700 mg + 1400 mg) were pooled with the concurrent placebo group (N = 141).

Symptom improvement and resolution were assessed with symptom questionnaires completed by the patients. Patients rated the severity of their COVID-19 symptoms daily through day 11, and on day 22 and day 29, on a scale of none/absent = 0; mild = 1; moderate = 2; and severe = 3. The time to symptom improvement and resolution were summarized using Kaplan–Meier estimates through day 29. The time to symptom improvement was defined as the time to a patient experiencing both any symptoms on the symptom questionnaire scored as moderate or severe at baseline are subsequently scored as mild or absent, and any symptoms on the symptom questionnaire scored as mild or absent at baseline are subsequently scored as absent. The time to sustained symptom resolution was defined as the time to two consecutive assessments with a score of 0 for shortness of breath, fever, body aches, sore throat, chills, and headaches, or a score of 0 or 1 for cough and fatigue on the symptom questionnaire. The time to sustained complete symptom resolution was defined as the time to the first of two consecutive days that all symptoms had been given a score of 0.

The proportion of patients experiencing treatment-emergent adverse events (TEAEs), defined as an event that first occurred or worsened in severity after baseline, was also summarized. COVID-19 signs and symptoms were not considered TEAEs in the study.

Patients were randomized 2:3 (placebo: 350/700 mg). A sample size of approximately 400 patients provides greater than 90% power to demonstrate that the effectiveness of BAM + ETE is statistically significantly better than placebo. This sample size calculation assumed a placebo event rate of 30% and a relative reduction of 60% for BAM + ETE, which were included in available data on PHVL rates. Because enrollment was stopped to ensure that patients were not randomized to placebo once the clinical efficacy of BAM + ETE was established, the study was not fully enrolled as originally planned.

The efficacy population included patients from the safety population who also had at least one non-missing post-baseline measurement. For continuous measures, the number of patients, mean, standard deviation, median, minimum, and maximum were included. For categorical measures, frequency counts and percentages were included.

Treatment comparisons for the proportion of patients with PHVL on day 7 were conducted using a logistic regression with a Firth penalized likelihood [15]. Missing viral load data on day 7 were imputed using the last observation carried forward (LOCF).

Change from baseline to days 3, 5, 7, and 11 in SARS-CoV-2 viral load was analyzed using a linear mixed-effect model. The model included log base 10 transformed baseline as a covariate, treatment, day, and treatment-by-day interaction as fixed effects. Missing viral load data were treated as missing at random.

The proportion of patients experiencing a COVID-19-related hospitalization or death from any cause was analyzed using logistic regression with a Firth penalized likelihood for the safety population. The model included a covariate for the duration from symptom onset to randomization (≤ 8 days, or > 8 days). Missing data were not imputed.

Time to symptom improvement, time to sustained, sustained complete, and complete symptom resolution were analyzed using a log-rank test stratified by duration from symptom onset to randomization. Patients who were either hospitalized, discontinued early, or did not experience an event by study completion were censored. Safety data were summarized descriptively. The final database lock occurred on October 10, 2021. The safety population included patients randomly assigned to treatment and who received any amount of study intervention.