Trial design and Consort diagram

A. COVASE Trial Design.

B. Consort diagram summary. Numbers not in parentheses indicate the participants in the ITT population and the numbers in parentheses indicate the number of participants in the per-protocol population. A complete consort diagram is shown in Supplementary figure 1.

Patient baseline characteristics

Longitudinal CRP predicts survival probability in severe COVID-19 pneumonia.

A. Individual CRP concentrations in 465 plasmas from 63 participants with maximum WHO severity grade 7 COVID-19 pneumonia segregated into survivor and deceased groups, extracted from the Berlin COVID-19 study.

B. Participants ordered by their longitudinal average CRP concentrations shown in the left column. Mortality is depicted in yellow in the right column.

C. Kaplan Meier survival probabilities (left panel) and numbers at risk (right panel) for patients segregated into three categories of longitudinal average CRP ranges: 0-100, 100-200, and 200-450 mg / L. Statistical significance (P), Hazard ratios (HR) and 95% confidence intervals (95% CI) for group 1 against group 3 and group 2 against group 3 are shown below the survival plot.

Statistics by Mann-Whitney and Mantel-Cox log rank tests.

Primary endpoint and sensitivity analysis

Analysis of primary and clinical endpoints

A. Fitted mean (95% confidence interval) from mixed model of natural log (CRP) over 7 days follow-up as the outcome. (Left panel) randomised participants only: Blue: participants randomised to R-BAC, N=9; Pink: participants randomised to R-BAC+DA, N=30. (Right panel) ITT population: Blue: T-BAC (CC-BAC and R-BAC) N=69; Pink: R-BAC+DA, N=30. Results were adjusted for natural log baseline CRP, age, sex, BMI, serious comorbidity (Diabetes, Cardiovascular disease or hypertension), time and a treatment × time interaction. P-value generated by comparing least-square means between arms.

B. Distribution of participants based on the change in CRP measured as a ratio of the final CRP reading within the 7-day treatment period over the baseline CRP reading per patient. Statistical analysis by Fisher’s test.

C. Kaplan-Meier plot showing time to discharge from hospital from baseline. Hazard ratio from Cox proportional hazards model adjusted for baseline CRP, age, sex, BMI, serious comorbidity (diabetes, cardiovascular disease of hypertension). P-value from log-rank test. (Blue: CC-BAC and participants randomised to R-BAC, N=69. Pink: participants randomised to R-BAC+DA, N=30).

D. Kaplan-Meier plot showing time to death over 35 days follow up. Hazard ratio from Cox proportional hazards model adjusted for baseline CRP, age, sex, BMI, serious comorbidity (Diabetes, Cardiovascular disease of hypertension). P-value from log-rank test.

Primary endpoint by day

Analysis of secondary and exploratory endpoints in blood

A. Difference between the lymphocyte count for each day of the treatment period and the baseline in each ITT participant who exhibited lymphopenia at baseline (<1×109 lymphocytes/mL). Mean and 95%CI interval is shown with statistical analysis by two-way Anova.

B. Mean D-dimer levels per day in randomised R-BAC (blue) and R-BAC+DA (pink) participants with error bars depicting 95% CI. Statistical difference by mixed effects Anova analysis.

C. Mean cf-DNA levels per day in randomised R-BAC (blue) and R-BAC+DA (pink) participants, with error bars depicting standard deviation. Statistical analysis by mixed effects Anova.

D. Correlation between the final cf-DNA levels and ratio of CRP at day-7 normalized to the baseline CRP (CRPfinal/CRPbaseline) per randomised participant. Fitting by non-linear regression.

E. Correlation between D-dimer and cf-DNA levels in the blood of participants randomised to R-BAC (blue) or to R-BAC+DA (DA) (pink), where samples were segregated depending on whether the corresponding levels of cf-DNA were below or above 100 μg/mL. Statistical analysis by unpaired parametric t-test.