Prespecified Primary and Secondary endpoints.

A. COVASE Trial Design.

B. Consort diagram. Numbers not in parentheses indicate those in the intention-to-treat population, numbers in parentheses indicate the numbers in the per-protocol population.

C. (left panel) Natural log CRP in BAC (HC and randomised participants; blue). (Right panel) Natural log CRP in participants randomised to BAC+DA (pink).

D. Fitted mean (95% confidence interval) from mixed model, with natural log (CRP) over 7 days follow-up as the outcome, adjusting 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. Intention to treat (ITT) population (Blue: HC and participants randomised to BAC, N=69; Pink: participants randomised to BAC+DA, N=30).

E. Same output as in (D) but examining randomised participants only: (Blue: participants randomised to BAC, N=9; Pink: participants randomised to BAC+DA, N=30).

Patient baseline characteristics

Primary endpoint and sensitivity analysis:

Secondary Endpoints

Analysis of secondary endpoints and exploratory endpoints.

A. Kaplan-Meier plot showing time to discharge from hospital from baseline. ITT population. 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: HC and participants randomised to BAC, N=69. Pink: participants randomised to BAC+DA, N=30).

B. Kaplan-Meier plot showing time to death over 35 days follow up. ITT population. 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: HC and participants randomised to BAC, N=69. Pink: participants randomised to BAC+DA, N=30). Abbreviations: BAC-best available care, CRP-C-reactive protein, DA-dornase alfa, ITT-intention-to-treat.

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

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

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

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

Baseline characteristics of patients analysed in the trial.

(A-C). Violin plots (left) and frequency distribution (right) of baseline clinical parameters between patients in the historical control and randomised BAC group and the randomised BAC+Dornase alfa (BAC+DA) group. A. Age, B. Baseline CRP and C. Body mass index (BMI).

D. Number of male and female patients in the two groups.

E. Incidence of cardiovascular comorbidities in the two groups.

A. Graph depicting the periodicity and frequency of blood sample collection for all post-baseline CRP values from historical control and randomised BAC (blue) or BAC+Dornase alfa (BAC+DA, pink) patients pooled into a single timeline.

B. Kaplan-Meier plot showing time to discharge from hospital from baseline. Randomised participants only. 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: participants randomised to BAC, N=9. Pink: participants randomised to BAC+DA, N=30).

C. D-dimer concentration in randomised patient post-baseline blood samples pooled into BAC and BAC + DA groups. Statistical analysis by two-tailed unpaired parametric t-test.

D. DNA concentration in randomised patient post-baseline blood samples pooled into BAC and BAC + DA groups. Statistical analysis by one-way Anova.

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

Randomised individuals and historical control, additional baseline characteristics. characteristics: white blood cell count, neutrophil count, procalcitonin count and D-dimer

Randomised participants only

Secondary clinical endpoints

Safety