Effectiveness and safety of Sanhan Huashi granules versus nirmatrelvir–ritonavir in adult patients with COVID-19: A randomized, open-label, multicenter trial

Sanhan Huashi granules (SHG) demonstrated therapeutic effects against coronavirus disease 2019 (COVID-19) in observational studies. In order to compare the effectiveness and safety of SHG and nirmatrelvir–ritonavir in treating adults with mild-to-moderate COVID-19, we conducted a randomized, active-controlled, open-label, multi-center trial conducted between February and July in 2023. The patients were randomized in a 1:1 ratio to the SHG group and the nirmatrelvir–ritonavir group. A total of 400 participants were randomized, among which 200 participants ultimately received SHG and 198 received nirmatrelvir–ritonavir. The primary outcome was time to sustained clinical recovery through day 28. SHG significantly shortened the median time to sustained clinical recovery compared to nirmatrelvir–ritonavir (6.0 [95% CI, 5.0 to 6.0] vs. 8.0 [CI,6.0 to 9.0] days; P = 0.001), particularly for individual symptoms including fever, sore throat, cough and fatigue. No participants in either group died and incidence of severe COVID-19 showed no difference between two groups. Participants who received nirmatrelvir–ritonavir demonstrated a higher rate of virus clearance on day 5 compared to those received SHG (46.4% [CI, 39.1 to 53.7] vs. 65.6% [CI, 58.3 to 72.4]; P < 0.001). Most adverse events were mild in both groups. In summary, SHG was superior to nirmatrelvir–ritonavir in shortening the time to sustained clinical recovery in participants with mild-to-moderate COVID-19, despite a lower virus clearance rate observed after 5 days of treatment (Chinese Clinical Trial Registry Identifier: ChiCTR2300067872).