Antiviral efficacy of RAY1216 monotherapy and combination therapy with ritonavir in patients with COVID-19: a phase 2, single centre, randomised, double-blind, placebo-controlled trial
Bei Wang, Hai-Jun Li, Mi-Mi Cai, Zhao-Xin Lin, Xia-Fei Ou, Shu-Hua Wu, Rui-Huan Cai, Ying-Na Wei, Fei Yang, Ya-Min Zhu, Zi-Feng Yang, Nan-Shan Zhong, Ling Lin
eClinicalMedicine, doi:10.1016/j.eclinm.2023.102189
Background This study aimed to evaluate the efficacy and safety of RAY1216, a novel inhibitor of 3-chymotrypsin-like cysteine protease (3CLpro), in adults with coronavirus disease 2019 (COVID-19). Methods This phase 2, single centre, randomised, double-blind, placebo-controlled trial included hospitalised patients between August 14, 2022, and September 26, 2022, in Sanya Central Hospital (The Third People's Hospital of Hainan Province) in China with no severe symptoms if they had laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection for not more than 120 h (5 days) and a real-time quantitative polymerase chain reaction (qPCR) cycle threshold (Ct) value of ≤30 for both the open reading frames 1 ab (ORF1ab) and nucleocapsid (N) genes within 72 h before randomisation. Half of the participants (n = 30) were randomly assigned (2:1) to receive either RAY1216 or a matched placebo three times a day (TID) for 5 days (15 doses in total), while the other half received RAY1216 plus ritonavir (RAY1216 plus RTV) or a matched placebo every 12 h for 5 days (10 doses in total). The primary endpoint was the time of viral clearance. Secondary outcomes included the changes of the SARS-CoV-2 RNA viral load, the positivity rate of the nucleic acid test, and the recovery time of clinical symptoms. A safety evaluation was performed to record and analyse all adverse events that occurred during and after drug administration as well as any cases in which dosing was halted because of these events. Clinicaltrials.gov identifier: ChiCTR2200062889. Findings The viral shedding times in the RAY1216 and RAY1216 plus RTV groups were 166 h (95% confidence interval (CI): 140-252) and 155 h (95%CI: 131-203), respectively, which were 100 h (4.2 days) and 112 h (4.6 days) shorter than that of the placebo group, respectively (RAY1216 group vs. Placebo p = 0.0060, RAY1216 plus RTV group vs. Placebo p = 0.0001). At 24 h, 72 h, and 120 h after administration, the viral RNA loads in the RAY1216 and RAY1216 plus RTV groups were significantly less than those of the placebo groups. At 280 h (11.5 days) after administration, the nucleic acid test results in the RAY1216 and RAY1216 plus RTV groups were both negative. The
Contributors Ling Lin was the chief investigator and led the clinical team. Ling Lin, Hai-jun Li, Zi-feng Yang, and Nan-shan Zhong contributed to the trial design and the safety assessments, monitoring, and oversight of drug interactions. Bei Wang contributed to produce the first draft of this article. Hai-jun Li contributed to statistical analysis and ran the economic assessments. Bei Wang, Mi-mi Cai, Zhao-xin Lin, Ying-na Wei, Fei Yang, Ya-min Zhu, and Ling Lin were responsible for study implementation and data acquisition. Xia-fei Ou and Rui-huan Cai were responsible for blood specimen collection. Shu-hua Wu contributed to drug management and distribution. Ling Lin, Hai-jun Li, Zi-feng Yang, and Nan-shan Zhong have verified the underlying data and have final responsibility for the decision to submit this article for publication. All authors had full access to all the data in this study, and the corresponding authors had the final responsibility to submit this study for publication. Appendix A. Supplementary data Supplementary data related to this article can be found at https://doi. org/10.1016/j.eclinm.2023.102189.
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