Hongzhou Lu: The Third People's Hospital of Shenzhen, Shenzhen, China.
George Zhang: Fujian Akeylink Biotechnology Co., Ltd., Shanghai, China.
John Mao: Fujian Akeylink Biotechnology Co., Ltd., Shanghai, China.
Xiaochun Chen: Fujian Medical University, Fuzhou, China.
Yangqing Zhan: The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China.
Ling Lin: Sanya Central Hospital (The Third People's Hospital of Hainan Province), Sanya, China.
Zhenyu Liang: The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China.
Ruilin Sun: Guangdong Second Provincial General Hospital, Guangzhou, China.
Liya Huo: Nanyang Central Hospital, Nanyang, China.
Peng Hu: The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Yihua Lin: The First Affiliated Hospital of Xiamen University, Xiamen, China.
Xibin Zhuang: Quanzhou First Hospital, Fujian, China.
Haijun Fu: Shanghai Zenith Medical Research Co., Ltd., Shanghai, China.
Zifeng Yang: The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China.
Xinwen Chen: Guangzhou National Laboratory, Guangdong Province, China.
Fu-Sheng Wang: The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China.
Nanshan Zhong: The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China.
Background: GST-HG171 is a potent, broad-spectrum, orally bioavailable small-molecule 3C like protease inhibitor that has demonstrated greater potency and efficacy compared to Nirmatrelvir in pre-clinical studies. We aimed to evaluate the efficacy and safety of orally administered GST-HG171 plus Ritonavir in patients with coronavirus disease 2019 (COVID-19) infected with emerging XBB and non-XBB variants. Methods: This randomised, double-blind, placebo-controlled phase 2/3 trial was conducted in 47 sites in China among adult patients with mild-to-moderate COVID-19 with symptoms onset ≤72 h. Eligible patients were randomised 1:1 to receive GST-HG171 (150 mg) plus Ritonavir (100 mg) or corresponding placebo tablets twice daily for 5 days, with stratification factors including the risk level of disease progression and vaccination status. The primary efficacy endpoint was time to sustained recovery of clinical symptoms within 28 days, defined as a score of 0 for 11 COVID-19-related target symptoms for 2 consecutive days, assessed in the modified intention-to-treat (mITT) population. This trial was registered at ClinicalTrials.gov (NCT05656443) and Chinese Clinical Trial Registry (ChiCTR2200067088). Findings: Between Dec 19, 2022, and May 4, 2023, 1525 patients were screened. Among 1246 patients who underwent randomisation, most completed basic (21.2%) or booster (74.9%) COVID-19 immunization, and most had a low risk of disease progression at baseline. 610 of 617 who received GST-HG171 plus Ritonavir and 603 of 610 who received placebo were included in the mITT population. Patients who received GST-HG171 plus Ritonavir showed shortened median time to sustained recovery of clinical symptoms compared to the placebo group (13.0 days [95.45% confidence interval 12.0-15.0] vs. 15.0 days [14.0-15.0], = 0.031). Consistent results were observed in both SARS-CoV-2 XBB (45.7%, 481/1053 of mITT population) and non-XBB variants (54.3%, 572/1053 of mITT population) subgroups. Incidence of adverse events was similar in the GST-HG171 plus Ritonavir (320/617, 51.9%) and placebo group (298/610, 48.9%). The most common adverse events in both placebo and treatment groups were hypertriglyceridaemia (10.0% vs. 14.7%). No deaths occurred. Interpretation: Treatment with GST-HG171 plus Ritonavir has demonstrated benefits in symptom recovery and viral clearance among low-risk vaccinated adult patients with COVID-19, without apparent safety concerns. As most patients were treated within 2 days after symptom onset in our study, confirming the potential benefits of symptom recovery for patients with a longer duration between symptom onset and treatment initiation will require real-world studies. Funding: Fujian Akeylink Biotechnology Co., Ltd.
