ABSTRACT
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 common adverse events related to the investigational drugs were mild and self-limiting laboratory examination abnormalities. Interpretation: Our findings suggest that RAY1216 monotherapy and RAY1216 plus ritonavir both demonstrated significant antiviral activity and reduced the duration of COVID-19 while maintaining a satisfactory safety profile. Considering the limited clinical application of RTV, it is recommended to use RAY1216 alone to further verify its efficacy and safety. Funding: This study was sponsored by the Key Research and Development Program of China (2022YFC0868700).
ABSTRACT
OBJECTIVE: A number of putative virulence factors have been postulated to be relevant to the clinical outcome of Helicobacter pylori infection based on strains identified in the western countries. The aim of this study was to investigate the association between genotypes of vacA, cagA and iceA and duodenal ulcer disease in patients from Hong Kong. METHODS: Seventy-two dyspeptic patients with or without duodenal ulcer disease, with proven H.pylori infection, were studied. Gastric biopsy specimens were analyzed by specific polymerase chain reaction and Southern blot to determine the genotypes of these virulence factors. RESULTS: Except 6 (8.3%) cases with evidence of multiple infections, all of the remaining 66 cases had vacA signal sequence s1 type strains. Twenty-seven (90%) of the 30 cases with duodenal ulcers were infected with cagA-positive strains, compared with 32 (88.9%) of 36 with non-ulcer dyspepsia (P > 0.05). Similarly, vacA middle region sequences were detected with no significant difference in the two groups, 9 (30.0%) versus 13 (36.1%) for m1b and 21 (70.0%) versus 23 (63.9%) for m2 type. IceA1 subtype was detected in the same frequency in 42 (63.6%) of the 66 cases. Neither cagA nor vacA and iceA were associated with duodenal ulcer disease. CONCLUSION: No clear differences were found in the distribution of cagA, vacA and iceA genotypes among patients with duodenal ulcer or non-ulcer dyspepsia. The association of these virulence genes and duodenal ulcer disease needs reappraisal, particularly under geographic considerations.
