2.1. Study designFor the specific epidemic situation of COVID-19, we chose to conduct an open-label nonrandomized control study in theisolation ward of the national clinical research center for infectious diseases (The Third People’s Hospital of Shenzhen),Shenzhen, China. From 30 January to 14 February 2020, laboratory-confirmed patients with COVID-19 were consecutivelyscreened, and eligible patients were included in the FPV arm of the study. Patients who had initially been treated with antiviraltherapy with LPV/RTV from 24 January to 30 January 2020 were screened, and eligible patients were included in the controlarm of the study. The study was conducted according to the guidelines of the Declaration of Helsinki and the principles ofgood clinical practice, and was approved by the ethics committee of The Third People’s Hospital of Shenzhen (No.:2020-002-02). Written informed consent was obtained from all patients. The study was reported according to the ConsolidatedStandards of Reporting Trials guidelines and was registered on the Chinese Clinical Trial Registry (ID: ChiCTR2000029600)
2.3. Trial treatmentFPV (Haizheng Pharmaceutical Co., 200 mg per tablet) was given orally. The dose was 1600 mg twice daily on Day 1 and600 mg twice daily on Days 2−14. LPV/RTV (AbbVie Inc., 200 mg/50 mg per tablet) were given orally. The dose was LPV400 mg/RTV 100 mg twice daily. Both FPV and LPV/RTV were continued until the viral clearance was confirmed or until14 d had passed. In addition, all participants received IFN-α1b 60 µg (Beijing Tri-Prime Gene Pharmaceutical Co., 30 μg perampule) twice daily by aerosol inhalation. Standard care included oxygen inhalation, oral or intravenous rehydration,electrolyte corre
4. DiscussionThis study investigated the effect of FPV versus LPV/RTV on the treatment of COVID-19. It was found that FPV wasindependently associated with faster viral clearance and a higher improvement rate in chest imaging. These findings suggestthat FPV has significantly better treatment effects on COVID-19 in terms of disease progression and viral clearance, ascompared with LPV/RTV. FPV, which is known as a prodrug, is a novel RNA-dependent RNA polymerase (RdRp) inhibitor,which has been shown to be effective in the treatment of influenza and Ebola virus [8,11–15]. Recently, a report from Wanget al.  showed that both FPV and remdesivir are effective in reducing the SARS-CoV-2 infection in vitro (EC50 = 61.88μmol·L−1, CC50 > 400 μmol·L−1, SI > 6.46). The finding of the preset study confirms the hypotheses conceived from thelaboratory finding: that FPV is effective treatment for COVID-19.The limitation of the present study is that it was not a randomized double-blinded placebo-controlled clinical trial, whichled to inevitable selection bias in patient recruitment. However, given the high number of patients presenting simultaneouslyand the very high infectivity of the disease, it was ethically unacceptable to allocate patients to receive a different experimentaldrug using a randomization process impossible for most of the patients to understand. Furthermore, in the context of rumorsand distrust of hospital isolation, using a randomized design at the outset might have led even more patients to refuse beingisolated. Therefore, we chose to conduct a nonrandomized trial, in which patients consecutively admitted to the hospital duringtwo separate periods were included in two groups, respectively. Importantly, all baseline characteristics of the two groupswere comparable and the effectiveness of FPV remained significant after adjustment for potential confounders.The current study also found that early viral clearance contributed to the improvement of chest imaging on Day 14. Thisfinding suggests that improvement of the disease may depend on inhibition of the SARS-CoV-2, and that FPV controls thedisease progression of COVID-19 by inhibiting the SARS-CoV-2. Until recently, the pathogenesis of COVID-19 had notbeen well clarified. Since the infection of SARS-CoV-2 was thought to be self-limited and characterized by systemicinflammation reaction, symptomatic and supportive treatment was mainly recommended by the WHO and the National HealthCommission of the PRC. This description is similar to MERS-CoV, for which nonspecific therapeutic interventions are oftenintroduced to prevent severe morbidity and mortality . How antivirals would contribute to control of the disease iscontroversial. Although there have been many registered clinical trials focusing on antiviral drugs for COVID-19, the timing,duration of treatment, and study endpoints have not been unified. In the current study, the time of viral clearance wasintroduced as a primary endpoint to evaluate the antiviral effect of FPV on the SARS-CoV-2 and successfully identify thepriority of FPV. The relationship between the time of viral clearance and the improvement in CT image indicates that viralclearance is an ideal surrogate for the clinical endpoint. A limitation of the present study was that the relationship betweenthe viral titer and the clinical prognosis was not well clarified. Future research could pay more attention to this point.More adverse events were observed in the control arm than in the experimental arm, and were similar to the adverse eventsobserved in studies of AIDS treated by LPV/RTV. It is worth mentioning that the treatment duration of FPV in the presentstudy was twice as long as that used for the treatment of influenza. However, the adverse events in the experimental arm wererare and tolerable, and none of the patients needed to discontinue FPV treatment. These results seem to suggest that thetreatment duration of FPV can be prolonged if necessary.SARS-CoV-2 infection has now spread quickly all over the world. At present, no effective treatment has beendemonstrated. The task at hand was to run a well-designed trial to identify effective treatments based on a high level ofevidence. However, at the beginning of this study, certain conditions did not allow the randomization of patients to receiveeither standard care or an experimental drug. In this pilot study of a non-randomized control trial, we found that FPV showedsignificantly better treatment effects on COVID-19 in terms of disease progression and viral clearance; if causal, these resultsshould be important information for establishing standard treatment guidelines to combat the SARS-CoV-2 infection.Furthermore, we introduced the time of viral clearance as a primary endpoint for experimental antiviral treatment anddemonstrated it to be a surrogate of clinical endpoint; this will be helpful for designing COVID-19 research.
μmol·L−1, CC50 > 400 μmol·L−1, SI > 6.46). The finding of the preset study confirms the hypotheses conceived from the laboratory finding: that FPV is effective treatment for COVID-19.The limitation of the present study is that it was not a randomized double-blinded placebo-controlled clinical trial, which led to inevitable selection bias in patient recruitment. However, given the high number of patients presenting simultaneously and the very high infectivity of the disease, it was ethically unacceptable to allocate patients to receive a different experimental drug using a randomization process impossible for most of the patients to understand. Furthermore, in the context of rumors and distrust of hospital isolation, using a randomized design at the outset might have led even more patients to refuse being isolated. Therefore, we chose to conduct a nonrandomized trial, in which patients consecutively admitted to the hospital during two separate periods were included in two groups, respectively. Importantly, all baseline characteristics of the two groups were comparable and the effectiveness of FPV remained significant after adjustment for potential confounders.
However, given the high number of patients presenting simultaneously and the very high infectivity of the disease, it was ethically unacceptable to allocate patients to receive a different experimental drug using a randomization process impossible for most of the patients to understand.
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