We read with interest the article by Udwadia et al. on the use of favipiravir in subjects with mild to moderate coronavirus disease 2019 (COVID-19) (Udwadia et al., 2021). The authors concluded that favipiravir may be a safe and effective treatment for mild to moderate COVID-19. We are concerned that the observations made do not support the conclusions.
It is unclear why asymptomatic patients were included in the mild category. This is contrary to widely accepted definitions for categorizing clinical severity of COVID-19 (COVID-19 Treatment Guidelines Panel, 2021). Moreover, additional criteria for determining severity, especially clinical symptoms, are highly subjective and have not been used or validated in any studies on COVID-19 treatments. It would have been appropriate to use the standard seven-point ordinal scale that has been used widely to assess the efficacy of COVID-19 therapeutics including remdesivir (Spinner et al., 2020).
It is uncertain how oxygen saturation (SpO2) ≥95% came to be used as a criterion for clinical cure, as it is likely that all patients had an SpO2 >94% to align with the mild to moderate disease definition (COVID-19 Treatment Guidelines Panel, 2021). Additionally, cough relief as a criterion is highly subjective and with an open-label design may have confounded the decision regarding clinical cure.
Having a range of 40–100 for the calculated sample size is surprising, and the final sample size was determined according to regulatory requirements. The analysis violates the ideal intention-to-treat (ITT) principle, as three patients randomized to the favipiravir arm were excluded and one patient because of no available post-baseline evaluation. Excluding patients disturbs the prognostic balance afforded by randomization (McCoy, 2017). The final results would likely be negatively impacted if an ideal ITT analysis was performed.
Approximately 75% of subjects did not have co-morbidities and with a mean age of 43 years would be expected to have a good prognosis. Additionally, periodic assessment of prognostic inflammatory markers was not described. With four times higher prevalence of adverse events, although self-limiting, the conclusion about the safety of favipiravir needs to be tempered. Finally, information on adherence and missed doses is lacking.
The trial failed to achieve the primary endpoint of time to viral clearance. However, conclusions on efficacy are based on multiple secondary outcomes. The validity of analyzing multiple secondary endpoints in the absence of a significant primary endpoint is controversial (Moye, 1999). Multiplicity adjustments and gate-keeping strategies for secondary endpoints are needed and at best lead to hypothesis generation rather than prove efficacy (Rockhold and Segreti, 2014).
In conclusion, we encourage against using expensive favipiravir as a treatment for mild to moderate COVID-19 until further evidence is available from well-designed randomized, placebo-controlled clinical trials.
Conflict of interest
None.
References
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