Review 1: "Favipiravir In Adults with Moderate to Severe COVID-19: A Phase 3 Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial"

 RR:C19 Evidence Scale rating by reviewer:

• Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review:

Shenoy, S. et al. [1] aim to assess the efficacy and safety of Favipiravir in adults with moderate to severe COVID-19 by running a randomized, double-blind, multicenter, phase 3 trial, of adults (21-80 years). Patients were randomized to oral Favipiravir (day 1: 1800 mg BID and days 2-10: 800 mg BID) plus standard supportive care (SoC) versus placebo plus SoC. The primary endpoint was time to resolution of hypoxia. Their results do not show any benefit from the use of Favipiravir in the moderate to severe, hospitalized COVID-19 patients, but favorable clinical trends were observed in patients with lower NEWS-2 risk when early administration of Favipiravir could be achieved.

Therapies for COVID-19 infection usually work better in the early stages rather than more advanced stages [2]. From the database of COVID-19 studies, a 51% improvement is attributed to the use of Favipiravir in the early stages, while the improvement in late stages is much less, at 29%. Then, usually, one drug is administered not in isolation, but with other agents. For example [3], published 20/12/2020 and thus known at the time of the trial [1], suggests for hospitalized patients with Confirmed COVID19 Pneumonia For 7 days, the use of Favipiravir 1600 mg PO BID X 2 doses then 600 mg PO BID ( total 7 days) + Hydroxychloroquine 400mg PO BID X 2 doses then 200mg PO BID (total 5 to 7 days) ± Camostat 200 mg PO TID for 5 to 7 days (optional), OR Favipiravir 1600 mg PO BID X 2 doses then 600 mg po BID from day2 ( total 7 days) + Chloroquine Phosphate 500 mg PO BID X 2 doses then 250 mg PO BID (total 5 to 7 days) ± Camostat 200 mg PO TID for 5 to 7 days (optional) OR alternatives, such as Lopinavir-Ritonavir (200/ 50 mg) 2 tablets PO BID (total 7 days) + Hydroxychloroquine 400 mg po BID X 2 doses, then 200 mg PO BID (total 5 to 7 days) (alternatively, Chloroquine 500 mg PO BID X 2 doses, then 250 mg PO BID) (5 to 7 days) ± Camostat 200 mg PO TID (5 to 7 days) (optional) OR Remdesivir 200 mg IV on day 1, followed by 100 mg IV daily. Interferon is optional.

Now, Shenoy et al. [1] propose for hospitalized adults with moderate to severe COVID-19 the use of oral Favipiravir (day 1: 1800 mg BID and days 2-10: 800 mg BID) plus standard supportive care (SoC). When reference is made to the above-mentioned protocol in the United Arab Emirates [3], contemporary to the study in Kuwait by Shenoy et al. [3], we note as CQ/HCQ is missing, the dose of Favipiravir is different, and the optional use of Camostat (or Interferon) is likely also missing (improbable they are included in the SoC). Regarding the average improvement of 29% with Favipiravir in individual or combinatory uses in late stages of [2], we note the large spreading between works that favor Favipiravir or control in [2], with the efficacy of Favipiravir generally declining with the severity of the infection. The results of Shenoy et al. [1] are thus consistent with other literary works. They could have been more positive by increasing the share of the less severe cases in the population, as they also notice, and likely, adopting combinatory regimes.

References

[1]   Shenoy, S. et al., 2021. Favipiravir In Adults with Moderate to Severe COVID-19: A Phase 3 Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial. doi.org/10.1101/2021.11.08.21265884

[2]   c19Favipiravir.com/

[3]   doh.gov.ae/-/media/7BD7B077D8F846B48A70C5872902DD1C.ashx