Favipiravir In Adults with Moderate to Severe COVID-19: A Phase 3 Multicentre, Randomized, Double-Blinded, Placebo-Controlled Trial
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Abstract
Aim
To assess the efficacy and safety of favipiravir in adults with moderate to severe coronavirus disease 2019 (COVID-19).
Methods
In this randomized, double-blind, multicenter, phase 3 trial, adults (21-80 years) with real-time reverse transcriptase polymerase chain reaction (rRT-PCR) confirmed SARS-CoV-2 infection and presenting with moderate to severe COVID-19 and requiring hospitalization were randomized 1:1 to oral favipiravir (day 1: 1800 mg BID and days 2-10: 800 mg BID) (FPV) plus standard supportive care (SoC) versus placebo plus SoC (placebo). The primary endpoint was time to resolution of hypoxia.
Results
In total, 353 patients were randomized to receive either FPV or placebo (175 and 178 in the FPV and placebo groups, respectively). Overall, 76% of the patients (240/315, 78% in FPV vs. 75% in placebo group) reached resolution of hypoxia on or before day 28. The median time to resolution of hypoxia was 7 days in the FPV group and 8 days in the placebo group. Treatment effect was not significant [Hazard ratio (HR) (95% CI): 0.991 (0.767, 1.280) ( p =0.94)].
Patients in the lower NEWS-2 clinical risk subgroup were more likely to achieve shorter time to resolution of hypoxia with the median time to resolution of hypoxia of 6 days in FPV and 7 days in placebo group [HR (95% CI): 1.21 (0.847, 1.731) ( p =0.29)]; shorter time to hospital discharge with a median time to discharge of 8 and 10 days in the FPV and placebo group, respectively [HR (95% CI): 1.47 (1.081, 1.997) ( p= 0.014)]; and shorter time to improvement by 1-point improvement over baseline in WHO 10-point clinical status score with the median time to improvement by 1-point from baseline of 6 and 7 days in the FPV and placebo group, respectively [HR (95% CI): 1.16 (0.830, 1.624) ( p= 0.38)] than higher NEWS-2 clinical risk subgroup.
Treatment emergent adverse event (TEAEs) were experienced by 62/334 (19%) patients [35/168 (21%) patients in FPV and 27/166 (16%) in placebo group]. Hyperuricaemia/increased blood uric acid was reported in 9 (3%)/2 (1%) patients [8 (5%)/1(1%) patients in FPV and 1 (1%)/1(1%) in placebo group], which were of mild intensity and transient. Overall, 36 serious adverse events (SAEs) were reported, 20 in FPV and 16 in placebo group.
Conclusion
The trial did not find favipiravir to be effective in moderate to severe, hospitalized COVID-19 patients; favourable clinical trends were observed in patients with lower NEWS-2 risk when early administration of favipiravir could be achieved.
Article activity feed
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Alberto Boretti
Review 1: "Favipiravir In Adults with Moderate to Severe COVID-19: A Phase 3 Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial"
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Alberto Boretti
Review of "Favipiravir In Adults with Moderate to Severe COVID-19: A Phase 3 Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial"
Reviewer: Alberto Boretti (Prince Mohammad Bin Fahd University ) | 📗📗📗📗◻️
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SciScore for 10.1101/2021.11.08.21265884: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Participating Patients: The study included patients of either sex, aged between 21 (age of giving informed consent in Kuwait) and 80 years (both inclusive) who had tested positive for SARS-CoV-2 by real-time Reverse Transcriptase Polymerase Chain Reaction (rRT-PCR) assay on a nasopharyngeal or oropharyngeal swab, were clinically assessed to have moderate or severe COVID-19 and were hospitalized for management. Sex as a biological variable Other main exclusion criteria were patients who had allergy or contraindication to the drug, pregnant and lactating mothers, and patients with congestive cardiac failure, moderate to severe hepatic dysfunction or renal failure, alanine … SciScore for 10.1101/2021.11.08.21265884: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Participating Patients: The study included patients of either sex, aged between 21 (age of giving informed consent in Kuwait) and 80 years (both inclusive) who had tested positive for SARS-CoV-2 by real-time Reverse Transcriptase Polymerase Chain Reaction (rRT-PCR) assay on a nasopharyngeal or oropharyngeal swab, were clinically assessed to have moderate or severe COVID-19 and were hospitalized for management. Sex as a biological variable Other main exclusion criteria were patients who had allergy or contraindication to the drug, pregnant and lactating mothers, and patients with congestive cardiac failure, moderate to severe hepatic dysfunction or renal failure, alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels > 5 times upper limit of normal (ULN) at screening evaluation, serum uric acid higher than the ULN at screening evaluation, those with history of gout or were on current treatment for gout. Randomization This was a prospective, interventional, multicentre, randomised (1:1), double-blind, placebo-controlled, parallel design phase 3 trial to evaluate the efficacy, safety and tolerability of favipiravir (FPV) with supportive care (SoC) in comparison to placebo with SoC in the acute treatment of hospitalized patients who tested positive for SARS-CoV-2 and presented with moderate to severe COVID-19. Blinding not detected. Power Analysis Statistical Methods: Inequality testing of the hazard ratio using the Cox proportional hazards (CPH) regression model with 371 subjects in Favipiravir group and 371 subjects in Placebo group achieved 80% power at the 0.05 significance level for an actual hazard ratio of 1.25 assuming the hazard ratio is 1 under the null hypothesis and that the total number of events achieved is 631. Table 2: Resources
Software and Algorithms Sentences Resources The SAS® package, Version 9.4, was used for statistical evaluation. SAS®suggested: (SASqPCR, RRID:SCR_003056)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Despite the limitation, the present study showed trends suggesting that FPV is associated with better clinical outcomes in some subgroups of patients (younger age, lower BMI, and lower baseline clinical risk based on NEWS-2) with tolerability and safety of FPV being comparable to placebo.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04529499 Active, not recruiting Clinical Trial Evaluating the Efficacy and Safety of Favipir… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a protocol registration statement.
Results from scite Reference Check: We found no unreliable references.
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