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

Abstract

AimTo assess the efficacy and safety of favipiravir in adults with moderate to severe coronavirus disease 2019 (COVID-19).MethodsIn 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.ResultsIn 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.ConclusionThe 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.

The efficacy and adverse effects of favipiravir on patients with COVID-19: A systematic review and meta-analysis of published clinical trials and observational studies

“…We performed meta-analysis for 16 RCTs ( Balykova et al, 2020a ;Balykova et al, 2020b ;Balykova et al, 2020c ;Bosaeed et al, 2021 ;Chen et al, 2020a ;Chuah et al, 2021 ;Doi et al, 2020 ;Finberg et al, 2021 ;Ivashchenko et al, 2021 ;Pushkar, 2020 ;Ruzhentsova et al, 2021 ;Shenoy et al, 2021 ;Shinkai et al, 2021 ;Solaymani-Dodaran et al, 2021 ;Tabarsi et al, 2021 ;Udwadia et al, 2021 ) and 1 non-RCTs ( Cai et al, 2020 ), which studied the effect of favipiravir on hospitalized patients. The baseline characteristics of the controlled trials can be found in Supplemental Table 3.…”

Comparison of Preprint Postings of Randomized Clinical Trials on COVID-19 and Corresponding Published Journal Articles

“…After abstract screening and full-text reading, 152 RCTs were included in the analysis. All 152 RCTs were posted on the medRxiv server …”

Japanese rapid/living recommendations on drug management for COVID‐19: updated guidelines (July 2022)

“…The inaccuracies in the net effect estimate across all outcomes were "Net benefit" in mild COVID-19 and "Likely net benefit" in moderate/severe COVID-19. From the above, it was ultimately determined that the overall evidence certainty was "low" in mild COVID- 19 Background Sotrovimab is a monoclonal antibody that binds to a specific site different from the ACE2 receptor on the SARS-CoV-2 spike protein, exhibiting a neutralizing effect on SARS-CoV-2. The drug targets a highly conservative epitope shared by SARS-CoV-2 and SARS-CoV-1, which is inconsistent with the site of a genetic mutation previously reported in the mutant strain.…”

“…There were 11 RCTs 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 with adopted evidence. Point estimates were not expected to have a clinically meaningful effect on clinical improvement at 28 days (an increase of 14 per 1,000).…”

“…Key words: Coronavirus, GRADE approach, MAGICapp, practice guideline, SARS-CoV-2 BACKGROUND C ORONAVIRUS DISEASE 2019 (COVID- 19), an infectious disease caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that developed at the end of 2019, has spread worldwide since the beginning of 2020, and there are still no signs of resolution. Initially, COVID-19 severely affected some elderly individuals and those with underlying diseases, and its lethal course became a socially critical problem.…”