key: cord-0958844-9asam4p8
authors: Shenoy, S.; Munjal, S.; Al Youha, S.; Alghounaim, M.; Almazeedi, S.; Alshamali, Y.; Kaszynski, R. H.; Al-Sabah, S. K.; Group, Kuwait Clinical Trial
title: Favipiravir In Adults with Moderate to Severe COVID-19: A Phase 3 Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial.
date: 2021-11-09
journal: nan
DOI: 10.1101/2021.11.08.21265884
sha: 6084713e3274140fa7085bb16d107980f6791f96
doc_id: 958844
cord_uid: 9asam4p8

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.

C l i e n t C o n f i d e n t i a l

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.

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The coronavirus disease 2019 (COVID- 19) pandemic has highlighted the need for safe and effective anti-viral treatments. This is particularly true for 'high risk' patient groups, such as the elderly and patients with underlying co-morbidities, who are more likely to experience poor outcomes from COVID-19 [1, 2] . Despite large scale vaccination efforts worldwide, a significant portion of the global population remain unvaccinated due to supply shortages and general vaccine hesitancy [3] . In addition, the emergence of variants such as Delta (B.1.617.2) continue to pose a threat owing to higher transmissibility, disease severity and ability to evade immune response elicited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination [4] .

A wide array of therapeutic agents are currently undergoing clinical trials including many repurposed antiviral drugs [5] . Favipiravir, an antiviral drug approved in Japan in 2014 to treat novel or re-emerging influenza virus infections, was evaluated as a potential therapeutic option during the COVID-19 pandemic. Favipiravir has also been employed in the treatment of Ebola during the 2014 epidemic and additional indications include severe fever with thrombocytopenia virus, rabies, Lassa fever, Jamestown Canyon virus, and norovirus [6] [7] [8] . The convenience of being an orally administered low-cost therapeutic, along with its inherent thermostability make the drug an appealing candidate for COVID-19 treatment, especially in low-income countries with limited access to novel vaccines and therapeutics.

Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is an anti-viral agent that selectively and potently inhibits the RNA-dependent RNA polymerase (RdRp) of RNA viruses. [6] An in-vitro study demonstrated that favipiravir effectively inhibits the SARS CoV-2 infection in Vero E6 cells (ATCC-1586). An optimal dosing regimen was derived based on the in-vitro study findings and prior clinical trial experience [9, 10] .

Though several anecdotal reports and observational studies have reported a positive trend for Favipiravir in hospitalized moderate to severe COVID-19 patients, none of these studies were double-blinded or adequately powered. The present study is a double-blind, placebo-controlled, phase 3 using Favipiravir administered in 1800/800 mg doses with a 10-day dosing regimen in [8] [9] [10] [11] [12] .

This was a prospective, interventional, multicentre, randomised NCT04529499.

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. Patients that agreed to participate in the study signed an informed consent statement. Critically ill patients and patients who had first onset of symptoms/signs suggestive of COVID-19 illness >10 days before randomization were excluded from the study.

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.

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or 'low-medium' baseline NEWS-2 clinical risk categories) and 'higher' risk subgroup (which consists of patients in 'medium' or 'high' risk NEWS-2 categories) in this report.

Compliance to study treatment was assessed daily when the patients were hospitalized. For patients who were discharged before the end of treatment period (Day 10), the compliance was assessed based on the details in the investigational medicinal product (IMP) accountability log/patient diary and the empty blister packs and/unused IMP.

The study's primary objective was to evaluate the efficacy of oral FPV in improving the time to resolution of hypoxia. The study's secondary objectives were to evaluate the efficacy of oral FPV on clinical and virological outcomes in moderate to severe COVID-19 patients and to assess the safety and tolerability of FPV [14] .

Time to resolution of hypoxia, the primary endpoint of this study, was considered to have been met when the patient had attained a score of 4 or lower on the WHO 10-point ordinal scale of clinical status (and either had a score ≤ 4 on consecutive assessments over the next 5 days if patient continued to remain in hospital, or the patient was discharged before five consecutive assessments after reaching a score of 4 and the patient had survived and had not been readmitted to hospital for COVID-19 management till Day 28).

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. Based on the above assumption and considering the dropout rate to be 5% overall, 390 patients were to be randomized in each treatment group. Sample size re-estimation was provisioned at interim analysis.

The continuous endpoints were summarized using descriptive statistics and categorical data were summarized using counts and percentages. Unadjusted between-treatment comparisons were made using Fisher's exact test (binary variables), Chi-square test (multi-categorical variables), Student's t-test (continuous variables), and Kaplan-Meier estimates / log-rank test (time to event . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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variables). The primary endpoint, time to resolution of hypoxia, was compared between the treatment groups using the Cox proportional hazards model with age and gender as covariates.

Two-sided p-values of less than 0.05 were considered statistically significant. The SAS ® package, Version 9.4, was used for statistical evaluation.

A data monitoring committee (DMC), consisting of 3 members specializing in critical care and a statistician, assessed emerging safety and efficacy data from the trial and made recommendations on study continuation after a single pre-specified interim analysis.

The scheduled interim analysis was performed on the data collected for the first 349 randomized patients (patients who were enrolled before the cutoff date of 31 December 2020), including 173

in the FPV and 176 in the placebo group, and was submitted for DMC review. The DMC recommended study termination due to futility (lack of evidence for efficacy) in the pre-specified primary endpoint, time to resolution of hypoxia, and key secondary endpoints: time to hospital discharge and mortality. In all three analyses, the estimated conditional power was very low (less than 10%). [ Figure 1 ]

The two treatment groups were balanced with respect to demographic characteristics and COVID-19 disease severity and symptoms at baseline. The mean (Standard deviation, SD) age of the patients randomized in the study was 51.9 (±12.5) years. There were 144 (40.8%) patients over the age of 50 years and the majority of the patients were male [238 (67.4%)]. At baseline, . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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the median number of days since onset of first symptom(s) associated with COVID-19 was 7.0 (IQR 5.0 -7.0) in both groups.

[ 

The population for the primary endpoint analysis included patients with baseline WHO 10-point ordinal scale of clinical status score of 5 or higher and consisted of 315 patients overall, with 157 (89.7%) in FPV and 158 (88.8%) in placebo group. The population for the primary endpoint analysis was 89.2% of the ITT population included in the study.

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The median time to resolution of hypoxia was 7 days in the FPV and 8 days in placebo group, as [ Figure 2 ]

[ [ . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted November 9, 2021. [ Figure 4 ]

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Of the 25 (7.1%) deaths reported during the study, 14 (8.0%) were reported in FPV and 11 (6.2%) in placebo group (p=0.54).

Treatment emergent adverse events (TEAEs) were experienced by 62/334 (19%) patients [ . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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Overall, 2 (1%) patients experienced at least one TEAE in Stage II with, 1 (1%) patient each in the FPV and placebo groups. SAE in the FPV group was attributed to hepatobiliary disorders (chronic calculous cholecystitis) and was assessed as not related to FPV treatment.

The demand for a reliable, safe, and effective anti-viral treatment option for COVID-19 is largely unmet and continues to drive clinical research efforts. The current Phase 3 study did not find trial is ongoing to evaluate the efficacy and safety of FPV when initiated earlier in the course of COVID-19 in the outpatient setting [15] .

The risk of rapid COVID-19 progression underlines the need for earlier intervention with an effective antiviral treatment in COVID-19 [16] . After virus clearance, the group with early antiviral treatment showed milder illness than the group with late antiviral treatment. The study concluded that early antiviral treatment could effectively shorten the virus clearance time and prevent the rapid progression of COVID-19 [18] .

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The copyright holder for this preprint this version posted November 9, 2021. [22] . The current study also demonstrated favourable trends on early administration of oral FPV in patients with 'lower' NEWS-2 clinical risk category.

The adverse events reported with FPV in the current study were consistent with previous experience with the drug. There were no unexpected adverse events in the study. The fatalities reported in the study were likely attributable to progression and complications associated with COVID-19 in both groups.

In the present study, higher blood uric acid levels were reported at days 10 and 28 or upon discharge in FPV group compared to placebo group patients. In the FPV group, 5.4% reported hyperuricaemia, of which 5% were considered treatment related in the current study. This was much lower compared to the incidence of 15.5% reported in trials conducted in Japan [23] and 13.8% in Russia and China [24] . This suggests that Asian population could be more susceptible to the FPV-associated hyperuricaemia but the reasons for this remain unknown. One possibility to consider for these variations across demographics could be related to variations in the enzymatic . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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activity of aldehyde oxidase and xanthine oxidase -the key enzymes responsible for metabolizing FPV. Functionally inactive human aldehyde oxidase (hAOX1) allelic variants as well as variants encoding enzymes with different catalytic activities exist within the human population. Future investigations into these allelic variants could offer further insight into these differences [25] . To date, no evidence has emerged that FPV-associated hyperuricaemia is associated with clinical manifestations. Longer trial follow-up periods would be required to assess this risk fully [26] .

Further studies evaluating the role of FPV in treating the disease in specific population groups and disease severity categories are warranted. The study analysis faced challenges from missing data at various timepoints due to large number of discontinuations and early discharges. 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.

The trial did not find favipiravir to be effective in moderate to severe COVID-19 patients but trends in favour of favipiravir were observed in the NEWS-2 low to low-medium clinical risk subgroup for several clinically meaningful endpoints. No new or unexpected adverse events were noted. Future studies should evaluate the efficacy of the drug when administered early in the disease.

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Stage I completed include both In-person and Day 28 telephonic follow-up completed patients Stage II completed include patients who completed both days 42/60 telephonic visits . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

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Dr Reddy's Laboratories Limited

Dr Reddy's Laboratories Limited

Jaber Al Ahmad Hospital at Mishref Field Hospital, Mubarak Al-Abdullah Street, Mishref-90005

Ebisu, Shibuya-ku

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Delta coronavirus variant: scientists brace for impact

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Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase

Post-exposure efficacy of oral T-705 (Favipiravir) against inhalational Ebola virus infection in a mouse model

T-705), a novel viral RNA polymerase inhibitor

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model

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Uric Acid Elevation by Favipiravir, an Antiviral Drug

The authors would like to thank all members of the Kuwait Clinical Trial Group*, DM Rao and team from Dr. Reddy's ( Regulatory support), David He (Biostatistician), Dr Jyoti Rao (Medical writer) and Navitas Life Sciences without whom the conduct of study would not be possible.

Drs. Srinivas Shenoy and Sagar Munjal are paid employees of Dr. Reddy's Laboratories and didn't receive any additional compensation for this study.Dr Salman Al-Sabah was the Principal Investigator and National Co-Ordinator (Kuwait) for the trial, while Drs. Sarah Al Youha, Mohammad Alghounaim, Sulaiman Almazeedi and Yousef Alshamali were sub-Investigators. The Investigators and sub-investigators are employees of various public sector hospitals in the State of Kuwait and did not receive any financial compensation for this study.Dr Richard H Kaczynski is a consultant to Fujifilm Toyoma Chemical Co. Ltd. and Chief Medical Officer of AiPharma. He contributed significantly to study design and did not receive any additional compensation for this study.