key: cord-0875888-07k4j6og
authors: Udwadia, Zarir F.; Singh, Pawan; Barkate, Hanmant; Patil, Saiprasad; Rangwala, Shabbir; Pendse, Amol; Kadam, Jatin; Wu, Wen; Caracta, Cynthia F.; Tandon, Monika
title: Efficacy and Safety of Favipiravir, an Oral RNA-Dependent RNA Polymerase Inhibitor, in Mild-to-Moderate COVID-19: A Randomized, Comparative, Open-Label, Multicenter, Phase 3 Clinical Trial
date: 2020-11-16
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.11.142
sha: 7c8987a6956a0f892c6d14619061592131b858c4
doc_id: 875888
cord_uid: 07k4j6og

Objective To assess efficacy and safety of favipiravir in adults with mild-to-moderate COVID-19. Methods In this randomized, open-label, parallel-arm, multicenter, Phase 3 trial, adults (18-75 years) with RT-PCR-confirmed COVID-19 and mild-to-moderate symptoms (including asymptomatic) were randomized 1:1 to oral favipiravir (Day 1: 1800 mg BID; Days 2-14: 800 mg BID) plus standard supportive care versus supportive care alone. The primary endpoint was time to cessation of viral shedding; time to clinical cure also was measured. Results From May 14-July 3, 2020, 150 patients were randomized to favipiravir (n = 75) or control (n = 75). Median time to cessation of viral shedding was 5 days (95% CI: 4 days, 7 days) versus 7 days (95% CI: 5 days, 8 days),P = 0.129, and median time to clinical cure was 3 days (95% CI: 3 days, 4 days) versus 5 days (95% CI: 4 days, 6 days), P = 0.030, for favipiravir and control, respectively. Adverse events were observed in 36% of favipiravir and 8% of control patients. One control patient died due to worsening disease. Conclusion Lack of statistical significance on the primary endpoint was confounded by limitations of the RT-PCR assay. Significant improvement in time to clinical cure suggests favipiravir may be beneficial in mild-to-moderate COVID-19.

A novel coronavirus (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2), emerged in late December 2019, resulting in the ongoing worldwide COVID-19 pandemic. 1, 2 As of September 25, 2020, the Johns Hopkins University COVID-19 global dashboard reports 32,390,204 confirmed cases and 985,302 deaths worldwide attributed to SARS-CoV-2. 3 Numerous antivirals, immunotherapies, and vaccines are being investigated to combat this global health crisis; however, to date, few have demonstrated efficacy in randomized, controlled clinical trials for the treatment or prevention of COVID-19. 1, 4, 5 Favipiravir is an RNA-dependent RNA polymerase (RdRp) inhibitor approved for the treatment of novel influenza viruses in Japan and China and exhibits antiviral activity across a wide range of RNA viruses. 4, [6] [7] [8] Since SARS-CoV-2 is a positive-sense, single-stranded RNA virus, RdRp represents a relevant target for the known mechanism of action of favipiravir. 9 Only a few favipiravir efficacy trials in COVID- 19 have been reported in the literature to date, including two comparative trials in which favipiravir showed an advantage over other antivirals. [10] [11] [12] [13] [14] Numerous other favipiravir COVID-19 trials are ongoing or as yet unreported. 15 Initial reports from China suggested that >80% of those infected with SARS-CoV-2 will experience mild or moderate disease, 16 

This was a randomized, open-label, parallel-arm, multicenter, Phase 3 study to evaluate the efficacy and safety of oral favipiravir combined with standard supportive care in adults with mildto-moderate COVID-19 (CTRI/2020/05/025114; 7 sites in India). The protocol (appendix) and informed consent form were approved by institutional/independent ethics committees and the Drugs Controller General of India (April 26, 2020). The trial was undertaken in accordance with current guidelines of the Central Drugs Standard Control Organization, which is the National Regulatory Authority in India, 17 

Practice, and the Declaration of Helsinki. Written informed consent followed study explanation to patients before screening procedures or assessments.

The study consisted of screening (Day -3 to Day 0), baseline/randomization (Day 1) at which standard supportive care was provided to all patients, and a treatment period (Day 1 up to a maximum of 14 days). Study participation was a maximum of 28 days from the day of randomization.

Patient care beyond Day 14 was provided as per investigator judgment.

Patients were randomized in a 1:1 ratio to oral favipiravir (1800 mg BID loading dose on Day 1; 800 mg BID maintenance dose thereafter) plus standard supportive care for up to a maximum of 14 days or standard supportive care alone (the control arm) that included antipyretics, cough suppressants, antibiotics, and vitamins. Drugs thought to have antiviral activity against SARS CoV-2 (including hydroxychloroquine) were prohibited. The randomization was stratified based on baseline disease severity into mild and moderate COVID-19. Patients were assigned to stratified randomized treatments based on a central, computer-generated randomization scheme coordinated J o u r n a l P r e -p r o o f by an independent third party. All subjects were hospitalized per prevailing treatment guidelines and to allow daily RT-PCR testing, and were discharged only after 2 consecutive negative SARS-CoV-2 tests and clinical cure were achieved.

The study population comprised patients admitted to the hospital with mild (including asymptomatic) to moderate COVID-19. Key inclusion criteria were age 18-75 years, infection with SARS-CoV-2 virus confirmed by RT-PCR within 48 hours prior to randomization, no participation in any other interventional clinical study, agreement to use effective contraception during the study and for ≥7 days following the last treatment, and, for female patients of child-bearing potential, a negative pre-treatment pregnancy test.

The time from symptom onset to randomization was to be no more than 7 days for mild disease and 10 days for moderate disease. Additional criteria to guide investigator assessment of mild disease severity included pyrexia (temperature <102.2°F), respiratory rate 12 to ≤20 breaths/min, and ≤4 of the following symptoms of mild severity (defined as symptoms not requiring any or minimal therapeutic intervention) and ≤2 of the following symptoms of moderate severity (defined as symptoms which produce small impairment of function and require some form of therapeutic intervention): cough, sore throat, headache, nasal congestion, body aches and pains, and fatigue. Additional criteria for moderate cases included pneumonia vasopressor support), oxygen saturation ≤93% or arterial oxygen partial pressure or fraction of inspired oxygen of ≤300 mmHg, requiring ICU care for management of ongoing clinical status, inability to take or tolerate oral medications, allergy or hypersensitivity to favipiravir, asthma or chronic obstructive lung disease, severe liver disease (underlying liver cirrhosis or alanine aminotransferase/aspartate aminotransferase elevated over 5 times the upper limit of normal [ULN] ), history of gout or hyperuricemia (above the ULN), prolonged QT (defined as QTcF ≥450 msec for men and as QTcF ≥470 msec for women), severely reduced left ventricular function (ejection fraction <30%), or severe renal impairment (creatinine clearance <30 mL/min), or having received continuous renal replacement therapy, hemodialysis or peritoneal dialysis. Prohibited concomitant medications included hydroxychloroquine or chloroquine, pyrazinamide, repaglinide, theophylline, and famciclovir or sulindac.

The pre-specified primary endpoint was time from randomization to cessation of oral shedding of the SARS-CoV-2 virus (28-days maximum; specified as a negative RT-PCR result for both oropharyngeal and nasopharyngeal swabs). SARS-CoV-2 RT-PCR on both oropharyngeal and nasopharyngeal swabs was performed at screening, daily during Days 2-28 until 2 consecutive negative results were achieved, and at hospital discharge.

Pre-specified secondary endpoints included time to clinical cure for patients who presented with clinical signs and symptoms at baseline. Clinical cure was based on clinician assessment and defined as recovery of fever (axillary temperature ≤97.8°F), respiratory rate of ≤20 breaths/minute, oxygen saturation ≥98% without oxygen supplementation (which was later revised to align with the discharge criterion of ≥95% oxygen saturation issued by the Indian J o u r n a l P r e -p r o o f Ministry of Health prior to the start of the study), and cough relief (mild or no cough) maintained for ≥72 hours.

Additional secondary time-to-event endpoints were time to first use of high flow supplemental oxygen, ventilation (non-invasive or mechanical), or ECMO, and time to hospital discharge. Hospital discharge was dependent on achieving both RT-PCR negativity on 2 consecutive tests and maintaining clinical cure for ≥72 hours. Rates of clinical cure and SARS-CoV-2 RT-PCR negativity at Days 4, 7, 10, and 14 also were assessed.

Clinical symptoms and vital sign parameters were assessed twice daily on Days 1-28.

Laboratory assessments (including hematology, chemistry, and urinalysis) were performed at screening, throughout the study as warranted per standard management for COVID-19, and at day of hospital discharge. Safety was assessed by frequency of serious adverse events (SAEs), and treatment emergent adverse events (TEAEs) were recorded.

Based on the hazard ratio of 3.434 reported in a favipiravir COVID-19 trial (Cai et al 2020), 10 a total of 28 viral clearance events assessed by RT-PCR negativity would need to be observed to obtain 90% power; therefore, a sample size of 40-100 patients would be required in each of the mild and moderate populations. In accordance with regulatory recommendations, 90 subjects were to be enrolled in the mild subgroup and 60 subjects were to be enrolled in the moderate subgroup. Statistical analyses were performed with SAS 9.4 version or the latest available (SAS Institute Inc., Cary, North Carolina).

Efficacy analyses used the intent-to-treat (ITT) population, defined as all randomized patients who received ≥1 treatment and had ≥1 post-baseline efficacy assessment. Safety J o u r n a l P r e -p r o o f analyses used the safety population, defined as all randomized patients who received any amount of study treatment (favipiravir or standard supportive care alone).

The primary endpoint and secondary endpoints assessing time to event were analyzed using the Kaplan-Meier method and log-rank test, as well as by Cox regression analysis. In the Cox model, time to event was set as the time variable, censoring was set as the status, and the variables, including age, treatment, and baseline co-morbidity were set as independent variables.

Secondary endpoints assessing categorical variables were analyzed using the chi-square or Fisher's exact test. A priori defined subgroup analyses for primary and secondary endpoints were done based on COVID-19 disease severity using the Kaplan-Meier method, log-rank test, and Cox regression analysis. Censoring was used to handle missing data in which time to event was not observed. Patients terminating the study without a documented event were censored at Day 28 to avoid bias in favor of either treatment group. Patients who died without a documented event were censored at Day 28 or date of death, whichever was later.

Safety data were summarized descriptively.

The study was conducted between May 14 and July 3, 2020; 150 patients were enrolled and randomized to favipiravir in addition to standard supportive care (n=75) or a control group with standard supportive care alone (n=75), Figure 1 . Two patients randomized to favipiravir did not receive study drug and were excluded from the safety population (n=148). An additional patient randomized to favipiravir did not have a post-baseline efficacy assessment and was excluded from the ITT population (n=147). Among patients in the ITT population, 70/72 randomized to J o u r n a l P r e -p r o o f favipiravir and 68/75 randomized to control completed the study. The most common reason for study discontinuation was withdrawal of consent (n=10) (Figure 1 ).

Baseline demographic and clinical characteristics were generally similar between favipiravir and control groups ( Table 1) Table 2 ).

Among patients requiring supportive oxygen therapy, median time to first use was 5 days (95% CI: 1 day, 6 days) in the favipiravir group (n=7) compared with 2 days (95% CI: 1 day, 4 days) J o u r n a l P r e -p r o o f in the control group (n=7), P=0.065; the Cox proportional hazard ratio of 0.065 (95% CI: 0.005, 0.809) was statistically significant (P=0.034; Table 2 ). A total of 97.2% (70/72) and 90.7% (68/75) of patients in the favipiravir and control groups, respectively, met criteria for hospital discharge within 28 days. Median time to hospital discharge was 9 days (95% CI: 7 days, 10 days) for favipiravir compared with 10 days (95% CI: 8 days, 12 days) for control (P=0.108; Table 2 ).

Among those in the ITT population with COVID-19 clinical symptoms at baseline, the proportion of patients in the favipiravir treatment group who achieved clinical cure at Days 4, 7, 10, and 14 was numerically higher at all timepoints compared with the control group, but the difference was statistically significant only at Day 4 ( Figure 3A) . Similarly, the proportion of patients in the favipiravir treatment group who achieved cessation of oral shedding of the SARS-CoV-2 virus as measured by negative RT-PCR in both oropharyngeal and nasopharyngeal swab at Days 4, 7, 10, and 14 was numerically higher at all timepoints compared with the control group, but did not reach statistical significance at any timepoint ( Figure 3B) .

Results of exploratory subgroup analyses by disease severity are shown in Table 3 . Briefly, analyses of time to cessation of viral shedding, time to clinical cure, and time to hospital discharge numerically favored favipiravir compared with control in all cases, regardless of baseline disease severity; however, only the analysis of time to clinical cure in patients with moderate disease at baseline achieved statistical significance ( (Table 4 ). The most common TEAEs that occurred in a higher proportion of patients treated with favipiravir compared with control were increased blood uric acid in 12/73 (16.4%), abnormal liver function tests in 5/73 (6.8%), and viral pneumonia in 2/73 (2.7%); all were considered mild (20/26) or moderate (6/26) in severity. Most (21/26) were considered related to treatment, while viral pneumonia (2/26) was related to the underlying infection. The most commonly reported TEAEs in the control group were abnormal liver function tests and gastrointestinal disorders, which occurred in 2 patients each (2.7%) and were considered mild in severity. One patient in the control group experienced an SAE, acute respiratory distress syndrome, which led to death and was not considered related to treatment but rather to worsening of COVID-19.

The present study evaluted the potential clinical benefit of favipiravir in patients with mild-tomoderate COVID-19 based on its oral administration, established use for novel influenza viruses, well-characterized safety profile, activity against RdRp of SARS-CoV-2, and promising efficacy in treating COVID-19 as reported from other countries, including China, Russia, Turkey, and Japan. [10] [11] [12] [13] [14] 18, 19 In this study, the primary endpoint of median time to RT-PCR negativity was 28.7% earlier for favipiravir plus standard supportive care compared with supportive care alone (5 days vs 7 days), consistent with median time to viral clearance of 4 days reported in an earlier favipiravir study in moderate COVID-19 patients also receiving interferon-α, 10 and with findings from a recent study in patients with mild COVID-19 suggesting that early treatment with favipiravir may J o u r n a l P r e -p r o o f be associated with more rapid viral clearance. 12 However, the median time to viral clearance in the control group of the present study was shorter (7 days) than in the study by Cai et al., (11 days) 10 and also shorter than that reported more widely for COVID-19 patients (12 to 20 days). 20

While a statistically significant difference in the primary endpoint was not achieved, statistically significant results were observed on the clinically meaningful secondary endpointof time to clinical cure. There also was a statistically significant difference in time to first use of oxygen, although this observation must be interpreted with utmost caution because of the small number of patients (7 in each treatment group) who required supplemental oxygen suppport in this population. In addition, when evaluating by COVID-19 severity, patients with moderate COVID-19 showed a statistically significant benefit with respect to time to clinical cure. The median time to clinical cure of 3 days in the favipiravir group was 40% faster than in the control arm (5 days) and within the range considered clinically relevant for antiviral therapy. 10-day course of remdesivir did not show a significant difference. 29 Remdesivir is intravenously administered and at this time reserved for more severely ill, hospitalized patients. Patients enrolled in the current study were hospitalized both per prevailing treatment guidelines and to enable daily RT-PCR testing to evaluate time to cessation of oral shedding of the SARS-CoV-2 virus. However, the relatively rapid time to RT-PCR negativity and clinical cure observed in both the favipiravir and control groups suggest that the population we studied -those who are mildly to moderately ill -could well be treated as outpatients. Availability of an effective oral antiviral like favipiravir would allow for earlier administration in patients who are mildly to moderately symptomatic but not severely ill requiring hospitalization. Availability of an oral medication is also expected to improve patient compliance and reduce burden on already stressed healthcare systems.

Favipiravir was found to be safe and well tolerated in this study, despite the potential bias for overreporting of TEAEs in open-label trials. There were no new safety signals, and no adverse events that led to drug discontinuation or change in dosing regimen; a single patient in the control group experienced an SAE, acute respiratory distress syndrome, which led to death. The majority of adverse events were mild to moderate, and the most commonly observed events There are limitations to this study. As previously discussed, the primary endpoint was confounded by interpretation issues with RT-PCR positivity and its lack of correlation with clinical cure. 26,27 Furthermore, the impact of RT-PCR assay variables such as cycle time was not evaluated in the current study, and it is not known how such factors may have influenced the results.

Additionally, the hazard ratios observed in this trial were much smaller than reported by Cai et al., 10 which had been used for sample size estimation. Thus, a larger sample size may have been required to have sufficient power to detect statistically significant differences between treatment groups. The open-label design of the current study is another limitation, particularly as some of the secondary endpoints rely on clinician assessment and are therefore subject to potential bias. Although the trial was conducted open-label, rather than double-blind and placebo-controlled, precautions were taken to reduce bias associated with the design. The primary endpoint, for example, was an objective measure (RT-PCR negativity), and allocation to treatment groups was randomized and conducted centrally by an independent third party to avoid selection bias.

In conclusion, the results of this study suggest that despite failure to achieve statistical significance on the primary endpoint of time to RT-PCR negativity, early administration of oral 

This study was sponsored and funded by Glenmark Pharmaceuticals Limited, India.

The protocol and informed consent form were approved by institutional/independent ethics committees and the Drugs Controller General of India (April 26, 2020). The trial was undertaken ITT, intent-to-treat. The ITT population excluded 2 subjects with no drug intake (favipiravir arm) and 1 subject with no post baseline efficacy assessment (favipiravir arm). The favipiravir arm received treatment with favipiravir + standard supportive care; the control arm received standard supportive care alone. Kaplan-Meier was used to estimate the median duration of time-to-event and 95% confidence intervals. The two treatment groups were compared using a log-rank test to estimate the P value. The hazard ratio of favipiravir/control and the corresponding P value were computed based on the Cox regression model with co-variates of age, treatment and baseline co-morbidity. Subjects who terminated the study without documented event were censored at Day 28. Subjects who died without documented event were censored at Day 28 or the date of death, whichever was later. Analyses of time to clinical cure and time to first use of supplemental oxygen included, respectively, only patients who were symptomatic at baseline and patients who required use of supplemental oxygen. ; subjects who terminated the study without documented event were excluded. Because most of the subjects did not require oxygen support, the censoring rate was too high for Kaplan-Meier analysis to estimate the median time-to-event; therefore, only results from non-censored data are presented for this endpoint. The safety population excluded 2 subjects with no drug intake (favipiravir arm). The favipiravir arm received treatment with favipiravir + standard supportive care; the control arm received standard supportive care alone. a An SAE (acute respiratory distress syndrome) was reported in 1 subject in the control group, and death due to SAE was reported in this same subject, which was considered to be not related to treatment.

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The authors declare the following financial interests/personal relationships which may be considered as ITT, intent-to-treat. The ITT population excluded 2 subjects with no drug intake (favipiravir arm) and 1 subject with no post baseline efficacy assessment (favipiravir arm). The favipiravir arm received treatment with favipiravir + standard supportive care; the control arm received standard supportive care alone. Kaplan-Meier was used to estimate the median duration of time-to-event and 95% confidence intervals. The two treatment groups were compared using a log-rank test to estimate the P value. The hazard ratio of favipiravir/control and the corresponding P value were computed based on the Cox regression model with co-variates of age, treatment and baseline co-morbidity. Subjects who terminated the study without documented event were censored at Day 28. Subjects who died without documented event were censored at Day 28 or the date of death, whichever was later.a Only patients with clinical signs and symptoms at baseline and were included in this analysis. b Because most of the subjects did not require oxygen support, the censoring rate is too high to run Kaplan-Meier analysis to estimate the median time-to-event; therefore, only results from non-censoring data were presented for this endpoint. ITT, intent-to-treat. The ITT population excluded 2 subjects with no drug intake (favipiravir arm) and 1 subject with no post baseline efficacy assessment (favipiravir arm). The favipiravir arm received treatment with favipiravir + standard supportive care; the control arm received standard supportive care alone. Kaplan-Meier was used to estimate the median duration of time-to-event and 95% confidence intervals. The two treatment groups were compared using a log-rank test to estimate the P value. The hazard ratio of favipiravir/control was computed based on the Cox regression model with co-variates of age, treatment and baseline co-morbidity. Subjects who terminated the study without documented event were censored at Day 28. Subjects who died without documented event were censored at Day 28 or the date of death, whichever was later. a Only patients with clinical signs and symptoms at baseline and were included in this analysis.