key: cord-0929935-q2tk3eui
authors: Bosaeed, Mohammad; Alharbi, Ahmad; Mahmoud, Ebrahim; Alrehily, Sanaa; Bahlaq, Mohannad; Gaifer, Zied; Alturkistani, Hanan; Alhagan, Khaled; Alshahrani, Saad; Tolbah, Ali; Musattat, Abrar; Alanazi, Maha; Jaha, Raniah; Sultana, Khizra; Alqahtani, Hajar; Al Aamer, Kholoud; Jaser, Saud; Alsaedy, Abdulrahman; Ahmad, Ayoub; Abalkhail, Mohammed; AlJohani, Sameera; Al Jeraisy, Majed; Almaziad, Sultan; Albaalharith, Nahlah; Alabdulkareem, Khaled; Alshowair, Abdulmajeed; Alharbi, Naif Khalaf; Alrabiah, Fahad; Alshamrani, Majid; Aldibasi, Omar; Alaskar, Ahmed
title: Efficacy of favipiravir in adults with mild COVID-19: a randomized, double-blind, multicenter, placebo-controlled trial clinical trial
date: 2022-01-11
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2021.12.026
sha: 8430db44f57439aaa3bd879e80b68983603a3441
doc_id: 929935
cord_uid: q2tk3eui

OBJECTIVE: To evaluate whether favipiravir reduces the time to viral clearance as documented by negative SARS-CoV-2 RT-PCR in mild COVID-19 cases compared to placebo. METHODS: In this randomized, double-blinded, multicenter, and placebo-controlled trial, adults with PCR confirmed mild COVID-19 were recruited in an outpatient setting at seven medical facilities across Saudi Arabia. Participants were randomized in a 1:1 ratio to receive either favipiravir 1800 mg by mouth twice daily on day one followed by 800 mg twice daily (n=112) or a matching placebo (n=119), for a total of 5 to 7 days. The primary outcome was the effect of favipiravir on reducing the time to viral clearance (by PCR test) within 15 days of starting the treatment compared to the placebo group. The trial included the following secondary outcomes: symptom resolution, hospitalization, ICU admissions, adverse events, and 28-day mortality. RESULTS: 231 patients were randomized and began the study (median age, 37 [interquartile range: 32-44] years; 155 [67%] men), and 112 (48.5%) were assigned to the treatment group and 119 (51.5%) into the placebo group. The data and safety monitoring board (DSMB) recommended stopping enrollment because of futility at the interim analysis. The median time to viral clearance was 10 (IQR: 6-12) days in the favipiravir group and 8 (IQR: 6-12) days in the placebo group, with a hazard ratio of 0.87 for the favipiravir group (95% CI 0.571 to 1.326; p-value =0.51). The median time to clinical recovery was 7 days (IQR: 4-11) in the favipiravir group and 7 days (IQR: 5-10) in the placebo group. There was no difference between the two groups on the secondary outcome of hospital admission. There were no drug-related severe adverse events. CONCLUSION: In this clinical trial, favipiravir therapy in mild COVID-19 patients did not reduce the time to viral clearance within 15 days of starting the treatment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier (NCT04464408): https://clinicaltrials.gov/ct2/show/NCT04464408.

a matching placebo (n=119), for a total of 5 to 7 days. The primary outcome was the effect of 48 favipiravir on reducing the time to viral clearance (by PCR test) within 15 days of starting the 49 treatment compared to the placebo group. The trial included the following secondary outcomes: 50 symptom resolution, hospitalization, ICU admissions, adverse events, and 28-day mortality. with a hazard ratio of 0.87 for the favipiravir group (95% CI 0.571 to 1.326; p-value =0.51). The 57 median time to clinical recovery was 7 days (IQR: 4-11) in the favipiravir group and 7 days 58 (IQR: 5-10) in the placebo group. There was no difference between the two groups on the 59 secondary outcome of hospital admission. There were no drug-related severe adverse events.

As of December 20, 2021, COVID-19 has affected more than 275 million people worldwide and caused 84 nearly five million deaths. 1 Since the WHO has declared COVID-19 as pandemic, researchers have 85 studied potential effective therapies. 2, 3, 4, 5, 6 Favipiravir is an RNA-dependent RNA polymerase (RdRp) 86 inhibitor with activity against influenza virus. It has also shown activity to block the replication of other 87 RNA viruses. 7,8 SARS-CoV-2 is a positive-sense single-strand RNA virus, making its RdRp a potential 88 target that favipiravir can block. 9 Favipiravir showed promising results in mild to moderate COVID-19 89 patients in earlier studies 10-12 and has been listed as a possible treatment in different regimen protocols for 90 mild to moderate COVID-19 cases by various health regulators and agencies. 13 

The trial enrolled patients from seven community medical centers and ambulatory care centers in Saudi 98

Arabia. The trial was sponsored by King Abdullah International Medical Research Center (KAIMRC). 99

Ethical approval was obtained from the Institutional Review Board (IRB) at the Ministry of National 100

Guard-Health Affairs (MNGHA) and the Ministry of Health (MOH). The trial was overseen by an 101 independent data and safety monitoring board (DSMB). The trial was conducted in accordance with the 102

Patients were randomized in a 1:1 ratio to oral favipiravir or placebo. The randomization schedule was 105 generated using the PLAN Procedure (SAS) with a block size of four, stratified by study site. The 106 generated list was embedded in the Research Electronic Data Capture (REDCap) system to ensure 107 allocation concealment. Participants, investigators, and study staff remained unaware of the treatment 108 assignment. The Sponsor's investigational drug unit, which is not part of the study team, held the 109 information for treatment allocation. 110

The study population was patients, aged 18 years and above, from community settings diagnosed with 112 mild COVID-19 (confirmed by positive PCR test for SARS2-CoV), and were enrolled within 5 days of 113 disease onset. Mild COVID-19 case defined as a patient with mild illness (with or without respiratory 114 symptoms), oxygen saturation >94% at room air, and can be managed at home with appropriate therapy. 115

Mild illness can include symptoms of uncomplicated upper respiratory tract viral infection such as fever, 116 fatigue, cough (with or without sputum production), anorexia, malaise, muscle pain, sore throat, dyspnea, 117 nasal congestion, or headache. Rarely, patients may also present with diarrhea, nausea, and vomiting. 118

Key exclusion criteria included hospitalized moderate or severe COVID-19 cases, pregnant or 119 breastfeeding females, those who used favipiravir or participated in other interventional drugs clinical 120 study within 30 days prior to the first dose of the study treatment. The exclusion criteria also included 121 major comorbidities such as hematologic malignancy, advanced (stage 4-5) chronic kidney disease 122 (including dialysis therapy), severe liver damage (Child-Pugh score C or AST> 5 times the upper limit), 123

HIV. Patients with history of gout or hyperuricemia (two times above the upper limit of normal), patients 124 with sensitivity/allergy to favipiravir, and cases with clinical prognostic non-survival, palliative care, or in 125 a deep coma were also excluded. 126

Study subjects were randomized to either receive favipiravir 1800 mg (9 tablets) twice daily as a loading 128 dose on day one followed by 800 mg (4 tablets) twice daily as a maintenance dose for a total duration of 5 129 to 7 days of therapy or matching placebo. Follow-up was started on the second day of enrollment by a 130 research coordinator or a study physician through daily phone calls for 14 days or until reaching 131 secondary endpoints. The follow-up also assessed subjects' compliance, health status, and clinical 132 symptoms. A final follow-up phone call was subsequently conducted on day 28 for all patients. Patients 133 were required to visit study sites on days 5±1 day, 10±1 day, 15±2 days for nasopharyngeal/ 134 oropharyngeal swabs and blood tests. The swabs were used for detecting SARS-CoV-2 by the Reverse 135

Transcriptase polymerase chain reaction (RT-PCR) to document the time of viral clearance (negative 136 PCR) or viral infection persistence (positive PCR). 137

The primary endpoint of this study was time from start of treatment to viral clearance defined as the 140 conversion of SARS-CoV-2 RT-PCR from positive to negative within 15 days as described in procedures. 141

Prespecified secondary endpoints included time from the start of treatment (favipiravir or placebo) to 142 clinical recovery with normalization of fever, respiratory symptoms, and relief of cough (or other relevant 143 symptoms at enrollment) that is maintained for at least 72 hours, need to use antibiotics within 15 days 144 after starting the medicine, progression of disease in a 28-day period including hospitalization, ICU 145 admissions with or without ventilation requirements, and 28-day mortality. Additional secondary safety 146 endpoints included the occurrence of allergic reactions, medication intolerance, and liver toxicity in 147 subjects within 15 days of taking the study drug. 148

A one-sided test of whether the hazard ratio HR is 1 with an overall sample size of 576 subjects (288 are 150 in the control group and 288 in the treatment group) achieve 90% power at a 0.025 significance level 151 when the HR is 1.330. An interim analysis was planned once after the recruitment and follow-up of 40% 152 of the total number of subjects (i.e. 230 subjects). The interim analysis was designed to test for early 153 stopping for futility or efficacy and sample size re-estimation. The decision rule based on the study 154 protocol were (1) stop the trial for early efficacy if the interim analysis p-value < 0.01, (2) stop the trial 155 for futility if the interim analysis p-value ≥ 0.25, or (3) declare the trial significant if the sum of the 156 interim analysis and final stage p-values < 0.1832. 12 157

The survival analysis method for interval-censored data was used to analyze the primary endpoints due to 158 the nature of the data collection (i.e., subjects' clearance is observed during specific follow-up time). 159

Results were reported in terms of HR and 95% CI and one-sided p-value based on the Cox proportional 

Participants 172 the 14 patients excluded after randomization, one did not meet eligibility criteria, and 13 withdrew 175 consent; none received the study treatment ( Figure 1) . 176

Participants had a median age of 37 (IQR: 32-44) years, and 155 (67%) were men. Overall, one patient 177 had cardiovascular disease, 14 (6%) had hypertension, 25 (10.8%) had diabetes, and 8 (3.4%) had asthma 178 at the baseline. Approximately 39 (16.8%) were obese (body mass index >30). Baseline characteristics 179

were well balanced between groups (Table 1 ) with a minor insignificant imbalance in BMI, diabetes, and 180

In the favipiravir group, 101 (90%) completed treatment duration (minimum five days total). 182

Discontinuing the treatment before five days in 10% of subjects was due to adverse events in two patients, 183 unexplained in three patients, and hospitalization in six patients. Of 119 patients in the placebo group, 113 184 (94.9%) completed the assigned treatment duration; discontinuing the placebo before five days was due to 185 adverse events in two patients, unexplained in three patients, and hospitalization in one patient. 186

Nonetheless, all patients were evaluated for the outcome on day 28. 187 188 Efficacy 189

The primary outcome was ascertained in all patients in the modified intention-to-treat (mITT) population. Figure S1 ). There was no 198 difference in the resolution of any symptoms or the need to use antibiotics.

Adverse events were experienced by eight (7.1%) patients in the favipiravir group and seven (5.8%) in the 202 placebo group; however, none were serious according to the protocol definition. Adverse events leading 203 to discontinuation of the study were only recorded in four patients, two in each group. Discontinuations 204 were mainly due to gastrointestinal symptoms, including nausea, vomiting, and abdominal pain. Adverse 205 events were more common in the favipiravir groups than in the placebo group, including skin rash, 206 respiratory symptoms, and vomiting (see Supplementary material Table S2 ). 207

Significant elevations in the levels of liver enzymes (AST and ALT) were noted more in the favipiravir 208 group; all returned to the normal range by the day 28 follow-up. Three patients in the favipiravir group 209 and one in the placebo group had worsened kidney functions with a drop in creatinine clearance below 60 210 mL/min. No patient had creatinine clearance less than 30 mL/min or required hemodialysis in our study. 211

By day 28 follow-up, emergency department/urgent care visits in the favipiravir group were more than in 212 the placebo group; 11 (9.8%) and 7 (5.8%), respectively (p =0.36). The eight hospitalizations in both 213 groups were all related to disease progression and none were related to treatment adverse events. No other 214 serious adverse events were reported and there were no deaths in either of the study groups. 215 216

The intervention did not impact on the primary outcome when age, sex, obesity, and symptoms duration 218 prior to the enrollment were considered as subgroups. In the subgroup of those who used the favipiravir 219 within 48-hours of the symptoms onset, clinical improvement or the time to viral clearance were not 220 significantly different (Figure 3 ; Figure S2 in supplementary material). 221

In this double-blinded, placebo-controlled, randomized trial, favipiravir was not associated with a faster 224 viral clearance nor a better clinical outcome when initiated in the first five days of the onset of the 225

Several antiviral agents with the potential ability to treat SARS-CoV-2 infections have been studied 227 including remdesivir, hydroxychloroquine, lopinavir-ritonavir, and interferon in the solidarity trial and 228 other trials and were found ineffective. 5,17,18 Due to the lack of impact on COVID-19 mortality of the 229 studied agents, evaluating other potential antivirals like favipiravir in a prospective setting was 230 needed. 19,20 A randomized study using favipiravir in mild-to-moderate COVID-19 patients failed to show 231 a statistical significance on the primary endpoint of time to RT-PCR negativity. In that trial, a significant 232 improvement in reducing the time to clinical recovery was observed; the difference tends to disappear in 233 mild cases where median time to clinical recovery was 3 versus 4 days in favipiravir and control groups, 234 respectively. 11 Contrary to these findings, a more recent randomized clinical trial noted positive results of 235 favipiravir treatment in moderate COVID-19. 21 The primary endpoint of this single-blinded trial of 156 236 patients was a composite of clinical, radiological, and microbiological outcomes. We previously reported 237 the efficacy of combined favipiravir and hydroxychloroquine in treating moderate to severe COVID-19 238 cases in a prospective randomized controlled trial. When compared to the standard of care, the 239 combination was found to be ineffective using a seven-category ordinal scale for clinical improvement. 22 240

The previous trial focused on a moderate to severe cases and did not evaluate single favipiravir treatment. 241

The discrepancies in results from favipiravir trials can be due to many factors such as study designs, 242 populations, and ethnicity; possibly, the inconsistency in defining COVID-19 severity could have also 243 impacted the variability of reported results. 244

Two systematic reviews did not reveal any significant difference between favipiravir and comparators on 245 fatality rate and mechanical ventilation requirement, 23,24 but noted that it may promote viral clearance 246 within 7 days and clinical improvement within 14 days of treatment, especially in mild-to-moderate 247 COVID-19 cases. 24 Data on the early initiation of antiviral therapy, which could lead to a rapid and 248 significant improvement of viral infections, supported our current trial. 25, 26 Our data provide consistent findings with previous studies on the absence of favipiravir activity/effect in 250 all examined endpoints (viral clearance, time to clinical improvement, and hospital admission), outweighing 251 the lack of favipiravir effectiveness in this population. Taken together, it could be extrapolated that there is 252 no favipiravir effect on COVID-19 regardless of the disease severity. 253

In terms of safety, adverse events reported in our trial were similar to previous reports. 27-29 Unlike our 254 study, some trials reported chest pain and increase in triglyceride levels as adverse events following 255 favipiravir treatment. 27, 28, 30 Other trials also reported hyperuricemia as a non-serious adverse drug 256 reaction secondary to favipiravir 29,30 but uric acid was not part of our follow up laboratory testing as we 257 excluded all patients with gout disease based on the study protocol. However, although no serious adverse 258 events were observed in either group, the daily pill burden was a major challenge. The recommended 259 daily doses to achieve acceptable plasma concentrations are 3600 mg (18 tablets) on the first day and 260 1600 mg (8 tablets) on the following days. Such number of pills with unproven benefits can be 261 undesirable due to the difficulties in administration and possible adverse effects. 262

The study has also encountered some limitations due to the sample size, noncompliance, missing data, 263 and withdrawal after randomization. Nevertheless, the study showed an almost certain result of non-264 efficacy of the investigational drug. Viral clearance as a primary endpoint was used commonly in viral 265 clinical trials, including prior influenza clinical trials. Since more than 80% of the COVID-19 disease 266

would not progress to severe illness or require hospitalization, clinical improvement might not reflect the 267 efficacy of the antiviral where symptom resolution occurs without therapy and can be very subjective. 268

The study team favored a more objective outcome of the viral clearance. Furthermore, reducing viral 269 clearance could strongly impact disease transmission, a critical infection control measure. The study is 270 still considered underpowered for the secondary clinical endpoints, but it can help design future clinical 271 trials and generate valuable systematic reviews and meta-analyses. To our knowledge, this is the largest All authors critically revised the report and approved the final version to be submitted for publication. 300

The corresponding author confirms that he had full access to all the data in the study and had final 301 responsibility for the decision to submit for publication 302 303 Funding: This work was supported by King Abdullah International Medical Research Center, Saudi 304

Arabia. Protocol No.RC20/220/R. The funder had no role in the design and conduct of the study; 305 collection, management, analysis, and interpretation of the data; preparation, review, or approval of the 306 manuscript; and decision to submit the manuscript for publication. 307

All the authors have full access to all the data in the study and had final responsibility for the decision to 308 submit for publication. 309 310 311

We express our sincere gratitude to the site's team members for the great efforts and help to enroll 313 participants (names are provided in Supplementary Appendix) and all the healthcare workers who took 314 care of the patients during this trial. We thank Dr. Saleh Altamimi, CEO of first Riyadh health cluster in 315

Saudi Arabia, and all other Healthcare leaders in the Ministry of Health for supporting this trial. We also 316 thank the DSMB members for their input and critical review of the data. 317

The study Statistical Analysis Plan is available with this publication as part of the supplementary 320 material. Individual participant data are available upon request addressed to the corresponding author, and 321 after approval of a proposal, can be shared within a secure online platform. A data-sharing agreement will 322 be needed. 

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Serum creatinine, μmol/L, median (IQR)

Total Bilirubin, μmol/L, median (IQR)

Aspartate aminotransferase, median (IQR), U/L 24

Alanine aminotransferase, median (IQR), U/L 28 (20 -40.3) 30