Summary

Introduction: Since the beginning of the Coronavirus disease-2019 (COVID-19) pandemic, scientists have studied many drugs to treat it, but none of them have been approved as a complete cure. Favipiravir is one of those drugs that effectively clears the body from the virus by interfering with the process of replication. This study aimed to determine the efficacy of favipiravir compared with supportive medication to treat moderate COVID-19 patients. Materials and
Methods: In this randomized, open-label, controlled clinical trial, we examined the efficacy of favipiravir to treat moderate COVID-19 patients. The study was conducted in Labbafinejad Hospital (Tehran, Iran) from April to September 2021. A 1:1 ratio of eligible patients were assigned to the intervention and control groups. The control group received supportive medication. In addition to supportive medication, the intervention group received favipiravir. The primary endpoint was the hospitalization rate during the seven-day follow-up. And the secondary endpoints were symptoms, signs, and laboratory tests of the patients.
Results: Out of 78 patients who were included in the study, 40 patients were assigned to the control group and 38 patients were assigned to the intervention group. At the beginning of treatment, the respiratory rate was higher in the intervention group (p=0.001), however, on the fifth (p=0.001) and seventh (p<0.001) days, it was significantly lower in the intervention group. In addition, oxygen saturation at the beginning of treatment was lower in the intervention group (p<0.001); however, on the fifth (p=0.016) and seventh (p<0.001) days, it was significantly higher in the intervention group. Furthermore, the consumption of favipiravir was not associated with the hospitalization rate (p=0.200).
Conclusion: Favipiravir enhances respiratory manifestations in patients with moderate COVID-19 when compared to supportive medication alone.

Introduction

The epidemic of Severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) was first reported in Wuhan, China, in December 2019. The disease caused by this virus, Coronavirus disease-2019 (COVID-19), spread quickly around the world until on March 11, 2020, the World Health Organization declared it a pandemic. So far, there have been millions of confirmed cases and thousands of deaths due to COVID-19. Accordingly, it is a priority of global health to control this disease^{[1, 2]}.

Severe acute respiratory syndrome-Coronavirus-2 is an RNA virus that multiplies through the replication system of host cells^[3]. The main target of SARS-CoV-2 is often the epithelial cells of the lung’s alveoli, which eventually lead to atypical pneumonia^[4]. Most COVID-19 patients have nonspecific symptoms and recover only with supportive therapies (fluid therapy, supplemental oxygen, antipyretics, analgesics, and antiemetics)^[5]. However, considering the mechanisms of infectivity and pathogenicity of SARS-CoV-2, scientists have proposed antiviral drugs to treat COVID-19^[6]. Some of them interfere with the replication, membrane fusion, and assembly of the virus, such as remdesivir, lopinavir/ritonavir, umifenovir, and favipiravir^[7].

Favipiravir is a nucleoside analog oral antiviral drug developed by the Japanese Toyama Chemical company. It selectively inhibits RNA-dependent RNA polymerase and causes lethal mutations in the replication process that produce nonviable viruses. The efficacy of favipiravir on a large number of viruses such as influenza A, yellow fever, Ebola, Lassa virus, and West Nile virus has been previously reported^{[8, 9]}. Additionally, a previous meta-analysis study has shown that virus clearance [Odds ratio (OR)=0.40, 95% CI=0.19-0.84, p=0.02] and clinical improvement (OR=1.60, 95% CI=1.03-2.40, p=0.04) of patients were significantly higher in the group treated with favipiravir compared to control group on day 7^[10].

This study aimed to determine the efficacy of favipiravir compared with supportive medication to treat moderate COVID-19 patients.

Methods

Study Design

This randomized, open-label, parallel-group clinical trial was conducted to assess the efficacy of favipiravir compared with supportive medication in patients with moderate COVID-19. The present clinical trial protocol has been approved by the Iranian Registry of Clinical Trials (IRCT ID: IRCT20211004052664N1).

Participants

The study population included all COVID-19 patients referred to the infectious diseases clinic of Labbafinejad hospital. This study was performed at Labbafinejad hospital, Tehran, Iran, between April and September 2021.

The following were the inclusion criteria for our study: (1) laboratory confirmation of SARS-CoV-2 by reverse transcription-polymerase chain reaction (RT-PCR) or imaging findings highly suggestive of COVID-19; (2) outpatients with moderate severity (respiratory rate <30/min, oxygen saturation >94%, or pulmonary infiltration <50% in both lungs)^[11]; (3) age of at least 18 y; (4) agreed to participate in this study; (5) oral tolerance to the medication. The PCR kits are made by the Pishtazteb company in Iran. Additionally, an expert radiologist read the lung computed tomography (CT) scan of the patients. Unilateral and bilateral multilobular infiltrations, especially peripheral, and ground-glass opacities in lung CT scan were considered highly suggestive of COVID-19.

Additionally, the exclusion criteria were: (1) immunocompromised patients defined as receiving immunosuppressive medications, solid organ transplant, hematopoietic stem cell transplant, infection with human immunodeficiency virus, and active cancer^[12]; (2) pregnancy; (3) consumption of other antiviral therapies from symptom onset; (4) severe hypersensitivity or anaphylactic shock after taking favipiravir.

Randomization and Blinding

First, we obtained written informed consent from eligible patients. Then, patients within 3-9 d of COVID-19 symptoms onset were randomized at a 1:1 ratio into two groups of control and intervention (simple randomization using a random numbers table). Random concealment is also performed using sequentially numbered sealed opaque envelopes. This study was an open-label, nonblinded study.

Interventions

Patients in the control group received supportive therapy. According to the national guideline for COVID-19 management at the time of the study, outpatients with moderate severity received the following oral drugs: acetaminophen (500 mg every 6 h, until fever stops), diphenhydramine (10-15 ml every 6-8 h, in cases of coughing), vitamin D₃ (50000 IU, weekly, if there was no history of vitamin D consumption), zinc and selenium supplements (daily)^[13]. Patients in the intervention group, in addition to supportive therapy, received oral favipiravir (Cytovex, made by Abidi company in Iran) at a dose of 1600 mg every 12 h for the first day and 600 mg every 12 h for the next 4 d. Additionally, the patients in both groups did not receive corticosteroids and anticoagulant drugs.

Outcomes

The primary endpoint was the hospitalization rate during the seven-days follow-up period. The secondary endpoints were symptoms and signs of the patients and laboratory tests. Patient symptoms were fever, sore throat, myalgia, cough, dyspnea, headache, gastrointestinal symptoms, and anorexia, which were assessed by an expert physician on days one (start of treatment), three, five, and seven. Patient signs were blood pressure (systolic and diastolic), pulse rate, respiratory rate, body temperature, and peripheral blood O₂saturation, which were assessed by an expert physician on days one (start of treatment), three, five, and seven. Also, laboratory tests included a complete blood count (CBC) and a serum level of C-reactive protein (CRP), which were obtained on days one (start of treatment) and seven.

Statistical Analysis

Statistical Package for the Social Sciences version 18.0 was used to analyze the data. We described the obtained data as frequency, percentage, mean, and standard deviation. We also analyzed variables using independent-samples t-test, Mann-Whitney U test, chi-square test, or Fisher^’s exact test as required. Also, in this study, the p<0.05 was considered significant.

The Ethics Committee of the School of Medicine, of Shahid Beheshti University of Medical Sciences, approved this study on March 3, 2021 (approval ID: IR.SBMU.MSP.REC.1399.750). The study was performed in accordance with the Helsinki Declaration.

Results

Baseline Characteristics of the Patients

According to the study’s flow chart, 78 patients were randomized, of which 40 patients were assigned to the control group and 38 patients were assigned to the intervention group (Figure 1). In this study, the mean age of patients was 52.50±12.55 y (range: 18-78 y), and 43 (55.12%) were male. The time from the symptom onset to randomization of the intervention group (5.29±1.39) was significantly shorter than the control group (5.90±1.15) (t=2.115, p=0.038). However, there was no distinction between the two groups in terms of other basic characteristics. The detailed basic characteristics of the patients in both groups are shown in Table 1. In the control and intervention groups, respectively, the RT-PCR results of 23 (57.50%) and 21 (55.26%) patients were both positive. Additionally, all patients had imaging results that were COVID-19 suggestive.

Table 1: Comparison of baseline characteristics of the patients

Figure 1: Flow chart of the study

The clinical symptoms of patients in the intervention and control groups at various time points are shown in Table 2. Although there was no difference in the two groups cough frequency at the beginning of treatment, on day seven, the intervention group’s frequency was considerably lower than the control group’s (c²=9.531, p=0.002). At the beginning of the course of treatment, the frequency of dyspnea was higher in the intervention group (c²=10.535, p=0.001); however, on the fifth day, it was much lower in the intervention group compared with the control group (c²=8.232, p=0.004).

Table 2: Comparison of symptoms of the patients over time

The physical examination of the patients at different time points is shown in Table 3. At the beginning of treatment, the respiratory rate was higher in the intervention group compared with the control group (t=-3.626, p=0.001); however, it was significantly lower on the fifth (t=3.463, p=0.001) and seventh (t=2.815, p<0.001) days in the intervention group. Additionally, oxygen saturation was lower in the intervention group compared with the control group (t=4.232, p<0.001); however, it was significantly higher on the fifth (t=-2.480, p=0.016) and seventh (t=-2.317, p<0.001) days in the intervention group.

Table 3: Comparison of vital signs of the patients over time

The laboratory results of patients at the start of treatment and on day seven are shown in Table 4. On the seventh day, there was no significant difference between the intervention and control groups in any of the laboratory variables.

Table 4: Comparison of laboratory findings of the patients

Figure 2 shows that there was no significant difference (c²=1.642, p=0.200) between the intervention and control groups’ (26.3% vs. 40.0%) overall hospitalization rates (26.3% vs. 40.0%) up until the end of the follow-up (c²=1.642, p=0.200). Additionally, we did not see any side effects in the patients.

Figure 2: Hospitalization rate of the patients

Discussion

We performed this study to evaluate the efficacy of favipiravir in the treatment of patients with moderate COVID-19. Based on our results, favipiravir was effective in improving the respiratory demonstrations of the patients; however, it was not associated with the hospitalization rate. As shown in Table 5, our findings were consistent with some previous studies^[14-17] and inconsistent with others^[18-20].

Table 5: A review of previous studies on favipiravir effectiveness on COVID-19 patients

The study by Szabo et al.^[18] has revealed that the consumption of favipiravir did not affect the clinical course and progression of the disease. The contradiction between our findings and this study can be attributed to several causes. The patients in the above study were moderate to severe, which is distinct from our study. In moderate to severe cases, the patient’s condition is usually more complicated, involving several organs. Additionally, the outcomes evaluated in this study included mortality and the need for immunomodulators and mechanical ventilation, which is different from ours.

Additionally, some studies were conducted to compare the therapeutic effects of favipiravir with other antiviral drugs. For example, a study by Solaymani-Dodaran et al.^[21] showed that the need for intensive care and intubation, length of hospitalization and recovery, and mortality rate in the favipiravir-treated group were not different from those in the lopinavir/ritonavir-treated group. In a study conducted by Chen et al.^[22] to compare the therapeutic effects of favipiravir with umifenovir, the rate of clinical recovery did not differ during the seven-day follow-up. Nevertheless, the time to improve fever and cough was shorter in the group treated with favipiravir. Generally, all of these drugs improve clinical symptoms by interfering with the replication and pathogenicity mechanisms of the virus.

Moreover, consumption of favipiravir significantly reduces pulmonary infiltration and decreases serum levels of erythrocyte sedimentation rate, CRP, and lactate dehydrogenase. However, it did not affect the concentration of inflammatory cytokines such as interleukin (IL)-8, IL-6, and interferons^[23]. As shown in our study, the use of favipiravir did not affect all organs and improved respiratory symptoms alone. However, the duration of virus clearance from respiratory secretions and the proportion of viral shedding decreased following favipiravir consumption^[24].

In terms of safety, most of the side effects of favipiravir are mild, such as increased uric acid and liver enzymes, gastrointestinal symptoms, and neutropenia. However, it should be used with caution in pregnant women, as cases of teratogenicity have been reported^[25]. Favipiravir is also metabolized in the liver and excreted by the kidneys. Consequently, it should be prescribed with caution in patients with liver or kidney disorders^[26].

Study Limitations

Our study had several limitations. This study was an open-label study without blinding and a placebo group. To remove the placebo effect, it is necessary to design a blinded controlled study. Some patients on days fifth and seventh had missing values in outcomes. Besides, we followed the patients for up to seven d. If we followed longer, we would have a more complete judgment of the effect of the intervention. The control PCR was not done after treatment. Additionally, we only considered CBC and CRP as laboratory tests. While additional enzymes

Conclusion

This study suggests that the consumption of favipiravir in moderate COVID-19 patients was associated with increased oxygen saturation and decreased respiratory rate. In the other words, taking favipiravir can suppress the respiratory demonstrations in moderate cases of COVID-19, and it can be used as an outpatient treatment.

Ethics

Ethics Committee Approval: The Ethics Committee of the School of Medicine, of Shahid Beheshti University of Medical Sciences, approved this study on March 3, 2021 (approval ID: IR.SBMU.MSP.REC.1399.750).

Informed Consent: Consent form was filled out by all participants.

Peer-review: Externally peer-reviewed.

Authorship Contributions

Concept: S.T., D.Y., Design: S.T., D.Y., A.B., L.G., Data Collection or Processing: S.T., A.B., Analysis or Interpretation: L.G., A.K., Literature Search: A.K., Writing: S.T., A.B., A.K.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

References

1Shrestha DB, Budhathoki P, Khadka S, Shah PB, Pokharel N, Rashmi P. Favipiravir versus other antiviral or standard of care for COVID-19 treatment: a rapid systematic review and meta-analysis. Virol J. 2020;17:141.

2Tehrani S, Khabiri N, Moradi H, Mosavat MS, Khabiri SS. Evaluation of vitamin D levels in COVID-19 patients referred to Labafinejad hospital in Tehran and its relationship with disease severity and mortality. Clin Nutr ESPEN. 2021;42:313-7.

3Samudrala PK, Kumar P, Choudhary K, Thakur N, Wadekar GS, Dayaramani R, Agrawal M, Alexander A. Virology, pathogenesis, diagnosis and in-line treatment of COVID-19. Eur J Pharmacol. 2020;883:173375.

4Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. Jama. 2020;323:1239-42.

5Chen C, Zhang Y, Huang J, Yin P, Cheng Z, Wu J, Chen S, Zhang Y, Chen B, Lu M, Luo Y, Ju L, Zhang J, Wang X. Favipiravir Versus Arbidol for Clinical Recovery Rate in Moderate and Severe Adult COVID-19 Patients: A Prospective, Multicenter, Open-Label, Randomized Controlled Clinical Trial. Front Pharmacol. 2021;12:683296.

6Han YJ, Ren ZG, Li XX, Yan JL, Ma CY, Wu DD, Ji XY. Advances and challenges in the prevention and treatment of COVID-19. Int J Med Sci. 2020;17:1803-10.

7Tu YF, Chien CS, Yarmishyn AA, Lin YY, Luo YH, Lin YT, Lai WY, Yang DM, Chou SJ, Yang YP, Wang ML, Chiou SH. A Review of SARS-CoV-2 and the Ongoing Clinical Trials. Int J Mol Sci. 2020;21:2657.

8McKee DL, Sternberg A, Stange U, Laufer S, Naujokat C. Candidate drugs against SARS-CoV-2 and COVID-19. Pharmacol Res. 2020;157:104859.

9Jean SS, Lee PI, Hsueh PR. Treatment options for COVID-19: The reality and challenges. J Microbiol Immunol Infect. 2020;53:436-43.

10Manabe T, Kambayashi D, Akatsu H, Kudo K. Favipiravir for the treatment of patients with COVID-19: a systematic review and meta-analysis. BMC Infect Dis. 2021;21:489.

11Gandhi RT, Lynch JB, Del Rio C. Mild or Moderate Covid-19. N Engl J Med. 2020;383:1757-66.

12Marra AR, Kobayashi T, Suzuki H, Alsuhaibani M, Tofaneto BM, Bariani LM, Auler MA, Salinas JL, Edmond MB, Doll M, Kutner JM, Pinho JRR, Rizzo LV, Miraglia JL, Schweizer ML. Short-term effectiveness of COVID-19 vaccines in immunocompromised patients: A systematic literature review and meta-analysis. J Infect. 2022;84:297-310.

13Tabriz University of Medical Sciences. Available from: https://treatment .tbzmed.ac.ir/Uploads/User/4734/1399/%D9%85%D8%B9%D8%A7 %D9%88%D 9%86%D8%AA%20 % D8%AF%D 8%B1%D9% 85%D8%A7 %D9%86/%D8% A7 %D8 %B9 %D8%A A%D8%A8%D8%A7%D8%B1%20 %D8%A8%D8%AE%D8%B4%DB%8C/%d9%86%d8% b3%d8%ae%d9%87%20%d9%86%d9%87%d9%85%20%d8%b1%d8%a7%d9%87%d9%86%d9%85% d8%a7%db%8c%20%d8%aa%d8%b4%d8%ae%db%8c%d8%b5%20%d9%88%20%d8 %af%d8%b1%d9%85.pdf

14Alamer A, Alrashed AA, Alfaifi M, Alosaimi B, AlHassar F, Almutairi M, Howaidi J, Almutairi W, Mohzari Y, Sulaiman T, Al-Jedai A, Alajami HN, Alkharji F, Alsaeed A, Alali AH, Baredhwan AA, Abraham I, Almulhim AS. Effectiveness and safety of favipiravir compared to supportive care in moderately to critically ill COVID-19 patients: a retrospective study with propensity score matching sensitivity analysis. Curr Med Res Opin. 2021;37:1085-97.

15Shinkai M, Tsushima K, Tanaka S, Hagiwara E, Tarumoto N, Kawada I, Hirai Y, Fujiwara S, Komase Y, Saraya T, Koh H, Kagiyama N, Shimada M, Kanou D, Antoku S, Uchida Y, Tokue Y, Takamori M, Gon Y, Ie K, Yamazaki Y, Harada K, Miyao N, Naka T, Iwata M, Nakagawa A, Hiyama K, Ogawa Y, Shinoda M, Ota S, Hirouchi T, Terada J, Kawano S, Ogura T, Sakurai T, Matsumoto Y, Kunishima H, Kobayashi O, Iwata S. Efficacy and Safety of Favipiravir in Moderate COVID-19 Pneumonia Patients without Oxygen Therapy: A Randomized, Phase III Clinical Trial. Infect Dis Ther. 2021;10:2489-509.

16Udwadia ZF, Singh P, Barkate H, Patil S, Rangwala S, Pendse A, Kadam J, Wu W, Caracta CF, Tandon M. 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. Int J Infect Dis. 2021;103:62-71.

17Ivashchenko AA, Dmitriev KA, Vostokova NV, Azarova VN, Blinow AA, Egorova AN, Gordeev IG, Ilin AP, Karapetian RN, Kravchenko DV, Lomakin NV, Merkulova EA, Papazova NA, Pavlikova EP, Savchuk NP, Simakina EN, Sitdekov TA, Smolyarchuk EA, Tikhomolova EG, Yakubova EV, Ivachtchenko AV. AVIFAVIR for Treatment of Patients With Moderate Coronavirus Disease 2019 (COVID-19): Interim Results of a Phase II/III Multicenter Randomized Clinical Trial. Clin Infect Dis. 2021;73:531-4.

18Szabo BG, Lenart KS, Petrik B, Gaspar Z, Kiss-Dala N, Szlavik J, Valyi-Nagy I, Lakatos B; Saint Ladislaus COVID-19 Collaborative. Favipiravir treatment does not influence disease progression among adult patients hospitalized with moderate-to-severe COVID-19: a prospective, sequential cohort study from Hungary. Geroscience. 2021;43:2205-13.

19Lou Y, Liu L, Yao H, Hu X, Su J, Xu K, Luo R, Yang X, He L, Lu X, Zhao Q, Liang T, Qiu Y. Clinical Outcomes and Plasma Concentrations of Baloxavir Marboxil and Favipiravir in COVID-19 Patients: An Exploratory Randomized, Controlled Trial. Eur J Pharm Sci. 2021;157:105631.

20Al-Muhsen S, Al-Numair NS, Saheb Sharif-Askari N, Basamh R, Alyounes B, Jabaan A, Saheb Sharif-Askari F, Alosaimi MF, Alsohime F, Halwani R, Al-Saud H. Favipiravir Effectiveness and Safety in Hospitalized Moderate-Severe COVID-19 Patients: Observational Prospective Multicenter Investigation in Saudi Arabia. Front Med (Lausanne). 2022;9:826247.

21Solaymani-Dodaran M, Ghanei M, Bagheri M, Qazvini A, Vahedi E, Hassan Saadat S, Amin Setarehdan S, Ansarifar A, Biganeh H, Mohazzab A, Khalili D, Hosein Ghazale A, Reza Heidari M, Taheri A, Khoramdad M, Mahdi Asadi M, Nazemieh M, Varshochi M, Abbasian S, Bakhtiari A, Mosaed R, Hosseini-Shokouh SJ, Shahrokhi M, Yassin Z, Ali Zohal M, Qaraati M, Rastgoo N, Sami R, Javad Eslami M, Asghari A, Namazi M, Ziaie S, Jafari-Moghaddam R, Kalantari S, Memarian M, Khodadadi J, Hossein Afshari M, Momen-Heravi M, Behzadseresht N, Reza Mobayen A, Mozafari A, Movasaghi F, Haddadzadeh Shoushtari M, Moazen J. Safety and efficacy of Favipiravir in moderate to severe SARS-CoV-2 pneumonia. Int Immunopharmacol. 2021;95:107522.

22Chen C, Zhang Y, Huang J, Yin P, Cheng Z, Wu J, Chen S, Zhang Y, Chen B, Lu M, Luo Y, Ju L, Zhang J, Wang X. Favipiravir Versus Arbidol for Clinical Recovery Rate in Moderate and Severe Adult COVID-19 Patients: A Prospective, Multicenter, Open-Label, Randomized Controlled Clinical Trial. Front Pharmacol. 2021;12:683296.

23Mortaz E, Bassir A, Dalil Roofchayee N, Dezfuli NK, Jamaati H, Tabarsi P, Moniri A, Rezaei M, Mehrian P, Varahram M, Marjani M, Mumby S, Adcock IM. Serum cytokine levels of COVID-19 patients after 7 days of treatment with Favipiravir or Kaletra. Int Immunopharmacol. 2021;93:107407.

24Zhao H, Zhang C, Zhu Q, Chen X, Chen G, Sun W, Xiao Z, Du W, Yao J, Li G, Ji Y, Li N, Jiang Y, Wang Y, Zeng Q, Li W, Gong B, Chang X, Zhu F, Jiang X, Li J, Wu Z, Liu Y, Peng P, Wang G. Favipiravir in the treatment of patients with SARS-CoV-2 RNA recurrent positive after discharge: A multicenter, open-label, randomized trial. Int Immunopharmacol. 2021;97:107702.

25Wang D, Li Z, Liu Y. An overview of the safety, clinical application and antiviral research of the COVID-19 therapeutics. J Infect Public Health. 2020;13:1405-14.

26Joshi S, Parkar J, Ansari A, Vora A, Talwar D, Tiwaskar M, Patil S, Barkate H. Role of favipiravir in the treat-ment of COVID-19. Int J Infect Dis. 2021;102:501-8.

Efficacy of Favipiravir in the Treatment of Moderate COVID-19 Patients: A Randomized, Open-label, Controlled Clinical Trial