Efficacy and Safety of Favipiravir and Ribavirin Formulation for Treatment of COVID-19

Study Overview
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Brief Summary
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This is a national, multicenter, open-label, randomized, phase II/III trial that evaluates the efficacy and safety of favipiravir and ribavirin in the treatment of patients with confirmed COVID-19 observed within 72 hours. Approximately 100 patients will be randomized in 1:1 ratio and divided into two groups.

Detailed Description
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The clinical picture of COVID-19 disease is in a broad spectrum, which includes asymptomatic infection, a mild upper respiratory tract infection, respiratory failure, and even severe viral pneumonia with death. The alarming levels of spread and severity of COVID-19 caused a global emergency and this outbreak has been characterized as a pandemic by the World Health Organization (WHO). Coronavirus entry into host cells is an important determinant of viral infectivity and pathogenesis. SARS-CoV S1 contains a receptor-binding domain (RBD) that specifically recognizes angiotensin-converting enzyme 2 (ACE2) as its receptor. SARS-CoV spike needs to be proteolytically activated at the S1/S2 boundary, such that S1 dissociates and S2 undergoes a dramatic structural change. These SARS-CoV entry-activating proteases include cell surface protease TMPRSS2 and lysosomal proteases cathepsins. These features of SARS-CoV entry contribute to its rapid spread and severe symptoms and high fatality rates of infected patients. Ribavirin is a guanosine analog that interferes with the replication of RNA and DNA viruses. Ribavirin was used during the Severe Acute Respiratory Syndrome (SARS) outbreak in combination with corticosteroids, which have an anti-inflammatory effect. Favipiravir is a substrate for viral RNA-dependent RNA polymerase (RdRp) and showed anti-influenza virus activity. Favipiravir is effective against other RNA viruses, poliovirus, rhinovirus, and respiratory syncytial virus and evaluated and developed as a broad spectrum anti-RNA virus drug, including lethal RNA virus infections. According to national guidelines, Favipiravir treatment is applied to COVID-19 infection in Turkey. The main purpose of this study is to obtain efficacy and safety data for ribavirin and favipiravir in the Turkish patient cohort diagnosed with COVID-19. This study designed as an open-label, multicenter, parallel-group, randomized, phase II/III clinical drug trial. This study will be conducted in 4 sites.

Official Title
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An Open-Label, Multicenter, Parallel-Group, Randomized, Phase II/III Study to Evaluate the Efficacy and Safety of Favipiravir and Ribavirin Formulation for Treatment of COVID-19

Conditions
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SARS-CoV2, COVID-19

Intervention / Treatment
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* Drug: Ribavirin Capsules
* Drug: Favipiravir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female or male patients aged 18 years and older infected with the SARS-CoV-2 virus. Patients that have COVID-19 symptoms within 72 hours and have a positive PCR test result. Patients in a stable clinical condition and referred as outpatient for COVID-19 infection. Patients who sign the informed consent before the any study procedures. Exclusion Criteria: Patients who have required hospitalization. Patients who have required intensive care. Patients who do not sign the informed consent. Any condition that in the investigator's judgement might interfere with study procedures or the ability of the patient to adhere to and complete the study. Patients who have been participating in any other clinical trial. Severe liver failure (Child Pugh score ≥ C, transaminase>5 times the upper limit of normal (ULN). Severe renal failure (GFR ≤30 mL/min/1.73 m2) or continuous dialysis (hemodialysis, peritoneal dialysis) or continuous renal replacement therapy. Severe cardiac disease. History of hypersensitivity to either ribavirin/favipiravir. Pregnant or breast-feeding. Patients who cannot use appropriate contraceptive method during and after the study. Patients who are treated with any other treatment agent for COVID-19 in the last 90 days. Patients who had COVID-19 vaccination. Patients who had ribavirin/favipiravir for any reason in the past 72 hours.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ribavirin Arm<br>Ribavirin dosage: 200 mg oral ribavirin capsules for 5 days Regimen: 1200 mg loading dose on day-1 (three capsules in the morning and three capsules in the evening) followed by 800 mg/day maintenance dose (two capsules in the morning and two capsules in the evening) on day-2 to day-5. | Drug: Ribavirin Capsules<br>* Ribavirin 200 mg capsules<br>|
| Active Comparator: Favipiravir Arm<br>Favipiravir dosage: 200 mg oral favipiravir tablets for 5 days Regimen: 2x1600 mg loading dose on day-1 (eight tablets in the morning and eight tablets in the evening) followed by 2x600 mg maintenance dose (three tablets in the morning and three tablets in the evening) on day-2 to day-5. | Drug: Favipiravir<br>* Favipiravir 200 mg tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospitalized patient rates | The number of hospitalized patients | 15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality rate | All-cause mortality rate | 15 days | 
| Time from randomization to relief of symptoms | The duration (days) from start of treatment to relief of clinical symptoms | 15 days | 
| Viral clearance | The day of viral clearance evaluated by real-time polymerase chain reaction (RT-PCR) | 15 days | 
| Changes in angiotensin-converting enzyme 2 (ACE2) receptor levels | Detection of RNA and/or protein levels of ACE2 gene in plasma samples via quantitative RT-PCR and/or flow cytometry | 15 days | 
| Changes in transmembrane protease serine II (TMPRSS2) activity | Assessment of proteolytic activity of TMPRSS2 | 15 days | 
| Emergency room visit rates of patients | The number of emergency room visits of patients (not hospitalized) | 15 days | 
| Time to emergency room visit | The time (days) until the emergency room visit | 15 days | 
| Time to hospitalization | The time (days) until the hospitalization | 15 days | 
| Inpatient length of stay | Length of stay in the hospital (days) | 15 days | 
| Time to ICU admission | The time (days) until admission to intensive care unit | 15 days | 
| Time to intubation | The time (days) until intubation | 15 days | 
| Family members rates with PCR positive test results | The number of family members with PCR positive | 15 days | 
| Changes in vital signs from baseline | Clinical evaluation of systolic and diastolic blood pressure, pulse, respiratory rate, fever, oxygen saturation changes from baseline until the end of study | 15 days | 
| Number/characteristics of AEs and SAEs | Number/characteristics of Adverse Event (AE) and Serious Adverse Event (SAE) related to study drug or hematological and biochemical parameters from baseline until the end of study | 28 days |