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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: COVID-19; SARS-CoV2
• Intervention / Treatment: Drug: Ribavirin Capsules; Drug: Favipiravir

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Alpay Azap, MD, Prof; Phone Number: +90 312 508 2681; Email: azap@medicine.ankara.edu.tr

Study Locations

• Turkey
  • Ankara, Turkey, 06800
    • Ankara City Hospital
    • Contact: Hatice R GUNER, MD, Prof; Phone Number: +90 533 7724078
  • Istanbul, Turkey, 34764
    • Umraniye Training and Research Hospital
    • Contact: Mehtap AYDIN, MD,Assc.Prof; Phone Number: +90 5333031819
  • Istanbul, Turkey, 34010
    • Koç University Hospital
    • Contact: Onder ERGONUL, MD, Prof; Phone Number: +90 5358152741
  • Cebeci
    • Ankara, Cebeci, Turkey, 06590
      • Ankara University, School of Medicine
      • Contact: Alpay Azap, MD, Prof; Phone Number: +90 312 508 2681; Email: azap@medicine.ankara.edu.tr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ribavirin Arm; 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; Ribavirin 200 mg capsules
Active Comparator: Favipiravir Arm; 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; Favipiravir 200 mg tablets

What is the study measuring?

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
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
Mortality rate	All-cause mortality rate	15 days
Family members rates with PCR positive test results	The number of family members with PCR positive	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
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

Collaborators and Investigators

• Sponsor: The Scientific and Technological Research Council of Turkey
• Collaborators: Koç University; Ankara City Hospital Bilkent; Monitor CRO; Istanbul Umraniye Training and Research Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): April 1, 2021
• Primary Completion (Anticipated): September 30, 2021
• Study Completion (Anticipated): December 31, 2021

Study Registration Dates

• First Submitted: April 1, 2021
• First Submitted That Met QC Criteria: April 1, 2021
• First Posted (Actual): April 2, 2021

Study Record Updates

• Last Update Posted (Actual): April 2, 2021
• Last Update Submitted That Met QC Criteria: April 1, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites; Favipiravir; Ribavirin
• Other Study ID Numbers: MON775.159.4

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No