Efficacy and Safety of Hydroxychloroquine and Favipiravir in the Treatment of Mild to Moderate COVID-19

An Open-Label, Multicenter, Parallel-Group, Randomized, Phase III Study to Evaluate the Efficacy and Safety of Hydroxychloroquine and Favipiravir in the Treatment of Mild to Moderate COVID-19

This is an open-label, multicenter, parallel-group, randomized, phase III trial that evaluates the efficacy and safety of hydroxychloroquine and favipiravir in the treatment of patients with possible or confirmed COVID-19 observed within the last 5 days. 1000 patients will be randomized in 2:1:2:2:2:1 ratio and divided into six groups.

The clinical picture of 2019-nCoV 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. Although the mortality rate is not yet clear, the reported case-fatality risk was 11-14% during the initial studies which included patients with severe disease. The overall case fatality rate was reported as approximately 2%. In addition, most cases have resulted in a pneumonia requiring supplemental oxygen therapy and ventilator support. 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).

The investigational product Favipiravir is an antiviral drug against RNA viruses and has been stated as effective for the treatment of COVID-19, first emerged from China, in various clinical studies. In February 2020, Favipiravir was used for the clinical treatment of COVID-19, has been shown to be more effective than the lopinavir / ritonavir combination in 80 people. In recent researches, the drug favipiravir is suggested that it may induce recovery in a short time in patients with COVID-19-mild type and decrease the treatment duration from 11 days to 4 days.

The investigational product hydroxychloroquine sulfate is a 4- aminoquinoline derivative and widely used for the treatment of many rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus in addition to its antimalarial effects. In vitro studies reported that hydroxychloroquine sulfate may be effective against many viruses, including SARS-CoV-2 in many in vitro experiments. Additionally, preliminary results of limited number of studies have been revealed that hydroxychloroquine sulfate reduces virus load and induces improvement in patients with COVID-19. This agent has been also suggested to be used in COVID-19 prophylaxis.

Until now, there is no official report on whether hydroxychloroquine combined with favipiravir show clinical activity against the new coronavirus, COVID-19, in Turkey. The main purpose of this study is to evaluate the efficacy and safety of hydroxychloroquine and favipiravir in the treatment of Turkey population with COVID-19.

This study designed as an open-label, multicenter, parallel-group, randomized, phase III clinical drug trial.

A total of 1000 subjects aged between 18 to 70 years with symptoms and complaints consistent with possible or confirmed COVID-19 observed within the last 5 days and meet all eligibility criteria will participate in the study.

This study will be conducted in 14 sites.

Inclusion Criteria:

• Subjects aged between 18 to 70 years,

• Patients with symptoms and complaints consistent with possible or confirmed COVID- 19 observed within the last 5 days,

• Patients with uncomplicated possible or confirmed COVID-19:

  1. Symptoms such as fever, muscle aches, joint pain, cough, sore throat, nasal congestion, however no respiratory distress, no tachypnea or no SpO2 < 93%,
  2. Chest imaging (X-ray or CT chest) documented as normal

• Patients with mild possible or confirmed COVID-19 pneumonia (no severe pneumonia symptoms):

  1. Symptoms such as fever, muscle aches, joint pain, cough, sore throat, nasal congestion, as well as respiratory rate <30/min and SpO2 above 93% on room air,
  2. Chest imaging (X-ray or CT chest)-documented mild pneumonia symptoms

• Patients who were decided to isolate and treat because of COVID-19 in the hospital,

• Patients who have not been involved in any other interventional studies.

Exclusion Criteria:

• Patients considered as inappropriate for this study for any reason like noncompliance by the researcher,
• Patients with persisting refractory nausea, vomiting, chronic diarrhoea or chronic gastrointestinal disorders, inability to swallow the study drug which may affect adequate absorption,
• Patients with chronic liver disease: alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevated over 5 times the upper limit of normal (ULN),
• Patients with gout or hyperuricemia (above the ULN),
• Patients with severe pneumonia symptoms,
• Patients with known allergy to Favipiravir or for substances used in the study,
• Patients did not receive specific antiviral drugs such as lopinavir/ritonavir, ribavirin, arbidol, chloroquine phosphate, hydroxychloroquine, and monoclonal antibodies within one week before admission.
• Patients with known chronic renal impairment/failure [creatinine clearance (CcCl) <30 mL/min],
• Pregnant and lactating women
• Patients undergoing cardiac ablation therapy
• Patients using antiarrhythmic drugs
• Patients actively receiving chemotherapy
• Acute immunosuppressed patients
• Patients undergoing psychosis therapy