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

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ClinicalTrials.gov Identifier: NCT04411433
Recruitment Status : Recruiting
First Posted : June 2, 2020
Last Update Posted : June 2, 2020
Sponsor:
Collaborators:
Hacettepe University, Faculty of Medicine
Prof. Dr. Cemil Tascıoglu Education and Research Hospital Organization
Umraniye Education and Research Hospital
SB Istanbul Education and Research Hospital
Sultan Abdulhamid Han Training and Research Hospital, Istanbul, Turkey
Tepecik Training and Research Hospital
Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine
Ankara University
Ankara City Hospital Bilkent
Ankara Training and Research Hospital
Ege University Hospital (Application and Research Center)
Kocaeli Derince Education and Research Hospital
Istanbul University, Istanbul Faculty of Medicine
Kayseri City Hospital
Information provided by (Responsible Party):
Prof. Ates KARA, MD, Hacettepe University

Tracking Information
First Submitted Date  ICMJE May 23, 2020
First Posted Date  ICMJE June 2, 2020
Last Update Posted Date June 2, 2020
Actual Study Start Date  ICMJE May 8, 2020
Estimated Primary Completion Date July 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 29, 2020)
  • Time to recovery (discharge) [ Time Frame: 14 days ]
    The evaluation of recovery (discharge) period until 14th day after administration.
  • Decrease in viral load [ Time Frame: 14 days ]
    The evaluation of decrease in viral load until 14th day after administration.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: May 29, 2020)
  • Adverse Event (AE), Serious Adverse Event (SAE) and discontinuation of treatment [ Time Frame: 14 days ]
    Number/characteristics of Adverse Event (AE), Serious Adverse Event (SAE) and discontinuation of treatment due to study drug from baseline until the end of study
  • Frequency of occurrence of lymphopenia from baseline [ Time Frame: 14 days ]
    Clinical evaluation of occurrence of lymphopenia from baseline until the end of study.
  • Frequency of occurrence of thrombocytopenia from baseline [ Time Frame: 14 days ]
    Clinical evaluation of occurrence of thrombocytopenia from baseline until the end of study.
  • Changes in alanine aminotransferase (ALT) levels from baseline [ Time Frame: 14 days ]
    Clinical evaluation of ALT levels from baseline until the end of study.
  • Changes in aspartate aminotransferase (AST) levels from baseline [ Time Frame: 14 days ]
    Clinical evaluation of AST levels from baseline until the end of study.
  • Changes in C-reactive protein (CRP) levels from baseline [ Time Frame: 14 days ]
    Clinical evaluation of CRP levels from baseline until the end of study.
  • Changes in level of D-dimer levels from baseline [ Time Frame: 14 days ]
    Clinical evaluation of D-dimer levels from baseline until the end of study.
  • Changes in prothrombin time (PT) values from baseline [ Time Frame: 14 days ]
    Clinical evaluation of PT values for blood to coagulate from baseline until the end of study.
  • Changes in partial thromboplastin time (PTT) values from baseline [ Time Frame: 14 days ]
    Clinical evaluation of PTT values for blood to coagulate from baseline until the end of study.
  • Changes in blood pressure from baseline [ Time Frame: 14 days ]
    Clinical evaluation of systolic and diastolic blood pressure levels from baseline until the end of study.
  • Changes in respiratory rate from baseline [ Time Frame: 14 days ]
    Clinical evaluation of respiratory rate levels from baseline until the end of study.
  • Changes in pulse oxymetry from baseline [ Time Frame: 14 days ]
    Clinical evaluation of pulse oxymetry levels from baseline until the end of study.
  • Changes in fever from baseline [ Time Frame: 14 days ]
    Clinical evaluation of changes in fever from baseline until the end of study.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety of Hydroxychloroquine and Favipiravir in the Treatment of Mild to Moderate COVID-19
Official Title  ICMJE 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
Brief Summary 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.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
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.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Sars-CoV2
  • COVID-19
Intervention  ICMJE
  • Drug: Favipiravir (3200 mg + 1200 mg)

    Dosage and method of administration: in a regimen of 2x1600 mg (oral) loading dose on day-1 followed by 1200 mg maintenance dose (2x600 mg, 2 times daily) on day-2 to day-5 (5 days in total).

    The treatment duration may be extended up to 14 days with the evaluation of principle investigator.

  • Drug: Favipiravir (3600 mg + 1600 mg)

    Drug: Favipiravir (3600 mg + 1600 mg) Dosage and method of administration: in a regimen of 2x1800 mg (oral) loading dose on day-1 followed by 1600 mg maintenance dose (2x800 mg, 2 times daily) on day-2 to day-5 (5 days in total).

    The treatment duration may be extended up to 14 days with the evaluation of principle investigator.

  • Drug: Favipiravir (3200 mg + 1200 mg) combined with Hydroxychloroquine

    Hydroxychloroquine Dosage and method of administration: in a regimen of 2x400 mg (oral) loading dose on day-1 followed by 400 mg maintenance dose (2x200 mg oral, 2 times daily) on day-2 to day-5 (5 days in total).

    Favipiravir Dosage and method of administration: in a regimen of 2x1600 mg (oral) loading dose on day-1 followed by 1200 mg maintenance dose (2x600 mg, 2 times daily) on day-2 to day-5 (5 days in total). The treatment duration may be extended up to 14 days with the evaluation of principle investigator.

  • Drug: Favipiravir (3200 mg + 1200 mg) combined with Azithromycin

    Azithromycin Dosage and method of administration: in a regimen of 1x500 mg (oral) loading dose on day-1 followed by 250 mg maintenance dose (oral daily) on day-2 to day-5 (5 days in total).

    Favipiravir Favipiravir Dosage and method of administration: in a regimen of 2x1600 mg (oral) loading dose on day-1 followed by 1200 mg maintenance dose (2x600 mg, 2 times daily) on day-2 to day-5 (5 days in total). The treatment duration may be extended up to 14 days with the evaluation of principle investigator.

  • Drug: Hydroxychloroquine

    Dosage and method of administration for patients with mild possible or confirmed COVID-19 pneumonia (no severe pneumonia symptoms): in a regimen of 2x400 mg (oral) loading dose on day-1 followed by 400 mg maintenance dose (200 mg oral 2 times daily) on day-2 to day-5 (5 days in total).

    Dosage and method of administration for patients with uncomplicated possible or confirmed COVID-19: in a regimen of 400 mg (200 mg oral 2 times daily) throughout 5 days (5 days in total).

  • Drug: Hydroxychloroquine combined with Azithromycin

    Drug: Hydroxychloroquine combined with Azithromycin Hydroxychloroquine Dosage and method of administration for patients with mild possible or confirmed COVID-19 pneumonia (no severe pneumonia symptoms): in a regimen of 2x400 mg (oral) loading dose on day-1 followed by 400 mg maintenance dose (2x200 mg oral, 2 times daily) on day-2 to day-5 (5 days in total).

    Hydroxychloroquine Dosage and method of administration for patients with uncomplicated possible or confirmed COVID-19: in a regimen of 400 mg (2x200 mg oral, 2 times daily) throughout 5 days (5 days in total).

    Azithromycin Dosage and method of administration: in a regimen of 1x500 mg (oral) loading dose on day-1 followed by 250 mg maintenance dose (oral daily) on day-2 to day-5 (5 days in total).

Study Arms  ICMJE
  • Experimental: Favipiravir (3200 mg + 1200 mg)

    Dosage and method of administration: in a regimen of 2x1600 mg (oral) loading dose on day-1 followed by 1200 mg maintenance dose (2x600 mg, 2 times daily) on day-2 to day-5 (5 days in total).

    The treatment duration may be extended up to 14 days with the evaluation of principle investigator.

    Intervention: Drug: Favipiravir (3200 mg + 1200 mg)
  • Experimental: Favipiravir (3600 mg + 1600 mg)

    Dosage and method of administration: in a regimen of 2x1800 mg (oral) loading dose on day-1 followed by 1600 mg maintenance dose (2x800 mg, 2 times daily) on day-2 to day-5 (5 days in total).

    The treatment duration may be extended up to 14 days with the evaluation of principle investigator.

    Intervention: Drug: Favipiravir (3600 mg + 1600 mg)
  • Experimental: Favipiravir combined with Hydroxychloroquine

    Hydroxychloroquine Dosage and method of administration: in a regimen of 2x400 mg (oral) loading dose on day-1 followed by 400 mg maintenance dose (2x200 mg oral, 2 times daily) on day-2 to day-5 (5 days in total).

    Favipiravir Dosage and method of administration: in a regimen of 2x1600 mg (oral) loading dose on day-1 followed by 1200 mg maintenance dose (2x600 mg, 2 times daily) on day-2 to day-5 (5 days in total). The treatment duration may be extended up to 14 days with the evaluation of principle investigator.

    Intervention: Drug: Favipiravir (3200 mg + 1200 mg) combined with Hydroxychloroquine
  • Experimental: Favipiravir combined with Azithromycin

    Azithromycin Dosage and method of administration: in a regimen of 1x500 mg (oral) loading dose on day-1 followed by 250 mg maintenance dose (oral daily) on day-2 to day-5 (5 days in total).

    Favipiravir Dosage and method of administration: in a regimen of 2x1600 mg (oral) loading dose on day-1 followed by 1200 mg maintenance dose (2x600 mg, 2 times daily) on day-2 to day-5 (5 days in total). The treatment duration may be extended up to 14 days with the evaluation of principle investigator.

    Intervention: Drug: Favipiravir (3200 mg + 1200 mg) combined with Azithromycin
  • Active Comparator: Hydroxychloroquine

    Dosage and method of administration for patients with mild possible or confirmed COVID-19 pneumonia (no severe pneumonia symptoms): in a regimen of 2x400 mg (oral) loading dose on day-1 followed by 400 mg maintenance dose (200 mg oral 2 times daily) on day-2 to day-5 (5 days in total).

    Dosage and method of administration for patients with uncomplicated possible or confirmed COVID-19: in a regimen of 400 mg (200 mg oral 2 times daily) throughout 5 days (5 days in total).

    Intervention: Drug: Hydroxychloroquine
  • Active Comparator: Hydroxychloroquine combined with Azithromycin

    Hydroxychloroquine Dosage and method of administration for patients with mild possible or confirmed COVID-19 pneumonia (no severe pneumonia symptoms): in a regimen of 2x400 mg (oral) loading dose on day-1 followed by 400 mg maintenance dose (2x200 mg oral, 2 times daily) on day-2 to day-5 (5 days in total).

    Hydroxychloroquine Dosage and method of administration for patients with uncomplicated possible or confirmed COVID-19: in a regimen of 400 mg (2x200 mg oral, 2 times daily) throughout 5 days (5 days in total).

    Azithromycin Dosage and method of administration: in a regimen of 1x500 mg (oral) loading dose on day-1 followed by 250 mg maintenance dose (oral daily) on day-2 to day-5 (5 days in total).

    Intervention: Drug: Hydroxychloroquine combined with Azithromycin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 29, 2020)
1000
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 30, 2020
Estimated Primary Completion Date July 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Prof. Ateş KARA, MD +90 532 4135130 ateskara@hacettepe.edu.tr
Listed Location Countries  ICMJE Turkey
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04411433
Other Study ID Numbers  ICMJE COVID-19-FAV
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Prof. Ates KARA, MD, Hacettepe University
Study Sponsor  ICMJE Ministry of Health, Turkey
Collaborators  ICMJE
  • Hacettepe University, Faculty of Medicine
  • Prof. Dr. Cemil Tascıoglu Education and Research Hospital Organization
  • Umraniye Education and Research Hospital
  • SB Istanbul Education and Research Hospital
  • Sultan Abdulhamid Han Training and Research Hospital, Istanbul, Turkey
  • Tepecik Training and Research Hospital
  • Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine
  • Ankara University
  • Ankara City Hospital Bilkent
  • Ankara Training and Research Hospital
  • Ege University Hospital (Application and Research Center)
  • Kocaeli Derince Education and Research Hospital
  • Istanbul University, Istanbul Faculty of Medicine
  • Kayseri City Hospital
Investigators  ICMJE Not Provided
PRS Account Ministry of Health, Turkey
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP