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Favipiravir vs Hydroxychloroquine vs Control in COVID -19

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ClinicalTrials.gov Identifier: NCT04387760
Recruitment Status : Recruiting
First Posted : May 14, 2020
Last Update Posted : March 9, 2021
Sponsor:
Collaborators:
Ebrahim Khalil Kanoo Community Medical Center
Hereditary blood Disorder Centre - Salmaniya Medical Complex
Mohammed Bin Khalifa Bin Sulman Al Khalifa Cardiac Centre, Awali
Jidhafs COVID-19 Centre
Sitra FICU
Salmaniya Medical Complex- 6th Floor
Salmaniya Medical Complex- Helipad
Information provided by (Responsible Party):
Royal College of Surgeons in Ireland - Medical University of Bahrain

Brief Summary:

Hydroxychloroquine is widely used to treat autoimmune diseases. Clinical investigation has found that a high concentration of cytokines were detected in the plasma of critically ill patients infected with SARS-CoV-2, therefore, hydroxychloroquine as anti-inflammatory agents may reduce this response in accord with their use in autoimmune disease where the cytokine response can be reduced.

Favipiravir is an antiviral drug developed in Japan that the data sheet notes that it is a pyrazinecarboxamide derivative with activity against influenza viruses, west nile virus, yellow fever virus, foot and mouth disease virus as well as against flaviviruses, arenaviruses, bunyaviruses and alphaviruses. In February the drug was used for COVID-19 disease in China and was declared effective in treatment, and a report published (in press) comparing Favipiravir with Lopinavir /ritonavir suggested that Favipiravir was superior for prevention of disease progression and viral clearance.

The objective of this pilot study is to compare three arms: hydroxychloroquine; favipiravir; standard care (no specific SARS-CoV-2 treatment) only, in symptomatic patients infected by SARS-CoV-2 in an open label randomized clinical trial. The difference between groups will allow an effect size to be determined for a definitive clinical trial.


Condition or disease Intervention/treatment Phase
SARS-CoV 2 COVID-19 Drug: Hydroxychloroquine Drug: Favipiravir Other: Routine care for COVID-19 patients Phase 2

Detailed Description:

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/2019-nCoV) and has developed into a pandemic with serious global public health and economic sequelae. As of June 30, 2020 over 10,000,000 cases have been confirmed worldwide leading to over 500,000 deaths (https://coronavirus.jhu.edu/map.html). Currently no vaccine exists, however chloroquine and hydroxychloroquine have been documented as potentially having antiviral properties with efficacy against COVID-19 disease. Chloroquine is used in the treatment of malaria and amebiasis and is still used in the prophylaxis of malaria. Hydroxychloroquine sulfate is a derivative of Chloroquine that has been demonstrated to be much less (~40%) toxic than Chloroquine in animals. Hydroxychloroquine is widely used to treat autoimmune diseases, due to its immunomodulatory properties, such as systemic lupus erythematosus and rheumatoid arthritis, with an excellent safety profile. In vitro studies have suggested that their mode of action in COVID-19 disease is blockade of SARS-CoV-2 transport from endosomes to endolysosomes, which appears to be a requirement to release the viral genome. Clinical investigation has found that high concentrations of cytokines are detectable in the plasma of critically ill patients infected with SARS-CoV-2, suggesting that cytokine storm is associated with disease severity; therefore, Chloroquine/ hydroxychloroquine may reduce this response by acting as anti-inflammatory agents in accord with their use in autoimmune disease, where their reduction in cytokine response has been extensively researched and demonstrated.

Favipiravir is an antiviral drug developed in Japan (as noted in the data sheets) that it is a pyrazinecarboxamide derivative with activity against influenza viruses, west nile virus, yellow fever virus, foot and mouth disease virus as well as against flaviviruses (i.e. arenaviruses, bunyaviruses and alphaviruses). Its mode of action is through inhibition of viral RNA-dependent RNA polymerase. In February the drug was used for COVID-19 disease in China and was declared effective in treatment, and a report published (in press) comparing Favipiravir with Lopinavir /ritonavir suggested that Favipiravir was superior for prevention of disease progression and viral clearance.

"The Solidarity Trial" is a global pragmatic clinical trial being undertaken by WHO that aims to explore the efficacy of different treatment modalities for SARS-CoV-2. An application for Bahrain to join the study for collaboration has been made. In "The Solidarity Study" there will be four treatment modalities investigated, including chloroquine phosphate alone, remdesivir, lopinarvir with ritonavir or lopinarvir with ritonavir plus interferon. Favipiravir is not included, and therefore this study will not be replicating features of "The Solidarity Trial" but instead will provide additional and novel findings on favipiravir efficacy.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This is a parallel, prospective, interventional and randomized open label pilot trial involving 150 patients with COVID-19 disease. On confirmation of SARS-CoV-2 infection subjects will be randomised to hydroxychloroquine or favipiravir or standard clinical care.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Treatment of Covid-19 With Favipiravir Versus Hydroxychloroquine: a Randomized Comparator Trial
Actual Study Start Date : August 11, 2020
Estimated Primary Completion Date : April 14, 2021
Estimated Study Completion Date : May 14, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Hydroxychloroquine
Hydroxychloroquine is widely used to treat autoimmune diseases, due to its immunomodulatory properties, such as systemic lupus erythematosus and rheumatoid arthritis, with an excellent safety profile. In vitro studies have suggested that their mode of action in COVID-19 disease is blockade of SARS-CoV-2 transport from endosomes to endolysosomes, which appears to be a requirement to release the viral genome.
Drug: Hydroxychloroquine

400mg BID PO day 1 then 200mg BID PO from day 2 to day 10.

In addition to Hydroxychloroquine all patients will receive the standard care (according to local Bahrain COVID19 guidelines). Any patient who is fit for discharge, can be discharged and medications will be stopped on discharge.

Other Names:
  • Hydroxychloroquine sulfate
  • Plaquenil

Other: Routine care for COVID-19 patients
Supportive care according to local guidelines
Other Name: Standard clinical care

Experimental: Favipiravir
Favipiravir is an antiviral drug that it is a pyrazinecarboxamide derivative with activity against influenza viruses, west nile virus, yellow fever virus, foot and mouth disease virus as well as against flaviviruses (i.e. arenaviruses, bunyaviruses and alphaviruses).
Drug: Favipiravir

1600mg BID PO day 1600mg BID PO day 2 to day 10.

In addition to Favipiravir all patients will receive the standard care (according to local Bahrain COVID19 guidelines). Any patient who is fit for discharge, can be discharged and medications will be stopped on discharge.

Other Names:
  • Avigan
  • T-705
  • favipira
  • favilavir

Other: Routine care for COVID-19 patients
Supportive care according to local guidelines
Other Name: Standard clinical care

Active Comparator: Standard clinical care
Supportive care according to local guidelines
Other: Routine care for COVID-19 patients
Supportive care according to local guidelines
Other Name: Standard clinical care




Primary Outcome Measures :
  1. Primary outcome is the Medial clinical scale at end of study follow up [ Time Frame: Until discharge, death or for a maximum of 30 days or readmission ]
    Median clinical scale at end of study follow up (day 14 or on discharge/death, whichever is earlier)


Secondary Outcome Measures :
  1. Requirement of Escalation of Respiratory Support [ Time Frame: Until discharge, death or for a maximum of 14 days or readmission ]
    Implementation of escalation of Respiratory Support

  2. Adverse effects(cardiac, renal, hepatic, hypoglycaemia (defined as RBS <3.9 mmol/L)) [ Time Frame: Until discharge,death or for a maximum of 14 days or readmission ]
    Monitor and document all adverse effects during therapy

  3. Requirement of ICU Admission [ Time Frame: Until discharge, death or for a maximum of 14 days or readmission ]
    Deterioration of clinical condition requiring ICU admission

  4. Mortality rate [ Time Frame: Mortality will be collected up to 30 days ]
    30 days Mortality rate due to COVID-19

  5. Readmission rate [ Time Frame: Readmission will be collected up to 30 days from start of the study ]
    30 days readmission rate will be captured

  6. Daily National Early Warning (NEWS) 2 Score [ Time Frame: Until discharge, death or for a maximum of 14 days ]
    Daily NEWS 2 will be calculated which is a tool that improves the detection and response to clinical deterioration in adult patients and is a key element of patient safety and improving patient outcomes

  7. Daily Sequential Organ Failure Assessment (SOFA) score [ Time Frame: Until discharge, death or for a maximum of 14 days ]
    Daily SOFA score will be calculated which can identify the critical point at which patients exhibit the highest degree of organ dysfunction

  8. Change in Laboratory indices [ Time Frame: Until discharge, death or for a maximum of 14 days ]
    Determination of the change in D-dimer, ratio of Lymphocyte to Neutrophil, lactate before and after treatments as a measure of disease activity

  9. Discharge and Length of Hospital Stay [ Time Frame: Until discharge, death or for a maximum of 14 days ]
    Patients will be followed during their hospital stay until discharge

  10. QT prolongation [ Time Frame: Until discharge, death or for a maximum of 14 days or readmission ]
    Determination of the change in QT prolongation, before and after treatments as a measure of disease activity

  11. Cardiac arrythmia (fatal and non fatal) [ Time Frame: Until discharge, death or for a maximum of 14 days or readmission ]
    Detection of Cardiac arrythmia (fatal and non fatal), before and after treatments as a measure of disease activity

  12. Viral clearance [ Time Frame: until discharge, death or for a maximum of 30 days ]
    Viral clearance defined as a single negative SARS-CoV2 PCR nasopharyngeal swab



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   21 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Admitted COVID-19 patients being treated as an in-patient at a hospital facility.
  • COVID-19 diagnosis confirmed by PCR nasopharyngeal swab.
  • Study participants must be symptomatic with any COVID-19 symptoms defined by the Bahrain National Protocol
  • Onset of symptoms must be within 10 days prior to enrolment.
  • Study participants must have the ability to give informed consent.
  • Participants must be at minimum 21 years of age.
  • Mild to Moderate COVID-19 disease defined as saturation equals to or more than 93% on room air or PaO2:FiO2 ratio more than 300 on enrolment.

Exclusion Criteria:

  • Severe COVID-19 disease: defined as presence of SpO₂ less than 93% on room air or a PaO₂ to FiO₂ ratio of 300 or lower.
  • Patients on ventilatory support.
  • Cardiac dysfunction that would preclude treatment with hydroxychloroquine:

    1. Patients on medication known to prolong QT segment.
    2. Known history of LQT syndrome.
    3. Acquired QT prolongation at baseline >500ms.
    4. AV block.
    5. Bundle Branch Block.
    6. Known history of Cardiomyopathy, Pulmonary Hypertension, or Sick Sinus Syndrome.
    7. History of ventricular tachyarrhythmia.
    8. Patients with implantable cardioverter-defibrillator (ICD).
    9. Patients with a baseline bradycardia of less than 50 beats per minute.
  • Renal dysfunction (estimated glomerular filtration rate less than 30ml/min).
  • Hepatic dysfunction defined as:

    1. Transaminitis more than three times the upper limit of normal or
    2. Chronic liver disease of Child Pugh Class B or higher.
  • Gout or a history of gout
  • Patients that are pregnant or breastfeeding.
  • Patients with a known allergy to an intervention medication.
  • Patients who receive any of the study medications prior to randomization
  • Patient with G6PD
  • Readmission due to COVID19 disease.
  • Participants in any other COVID-19 disease trial.
  • Patients on immunosuppressants, HIV patients, cancer patients who received chemotherapy within the past 6 months, or who are on chronic oral steroids.
  • Patients unable to give informed consent.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04387760


Contacts
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Contact: Manaf Al Qahtani, Dr. +97339766000 mqahtani@rcsi-mub.com
Contact: Sawsan Saeed, MDPH. +97333652016 SSaeed@rcsi-mub.com

Locations
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Bahrain
Royal College of Surgeons in Ireland - Bahrain Recruiting
Manama, Bahrain
Contact: Manaf Al Qahtani, Dr.    +97339766000    mqahtani@rcsi-mub.com   
Contact: Sawsan Saeed, MDPH.    +97333652016    SSaeed@rcsi-mub.com   
Principal Investigator: Manaf Al Qahtani, Dr.         
Sub-Investigator: Abdulkarim Abdulrahman, Dr.         
Sub-Investigator: Salman Yousif Alali, Dr.         
Sub-Investigator: Mohamed Wael, Dr.         
Sub-Investigator: Stephen Atkin, Prof.         
Sub-Investigator: Sameer Otoom, Prof.         
Sub-Investigator: Dhuha Aljawder, Dr.         
Sub-Investigator: Sawsan Saeed, MDPH.         
Sub-Investigator: Zainab Abdulrahim, Dr.         
Sub-Investigator: Shereen AlShaikh, Dr.         
Sub-Investigator: Mohammed Ayed, Dr.         
Sub-Investigator: Alaa Al Zamrooni, Dr.         
Sub-Investigator: Faisal AlShaikh, Ph.         
Sponsors and Collaborators
Royal College of Surgeons in Ireland - Medical University of Bahrain
Ebrahim Khalil Kanoo Community Medical Center
Hereditary blood Disorder Centre - Salmaniya Medical Complex
Mohammed Bin Khalifa Bin Sulman Al Khalifa Cardiac Centre, Awali
Jidhafs COVID-19 Centre
Sitra FICU
Salmaniya Medical Complex- 6th Floor
Salmaniya Medical Complex- Helipad
Investigators
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Principal Investigator: Manaf Al Qahtani, Dr. Royal College of Surgeons in Ireland - Bahrain
Publications:

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Responsible Party: Royal College of Surgeons in Ireland - Medical University of Bahrain
ClinicalTrials.gov Identifier: NCT04387760    
Other Study ID Numbers: 40 / 07-May-2020
First Posted: May 14, 2020    Key Record Dates
Last Update Posted: March 9, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Monitoring, audits, and REC review will be permitted and provide direct access to source data and documents. The Lead PI and the researchers assigned by him will have access to the stored data/specimens. Only the Lead PI and the researchers assigned working on this study will be eligible to obtain the data/specimens from the participants during data collection.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Analytic Code
Time Frame:

Dr Manaf will act as the data custodian and is responsible for the storage, handling and quality of the study data.

Data will be collected in the case report form to allow for cross referencing to check validity.

Study documents (paper and electronic) will be retained in a secure (kept locked when not in use) location during and after the trial has finished. All essential documents including source documents will be retained for a period of 5 years after study completion (last patient, last study point). A label stating the date after which the documents can be destroyed will be placed on the inside front cover of the case notes of trial participants.

Access Criteria: Study documents (paper and electronic) will be retained in a secure (kept locked when not in use) location during and after the trial has finished.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Royal College of Surgeons in Ireland - Medical University of Bahrain:
Favipiravir
hydroxychloroquine
COVID-19
Additional relevant MeSH terms:
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Hydroxychloroquine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents