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Favipiravir vs Hydroxychloroquine in COVID -19

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ClinicalTrials.gov Identifier: NCT04387760
Recruitment Status : Not yet recruiting
First Posted : May 14, 2020
Last Update Posted : May 14, 2020
Sponsor:
Collaborators:
Bahrain Defence Force Royal Medical Services, Military Hospital
Ebrahim Khalil Kanoo Community Medical Center
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 3 arms: hydroxychloroquine; favipiravir; supportive 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 Phase 3

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 April 27, 2020 over 2,973,000 cases have been confirmed worldwide leading to over 206,000 deaths (https://coronavirus.jhu.edu/map.html). There is no current vaccine available, but there have been a number of reports of chloroquine and hydroxychloroquine 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 to block the transport of SARS-CoV-2 from endosomes to endolysosomes, which appears to be a requirement to release the viral genome as in the case of SARS-CoV. Clinical investigation has found that a high concentration of cytokines were detected in the plasma of critically ill patients infected with SARS-CoV-2, suggesting that cytokine storm was associated with disease severity; therefore, Chloroquine/ 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. 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.

A large pragmatic clinical trial is being undertaken globally by WHO, the solidarity trial, and application has been made in Bahrain to be part of that study. In the solidarity study there are to be 4 arms; chloroquine phosphate alone, remdesivir, lopinarvir with ritonavir or lopinarvir with ritonavir plus interferon. It may therefore be seen that this Favipiravir does not replicate the features of the solidarity trial.

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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
Estimated Study Start Date : May 14, 2020
Estimated Primary Completion Date : July 14, 2020
Estimated Study Completion Date : August 14, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Hydroxychloroquine
400mg BID PO day 1 then 200mg BID PO from day 2-day 10.
Drug: Hydroxychloroquine
In addition to Hydroxychloroquine all patients will receive the standard clinical care according to local Bahrain COVID19 guidelines
Other Names:
  • Hydroxychloroquine sulfate
  • Plaquenil

Other: Routine care for COVID-19 patients
Local standard of care which include antivirals and supportive care
Other Name: Standard clinical care

Experimental: Favipiravir
1600mg BID PO day 1, 600mg BID PO day 2 to 10.
Drug: Favipiravir
In addition to Favipiravir all patients will receive the standard clinical care according to local Bahrain COVID19 guidelines
Other Names:
  • Avigan
  • T-705
  • favipira
  • favilavir

Other: Routine care for COVID-19 patients
Local standard of care which include antivirals and supportive care
Other Name: Standard clinical care

Active Comparator: Standard clinical care
Local standard of care which include antivirals and supportive care
Other: Routine care for COVID-19 patients
Local standard of care which include antivirals and supportive care
Other Name: Standard clinical care




Primary Outcome Measures :
  1. Primary outcome measure will be time to viral clearance [ Time Frame: through study completion up to 21 days ]
    Two consecutive negative (SARS-CoV-2 PCR) nasopharyngeal swabs


Secondary Outcome Measures :
  1. Requirement of Escalation of Respiratory Support [ Time Frame: through study completion up to 21 days ]
    Implementation of escalation of Respiratory Support

  2. Time until resolution of presenting symptoms [ Time Frame: through study completion up to 21 days ]
    Time frame for presenting symptoms to resolve

  3. Adverse effects [ Time Frame: through study completion up to 21 days ]
    Monitor and document all adverse effects during therapy

  4. Requirement of ICU Admission [ Time Frame: through study completion up to 21 days ]
    Deterioration of clinical condition requiring ICU admission

  5. Mortality rate [ Time Frame: Mortality will be collected at 28 days ]
    Mortality rate due to COVID-19

  6. Serum lactate measurement [ Time Frame: through study completion up to 21 days ]
    Determination of the change in lactate levels before and after treatment as a measure of disease activity

  7. Serum Ferritin measurement [ Time Frame: through study completion up to 21 days ]
    Determination of the change in ferritin levels before and after treatments as a measure of disease activity

  8. Serum D Dimer measurement [ Time Frame: through study completion up to 21 days ]
    Determination of the change in D Dimer levels before and after treatments as a measure of disease activity

  9. Serum procalcitonin measurement [ Time Frame: through study completion up to 21 days ]
    Determination of the change in procalcitonin levels before and after treatments as a measure of disease activity

  10. Serum brain naturetic peptide measurement [ Time Frame: through study completion up to 21 days ]
    Determination of the change in brain naturetic peptide levels before and after treatments as a measure of disease activity

  11. Ratio of Lymphocyte to Neutrophil, measurement [ Time Frame: through study completion up to 21 days ]
    Determination of the change in Ratio of Lymphocyte to Neutrophil, before and after treatments as a measure of disease activity



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:

  • COVID-19 diagnosis in the last 48hrs confirmed by PCR nasopharyngeal swab.
  • Symptomatic with at least 1 of the following symptoms : Oral Temperature >37.8C, cough, shortness of breath, extreme fatigue, headache, myalgia or Sore throat
  • Able to give informed consent
  • Patients between the ages of 21 and above with no upper age.

Exclusion Criteria:

  • Asymptomatic.
  • Patient unable to give informed consent.
  • Cardiac dysfunction that would preclude treatment with hydroxychloroquine (known cardiomyopathy, known ventricular arrhythmia, presence of pacemaker), prolonged QT interval, prolonged PR interval, Heart block prior to randomization
  • Renal dysfunction (estimated glomerular filtration rate less than 45ml/min)
  • Hepatic dysfunction defined as Transaminitis more the 3 times the upper limit of normal or chronic liver disease of Child Pugh Class B or more
  • Gout/history of gout or hyperuricemia (above the ULN)
  • Pregnant or lactating female patients (all premenapausal female patients will need a pregnancy test if randomised to Favipiravir)
  • Patients with known allergies to intervention medications
  • Readmission due to COVID19 disease
  • Randomised to any other COVID-19 disease trial
  • Patients on immunosuppressants, HIV patients, Malignancy; patients who received chemotherapy within the last 6 months or on chronic oral steroids.

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: Pearl Wasif, MSc. +97333180191 PSulaiman@rcsi-mub.com

Locations
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Bahrain
Royal College of Surgeons in Ireland - Bahrain
Manama, Bahrain
Contact: Manaf Al Qahtani, Dr.    +97339766000    mqahtani@rcsi-mub.com   
Contact: Pearl Wasif, MSc.    +97333180191    PSulaiman@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: Pearl Wasif, MSc.         
Sub-Investigator: Omar Yaghi, Dr.         
Sub-Investigator: Sawsan Saeed, MDPH         
Sponsors and Collaborators
Royal College of Surgeons in Ireland - Medical University of Bahrain
Bahrain Defence Force Royal Medical Services, Military Hospital
Ebrahim Khalil Kanoo Community Medical Center
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: May 14, 2020
Last Verified: May 2020
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