Favipiravir vs Hydroxychloroquine vs Control in COVID -19

NCT04387760 | Completed Phase 2 DMC

• 1 other identifier: 40 / 07-May-2020
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 1

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.

Conditions

SARS-CoV 2; COVID-19

Keywords

Favipiravir; hydroxychloroquine; COVID-19

Outcome Measures

Primary Outcomes (1)

• Primary outcome is the Medial clinical scale at end of study follow up

  Median clinical scale at end of study follow up (day 14 or on discharge/death, whichever is earlier)

  Until discharge, death or for a maximum of 30 days or readmission

Secondary Outcomes (12)

• Requirement of Escalation of Respiratory Support

  Until discharge, death or for a maximum of 14 days or readmission

• Adverse effects(cardiac, renal, hepatic, hypoglycaemia (defined as RBS <3.9 mmol/L))

  Until discharge,death or for a maximum of 14 days or readmission

• Requirement of ICU Admission

  Until discharge, death or for a maximum of 14 days or readmission

• Mortality rate

  Mortality will be collected up to 30 days

• Readmission rate

  Readmission will be collected up to 30 days from start of the study

Study Arms (3)

Hydroxychloroquine

EXPERIMENTAL

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; Other: Routine care for COVID-19 patients

Favipiravir

EXPERIMENTAL

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; Other: Routine care for COVID-19 patients

Standard clinical care

ACTIVE COMPARATOR

Supportive care according to local guidelines

Other: Routine care for COVID-19 patients

Interventions

Hydroxychloroquine DRUG

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.

Also known as: Hydroxychloroquine sulfate, Plaquenil

Hydroxychloroquine

Favipiravir DRUG

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.

Also known as: Avigan, T-705, favipira, favilavir

Favipiravir

Routine care for COVID-19 patients OTHER

Supportive care according to local guidelines

Also known as: Standard clinical care

Favipiravir; Hydroxychloroquine; Standard clinical care

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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:
• Patients on medication known to prolong QT segment.
• Known history of LQT syndrome.
• Acquired QT prolongation at baseline \>500ms.
• AV block.
• Bundle Branch Block.
• Known history of Cardiomyopathy, Pulmonary Hypertension, or Sick Sinus Syndrome.
• History of ventricular tachyarrhythmia.
• Patients with implantable cardioverter-defibrillator (ICD).
• 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:
• Transaminitis more than three times the upper limit of normal or

Sponsors & Collaborators

• Royal College of Surgeons in Ireland - Medical University of Bahrain: lead
• Ebrahim Khalil Kanoo Community Medical Center: collaborator
• Hereditary blood Disorder Centre - Salmaniya Medical Complex: collaborator
• Mohammed Bin Khalifa Bin Sulman Al Khalifa Cardiac Centre, Awali: collaborator
• Jidhafs COVID-19 Centre: collaborator
• Sitra FICU: collaborator
• Salmaniya Medical Complex- 6th Floor: collaborator
• Salmaniya Medical Complex- Helipad: collaborator

Study Sites (1)

Royal College of Surgeons in Ireland - Bahrain

Manama, Bahrain

Location

Related Publications (12)

• McChesney EW. Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate. Am J Med. 1983 Jul 18;75(1A):11-8. doi: 10.1016/0002-9343(83)91265-2.

  PMID: 6408923 BACKGROUND

• Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, Li Y, Hu Z, Zhong W, Wang M. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020 Mar 18;6:16. doi: 10.1038/s41421-020-0156-0. eCollection 2020. No abstract available.

  PMID: 32194981 BACKGROUND

• Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24.

  PMID: 31986264 BACKGROUND

• Delang L, Abdelnabi R, Neyts J. Favipiravir as a potential countermeasure against neglected and emerging RNA viruses. Antiviral Res. 2018 May;153:85-94. doi: 10.1016/j.antiviral.2018.03.003. Epub 2018 Mar 7.

  PMID: 29524445 BACKGROUND

• Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discov Ther. 2020;14(1):58-60. doi: 10.5582/ddt.2020.01012.

  PMID: 32147628 BACKGROUND

• Cai Q, Yang M, Liu D, Chen J, Shu D, Xia J, Liao X, Gu Y, Cai Q, Yang Y, Shen C, Li X, Peng L, Huang D, Zhang J, Zhang S, Wang F, Liu J, Chen L, Chen S, Wang Z, Zhang Z, Cao R, Zhong W, Liu Y, Liu L. Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study. Engineering (Beijing). 2020 Oct;6(10):1192-1198. doi: 10.1016/j.eng.2020.03.007. Epub 2020 Mar 18.

  PMID: 32346491 BACKGROUND

• Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Tissot Dupont H, Honore S, Colson P, Chabriere E, La Scola B, Rolain JM, Brouqui P, Raoult D. RETRACTED: Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Jul;56(1):105949. doi: 10.1016/j.ijantimicag.2020.105949. Epub 2020 Mar 20.

  PMID: 32205204 BACKGROUND

• Birkett MA, Day SJ. Internal pilot studies for estimating sample size. Stat Med. 1994 Dec 15-30;13(23-24):2455-63. doi: 10.1002/sim.4780132309.

  PMID: 7701146 BACKGROUND

• Senn SJ. Covariate imbalance and random allocation in clinical trials. Stat Med. 1989 Apr;8(4):467-75. doi: 10.1002/sim.4780080410.

  PMID: 2727470 BACKGROUND

• Senn S. Testing for baseline balance in clinical trials. Stat Med. 1994 Sep 15;13(17):1715-26. doi: 10.1002/sim.4780131703.

  PMID: 7997705 BACKGROUND

• Knol MJ, Groenwold RH, Grobbee DE. P-values in baseline tables of randomised controlled trials are inappropriate but still common in high impact journals. Eur J Prev Cardiol. 2012 Apr;19(2):231-2. doi: 10.1177/1741826711421688. No abstract available.

  PMID: 22512015 BACKGROUND

• AlQahtani M, Kumar N, Aljawder D, Abdulrahman A, Mohamed MW, Alnashaba F, Fayyad MA, Alshaikh F, Alsahaf F, Saeed S, Almahroos A, Abdulrahim Z, Otoom S, Atkin SL. Randomized controlled trial of favipiravir, hydroxychloroquine, and standard care in patients with mild/moderate COVID-19 disease. Sci Rep. 2022 Mar 23;12(1):4925. doi: 10.1038/s41598-022-08794-w.

  PMID: 35322077 DERIVED

MeSH Terms

Conditions

COVID-19

Interventions

Hydroxychloroquine; favipiravir

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Manaf Al Qahtani, Dr.

  Royal College of Surgeons in Ireland - Bahrain

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: May 9, 2020
• First Posted: May 14, 2020
• Study Start: August 11, 2020
• Primary Completion: March 6, 2021
• Study Completion: April 7, 2021
• Last Updated: October 26, 2021

Record last verified: 2021-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, 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.

Locations

BA (1)