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Efficacy and Safety of Anti HCV Drugs in the Treatment of COVID-19

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ClinicalTrials.gov Identifier: NCT04443725
Recruitment Status : Not yet recruiting
First Posted : June 23, 2020
Last Update Posted : June 25, 2020
Sponsor:
Information provided by (Responsible Party):
Gamal Esmat, Cairo University

Tracking Information
First Submitted Date  ICMJE June 20, 2020
First Posted Date  ICMJE June 23, 2020
Last Update Posted Date June 25, 2020
Estimated Study Start Date  ICMJE July 2020
Estimated Primary Completion Date October 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 20, 2020)
Virological cure [ Time Frame: 28 days ]
virological cure using the triple therapy as compared to mono hydroxychloroquine treatment..
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
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 Anti HCV Drugs in the Treatment of COVID-19
Official Title  ICMJE Efficacy and Safety of Anti-hepatitis C Drugs in the Treatment of COVID-19
Brief Summary

COVID 19 which started from a zoonotic transmission related to crowded markets was confirmed to have a high potential for transmission to close contacts on 20 January 2020 by the National Health Commission of China and it was announced as a pandemic by the WHO on 11 March 2020.

There is currently no clinically proven specific antiviral agent available for SARS-CoV-2 infection. Supportive treatment, including oxygen therapy, conservation fluid management, and broad-spectrum antibiotics to cover secondary bacterial infection, remains the most important management strategy.

Interestingly, sofosbuvir has recently been proposed as an antiviral for the SARS-CoV-2 based on the similarity between the replication mechanisms of the HCV and the coronaviruses.

Aim of the study is to assess the safety and efficacy of of the addition of HCV treatment to the standard regimen for the treatment of patients who are candidates to receive Hydroxy Chloroquine according to Egyptian MOHP protocol

Detailed Description

In December, 2019, an outbreak of pneumonia with unknown cause occurred in Wuhan city, the capital of Hubei province in China. On January 7th, the scientists succeeded to isolate a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). WHO nominated it as coronavirus disease 2019 (COVID-19) in February, 2020.

COVID 19 which started from a zoonotic transmission related to crowded markets was confirmed to have a high potential for transmission to close contacts on 20 January 2020 by the National Health Commission of China and it was announced as a pandemic by the WHO on 11 March 2020.

SARS-CoV-2 infection have a wide clinical spectrum ranging between asymptomatic infection, mild upper respiratory tract symptoms, and severe viral pneumonia (fever, malaise, dry cough, shortness of breath, and respiratory distress) that may result in respiratory failure and finally death.

There is currently no clinically proven specific antiviral agent available for SARS-CoV-2 infection. Supportive treatment, including oxygen therapy, conservation fluid management, and broad-spectrum antibiotics to cover secondary bacterial infection, remains the most important management strategy.

For direct antiviral treatment of SARS-CoV-2, the China International Exchange and Promotive Association for Medical and Health Care (CPAM) recommended usage of lopinavir; ritonavir. Their recommendation was based on weak evidence from retrospective cohort, historically controlled studies, case reports, and case series reporting a clinical benefit of lopinavir; ritonavir in the management of other coronavirus infection [i.e., SARS-CoV 1 and Middle East respiratory syndrome coronavirus (MERS-CoV)] .

However, the first randomized clinical trial with lopinavir/ritonavir demonstrated no benefit over standard care in 199 hospitalized adults with severe COVID-19. There is no evidence to support the use of other antiretrovirals, including protease inhibitors; indeed, structural analysis demonstrates no darunavir binding to COVID-19 protease.

A group of Korean physicians experienced in SARS-CoV-2 infected patients' treatment developed recommendations for the treatment of COVID-19. According to them, antiviral medications lopinavir 400 mg; ritonavir 100 mg or chloroquine is considered to be used in older patients or patients with chronic health conditions and life threatening symptoms. If chloroquine is unavailable, hydroxychloroquine is recommended. Both of them have reported ability of inhibition of SARS-CoV-2 in vitro.

CPAM guidelines included them as they were associated with reduced progression of disease and decreased duration of symptoms. In an open-label study of 36 patients with COVID-19, use of hydroxychloroquine (200 mg three times per day for 10 days) was associated with a higher rate of undetectable SARS-CoV-2 RNA on nasopharyngeal specimens at day 6 compared with no specific treatment (70 versus 12.5 percent). In this study, the use of azithromycin in combination with hydroxychloroquine appeared to have additional benefit, but there are methodologic concerns about the control groups for the study, and the biologic basis for using azithromycin in this setting is unclear. In the United States, the FDA issued an emergency use authorization to allow the use of these agents in adolescents or adults hospitalized for COVID-19.

One of the studies done on SARS-COV-1 strongly suggested that using ribavirin as therapy should be reconsidered until further animal studies clarify the effects of ribavirin on cytokine and chemokine profiles during an infection and until ribavirin can be demonstrated to have a significant effect on reducing viral replication in vivo. Data from a molecular docking experiment using the SARS-CoV-2 RNA dependent RNA polymerase (RdRp) model identified tight binding of sofosbuvir and ribavirin to the coronavirus RdRp, thereby suggesting possible efficacy of sofosbuvir and ribavirin in treating the COVID-19 infection.

Chen et al. prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like protease (3CL ) then performed virtual screening for purchasable drugs checking the actions, targets and side effects of the 16 candidates. Among these, we first noticed velpatasvir and ledipasvir, which are inhibitors of the NS5A protein of the hepatitis C virus (HCV). Both are marketed as approved drugs in combination with sofosbuvir, which is a prodrug nucleotide analogue inhibitor of RNA-dependent RNA polymerase (RdRp, or NS5B).

Interestingly, sofosbuvir has recently been proposed as an antiviral for the SARS-CoV-2 based on the similarity between the replication mechanisms of the HCV and the coronaviruses.

Based on this data the investigators suggest that these dual-component HCV drugs, Epclusa (velpatasvir/sofosbuvir) and Harvoni (ledipasvir/sofosbuvir), may be attractive candidates to repurpose because they may inhibit two coronaviral enzymes. A drug that can target two viral proteins substantially reduces the ability of the virus to develop resistance. These direct-acting antiviral drugs are also associated with very minimal side effects and are conveniently orally administered.

Aim of the study is to assess the safety and efficacy of the addition of HCV treatment to the standard regimen for the treatment of patients who are candidates to receive Hydroxy Chloroquine according to MOHP protocol.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE COVID-19
Intervention  ICMJE
  • Drug: Hydroxychloroquine , Sofosbuvir, daclatasvir
    Hydroxychloroquine (hydroxychloroquine 400 mg by mouth twice daily for 1 day, then 200 mg by mouth twice daily for 14 days (dose reductions for weight < 45 kg or GFR (glomerular filtration rate) <50ml/min) alone; as provided by the MOHP protocol), Sofosbuvir 400 mg once daily for 14 days and daclatasvir 90 mg for 14 days.
  • Drug: Standard of care treatment
    Hydroxychloroquine (hydroxychloroquine 400 mg by mouth twice daily for 1 day, then 200 mg by mouth twice daily for 14 days (dose reductions for weight < 45 kg or GFR (glomerular filtration rate) <50ml/min) alone; as provided by the MOHP protocol),
Study Arms  ICMJE
  • Experimental: Hydroxychloroquine plus Sofosbuvir/Daclatasvir
    Hydroxychloroquine (hydroxychloroquine 400 mg by mouth twice daily for 1 day, then 200 mg by mouth twice daily for 14 days, Sofosbuvir 400 mg once daily for 14 days and daclatasvir 90 mg for 14 days
    Intervention: Drug: Hydroxychloroquine , Sofosbuvir, daclatasvir
  • Active Comparator: Standard of care
    Hydroxychloroquine 400 mg by mouth twice daily for 1 day, then 200 mg by mouth twice daily for 14 days
    Intervention: Drug: Standard of care treatment
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 Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: June 20, 2020)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2020
Estimated Primary Completion Date October 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • positive reverse-transcriptase-polymerase chain- reaction (RT-PCR) assay for SARS- CoV-2 in a respiratory tract sample

Exclusion Criteria:

  • ● Known allergy or hypersensitivity to the used medications

    • Known severe liver disease (e.g., cirrhosis, with an alanine aminotransferase level >5× the upper limit of the normal range or an aspartate aminotransferase level >5× the upper limit of the normal range)
    • Use of medications that are contraindicated with the trial medications and that could not be replaced or stopped during the trial period
    • Pregnancy or breast-feeding or known active HCV infection, because of concerns about the development of resistance
    • History of bone marrow transplant
    • Known G6PD deficiency
    • Chronic hemodialysis or Glomerular Filtration Rate < 20ml/min
    • Psoriasis
    • Porphyria
    • Concomitant use of digitalis, flecainide, amiodarone, procainamide, or propafenone
    • Known history of long QT syndrome
    • Current known QTc>500 msec
    • Pregnant or nursing
    • Weight < 35kg
    • Seizure disorder
    • Patients receiving Amiodarone.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04443725
Other Study ID Numbers  ICMJE CUKA-003
Has Data Monitoring Committee Yes
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
Plan to Share IPD: Undecided
Responsible Party Gamal Esmat, Cairo University
Study Sponsor  ICMJE Cairo University
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Cairo University
Verification Date June 2020

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