Efficacy and Safety of Direct Anti HCV Drugs in the Treatment of SARS-COV-2 (COVID-19) (CCOVID-19)

• ClinicalTrials.gov Identifier: NCT04535869
• Recruitment Status: Recruiting
• First Posted: September 2, 2020
• Last Update Posted: February 24, 2021
• Sponsor: Mansoura University
• Information provided by (Responsible Party): Mahmoud Elbendary, Mansoura University

Study Description

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 our study is to assess the safety and efficacy of of the addition of HCV treatment to the standard regimen for the treatment of patients according to MOHP protocol.

Condition or disease	Intervention/treatment	Phase
COVID-19	Drug: Sofosbuvir 400 MG plus Daclatasvir 200mg	Phase 3

Detailed Description:

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 the ability of inhibition of SARS-CoV-2 in vitro.

CPAM guidelines included them as they were associated with reduced progression of the disease and decreased duration of symptoms. In an open-label study of 36 patients with COVID-19, the 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 an 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 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 the tight binding of sofosbuvir and ribavirin to the coronavirus RdRp, thereby suggesting possible efficacy of sofosbuvir and ribavirin in treating the COVID-19 infection.

A three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like protease (3CL ) was prepared then performed virtual screening for purchasable drugs checking the actions, targets, and side effects of the 16 candidates. Velpatasvir and ledipasvir are examples of these drugs ( 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 analog 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 it was suggested 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.

The aim of this study is to assess the safety and efficacy of the addition of HCV treatment to the standard regimen for the treatment of COVID-19 patients according to MOHP protocol .

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 50 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Direct Anti HCV Drugs in the Treatment of SARS-COV-2 (COVID-19)
• Actual Study Start Date: December 28, 2020
• Estimated Primary Completion Date: April 1, 2021
• Estimated Study Completion Date: September 3, 2021

Arms and Interventions

Arm	Intervention/treatment
No Intervention: A)standard therapy group; No intervention COVID- 19 patients who received a standard therapy group according to the ministry of health protocol
Active Comparator: B)Standard Therapy group plus Ant-HCV drugs; Intervention COVID- 19 patients who received a standard therapy group according to the ministry of health protocol plus sofosbuvir 400 mg and Daclatasvir 200mg	Drug: Sofosbuvir 400 MG plus Daclatasvir 200mg; This group which receive sofosbuvir and daclatasvir for 14 days plus standard therapy; Other Name: Direct antiviarl agents

Outcome Measures

Primary Outcome Measures :

1. rate of virological cure by Rt -PCR for COVID -19using the triple therapy as compared to standard treatment [ Time Frame: for every case must be done after 2 weeks from the start of treatment. ]
   All PCR for COVID must be negative

Secondary Outcome Measures :

1. resolution of pneumonia BY high resolution Computed tomography [ Time Frame: Computed tomography must be done after 2 weeks to detect resolution of pneumonia ]
   clinical status as assessed by earlier resolution of pneumonia in the intervention arm when compared to the control group

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• All cases positive for COVID-19
• Male and non-pregnant female patients,
• 18 years of age or older,
• All moderate and severe caseswith pneuomnia.

Exclusion Criteria:

• Known allergy or hypersensitivity to the used medications
• Known severe liver disease
• 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.

Contacts and Locations

Contacts

Contact: Mahmoud El-Bendary, M.D; 00201002592205; mmelbendary@gmail.com

Contact: Hatem Elalfy, M.D; 00201224790518; elalfy_hatem66@yahoo.com

Locations

Egypt

Mansoura Faculty of Medicine; Recruiting

Mansoura, Dakahlyia, Egypt, 35516

Contact: Mahmoud El-Bendary, M.D 00201002592205 mmelbendary@gmail.com

Sponsors and Collaborators

Mansoura University

More Information

Publications of Results:

Phelan AL, Katz R, Gostin LO. The Novel Coronavirus Originating in Wuhan, China: Challenges for Global Health Governance. JAMA. 2020 Feb 25;323(8):709-710. doi: 10.1001/jama.2020.1097.

Other Publications:

Hallin RW. Femoropopliteal versus femorotibial bypass grafting for lower extremity revascularization. Am Surg. 1976 Jul;42(7):522-6.

Depo-Provera may be linked to uterine cancer, preliminary data imply. Fam Plann Perspect. 1979 Jan-Feb;11(1):47.

O'Brien PJ, Hawco FJ. Hydroxyl-radical formation during prostaglandin formation catalysed by prostaglandin cyclo-oxygenase [proceedings]. Biochem Soc Trans. 1978;6(6):1169-71.

Kirkegaard C, Faber J, Hummer L, Rogowski P. Increased levels of TRH in cerebrospinal fluid from patients with endogenous depression. Psychoneuroendocrinology. 1979 Jul;4(3):227-35.

• Responsible Party: Mahmoud Elbendary, Professor of Tropical Medicine and Hepatogastroenterology, Mansoura University
• ClinicalTrials.gov Identifier: NCT04535869
• Other Study ID Numbers: MS.20.08.1214
• First Posted: September 2, 2020
• Last Update Posted: February 24, 2021
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Mahmoud Elbendary, Mansoura University:

COVID; Anti- HCV drugs,; Sofosbuvir; Daclatasvir; DAAs; Efficacy

Additional relevant MeSH terms:

Sofosbuvir; Antiviral Agents; Anti-Infective Agents