<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04443725</url>
  </required_header>
  <id_info>
    <org_study_id>CUKA-003</org_study_id>
    <nct_id>NCT04443725</nct_id>
  </id_info>
  <brief_title>Efficacy and Safety of Anti HCV Drugs in the Treatment of COVID-19</brief_title>
  <official_title>Efficacy and Safety of Anti-hepatitis C Drugs in the Treatment of COVID-19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cairo University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Cairo University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      COVID 19 which started from a zoonotic transmission related to crowded markets was confirmed&#xD;
      to have a high potential for transmission to close contacts on 20 January 2020 by the&#xD;
      National Health Commission of China and it was announced as a pandemic by the WHO on 11 March&#xD;
      2020.&#xD;
&#xD;
      There is currently no clinically proven specific antiviral agent available for SARS-CoV-2&#xD;
      infection. Supportive treatment, including oxygen therapy, conservation fluid management, and&#xD;
      broad-spectrum antibiotics to cover secondary bacterial infection, remains the most important&#xD;
      management strategy.&#xD;
&#xD;
      Interestingly, sofosbuvir has recently been proposed as an antiviral for the SARS-CoV-2 based&#xD;
      on the similarity between the replication mechanisms of the HCV and the coronaviruses.&#xD;
&#xD;
      Aim of the study is to assess the safety and efficacy of of the addition of HCV treatment to&#xD;
      the standard regimen for the treatment of patients who are candidates to receive Hydroxy&#xD;
      Chloroquine according to Egyptian MOHP protocol&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In December, 2019, an outbreak of pneumonia with unknown cause occurred in Wuhan city, the&#xD;
      capital of Hubei province in China. On January 7th, the scientists succeeded to isolate a&#xD;
      novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). WHO&#xD;
      nominated it as coronavirus disease 2019 (COVID-19) in February, 2020.&#xD;
&#xD;
      COVID 19 which started from a zoonotic transmission related to crowded markets was confirmed&#xD;
      to have a high potential for transmission to close contacts on 20 January 2020 by the&#xD;
      National Health Commission of China and it was announced as a pandemic by the WHO on 11 March&#xD;
      2020.&#xD;
&#xD;
      SARS-CoV-2 infection have a wide clinical spectrum ranging between asymptomatic infection,&#xD;
      mild upper respiratory tract symptoms, and severe viral pneumonia (fever, malaise, dry cough,&#xD;
      shortness of breath, and respiratory distress) that may result in respiratory failure and&#xD;
      finally death.&#xD;
&#xD;
      There is currently no clinically proven specific antiviral agent available for SARS-CoV-2&#xD;
      infection. Supportive treatment, including oxygen therapy, conservation fluid management, and&#xD;
      broad-spectrum antibiotics to cover secondary bacterial infection, remains the most important&#xD;
      management strategy.&#xD;
&#xD;
      For direct antiviral treatment of SARS-CoV-2, the China International Exchange and Promotive&#xD;
      Association for Medical and Health Care (CPAM) recommended usage of lopinavir; ritonavir.&#xD;
      Their recommendation was based on weak evidence from retrospective cohort, historically&#xD;
      controlled studies, case reports, and case series reporting a clinical benefit of lopinavir;&#xD;
      ritonavir in the management of other coronavirus infection [i.e., SARS-CoV 1 and Middle East&#xD;
      respiratory syndrome coronavirus (MERS-CoV)] .&#xD;
&#xD;
      However, the first randomized clinical trial with lopinavir/ritonavir demonstrated no benefit&#xD;
      over standard care in 199 hospitalized adults with severe COVID-19. There is no evidence to&#xD;
      support the use of other antiretrovirals, including protease inhibitors; indeed, structural&#xD;
      analysis demonstrates no darunavir binding to COVID-19 protease.&#xD;
&#xD;
      A group of Korean physicians experienced in SARS-CoV-2 infected patients' treatment developed&#xD;
      recommendations for the treatment of COVID-19. According to them, antiviral medications&#xD;
      lopinavir 400 mg; ritonavir 100 mg or chloroquine is considered to be used in older patients&#xD;
      or patients with chronic health conditions and life threatening symptoms. If chloroquine is&#xD;
      unavailable, hydroxychloroquine is recommended. Both of them have reported ability of&#xD;
      inhibition of SARS-CoV-2 in vitro.&#xD;
&#xD;
      CPAM guidelines included them as they were associated with reduced progression of disease and&#xD;
      decreased duration of symptoms. In an open-label study of 36 patients with COVID-19, use of&#xD;
      hydroxychloroquine (200 mg three times per day for 10 days) was associated with a higher rate&#xD;
      of undetectable SARS-CoV-2 RNA on nasopharyngeal specimens at day 6 compared with no specific&#xD;
      treatment (70 versus 12.5 percent). In this study, the use of azithromycin in combination&#xD;
      with hydroxychloroquine appeared to have additional benefit, but there are methodologic&#xD;
      concerns about the control groups for the study, and the biologic basis for using&#xD;
      azithromycin in this setting is unclear. In the United States, the FDA issued an emergency&#xD;
      use authorization to allow the use of these agents in adolescents or adults hospitalized for&#xD;
      COVID-19.&#xD;
&#xD;
      One of the studies done on SARS-COV-1 strongly suggested that using ribavirin as therapy&#xD;
      should be reconsidered until further animal studies clarify the effects of ribavirin on&#xD;
      cytokine and chemokine profiles during an infection and until ribavirin can be demonstrated&#xD;
      to have a significant effect on reducing viral replication in vivo. Data from a molecular&#xD;
      docking experiment using the SARS-CoV-2 RNA dependent RNA polymerase (RdRp) model identified&#xD;
      tight binding of sofosbuvir and ribavirin to the coronavirus RdRp, thereby suggesting&#xD;
      possible efficacy of sofosbuvir and ribavirin in treating the COVID-19 infection.&#xD;
&#xD;
      Chen et al. prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like&#xD;
      protease (3CL ) then performed virtual screening for purchasable drugs checking the actions,&#xD;
      targets and side effects of the 16 candidates. Among these, we first noticed velpatasvir and&#xD;
      ledipasvir, which are inhibitors of the NS5A protein of the hepatitis C virus (HCV). Both are&#xD;
      marketed as approved drugs in combination with sofosbuvir, which is a prodrug nucleotide&#xD;
      analogue inhibitor of RNA-dependent RNA polymerase (RdRp, or NS5B).&#xD;
&#xD;
      Interestingly, sofosbuvir has recently been proposed as an antiviral for the SARS-CoV-2 based&#xD;
      on the similarity between the replication mechanisms of the HCV and the coronaviruses.&#xD;
&#xD;
      Based on this data the investigators suggest that these dual-component HCV drugs, Epclusa&#xD;
      (velpatasvir/sofosbuvir) and Harvoni (ledipasvir/sofosbuvir), may be attractive candidates to&#xD;
      repurpose because they may inhibit two coronaviral enzymes. A drug that can target two viral&#xD;
      proteins substantially reduces the ability of the virus to develop resistance. These&#xD;
      direct-acting antiviral drugs are also associated with very minimal side effects and are&#xD;
      conveniently orally administered.&#xD;
&#xD;
      Aim of the study is to assess the safety and efficacy of the addition of HCV treatment to the&#xD;
      standard regimen for the treatment of patients who are candidates to receive Hydroxy&#xD;
      Chloroquine according to MOHP protocol.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">July 2020</start_date>
  <completion_date type="Anticipated">December 2020</completion_date>
  <primary_completion_date type="Anticipated">October 2020</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Virological cure</measure>
    <time_frame>28 days</time_frame>
    <description>virological cure using the triple therapy as compared to mono hydroxychloroquine treatment..</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>COVID-19</condition>
  <arm_group>
    <arm_group_label>Hydroxychloroquine plus Sofosbuvir/Daclatasvir</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard of care</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Hydroxychloroquine 400 mg by mouth twice daily for 1 day, then 200 mg by mouth twice daily for 14 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Hydroxychloroquine , Sofosbuvir, daclatasvir</intervention_name>
    <description>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 &lt; 45 kg or GFR (glomerular filtration rate) &lt;50ml/min) alone; as provided by the MOHP protocol), Sofosbuvir 400 mg once daily for 14 days and daclatasvir 90 mg for 14 days.</description>
    <arm_group_label>Hydroxychloroquine plus Sofosbuvir/Daclatasvir</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Standard of care treatment</intervention_name>
    <description>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 &lt; 45 kg or GFR (glomerular filtration rate) &lt;50ml/min) alone; as provided by the MOHP protocol),</description>
    <arm_group_label>Standard of care</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  positive reverse-transcriptase-polymerase chain- reaction (RT-PCR) assay for SARS-&#xD;
             CoV-2 in a respiratory tract sample&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  ● Known allergy or hypersensitivity to the used medications&#xD;
&#xD;
               -  Known severe liver disease (e.g., cirrhosis, with an alanine aminotransferase&#xD;
                  level &gt;5× the upper limit of the normal range or an aspartate aminotransferase&#xD;
                  level &gt;5× the upper limit of the normal range)&#xD;
&#xD;
               -  Use of medications that are contraindicated with the trial medications and that&#xD;
                  could not be replaced or stopped during the trial period&#xD;
&#xD;
               -  Pregnancy or breast-feeding or known active HCV infection, because of concerns&#xD;
                  about the development of resistance&#xD;
&#xD;
               -  History of bone marrow transplant&#xD;
&#xD;
               -  Known G6PD deficiency&#xD;
&#xD;
               -  Chronic hemodialysis or Glomerular Filtration Rate &lt; 20ml/min&#xD;
&#xD;
               -  Psoriasis&#xD;
&#xD;
               -  Porphyria&#xD;
&#xD;
               -  Concomitant use of digitalis, flecainide, amiodarone, procainamide, or&#xD;
                  propafenone&#xD;
&#xD;
               -  Known history of long QT syndrome&#xD;
&#xD;
               -  Current known QTc&gt;500 msec&#xD;
&#xD;
               -  Pregnant or nursing&#xD;
&#xD;
               -  Weight &lt; 35kg&#xD;
&#xD;
               -  Seizure disorder&#xD;
&#xD;
               -  Patients receiving Amiodarone.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>June 20, 2020</study_first_submitted>
  <study_first_submitted_qc>June 20, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 23, 2020</study_first_posted>
  <last_update_submitted>June 23, 2020</last_update_submitted>
  <last_update_submitted_qc>June 23, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 25, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Cairo University</investigator_affiliation>
    <investigator_full_name>Gamal Esmat</investigator_full_name>
    <investigator_title>Professor of Endemic Medicine</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hydroxychloroquine</mesh_term>
    <mesh_term>Sofosbuvir</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04443725
org study id: CUKA-003
nct id: NCT04443725
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Virological cure
time frame: 28 days
description: virological cure using the triple therapy as compared to mono hydroxychloroquine treatment..
arm group label: Hydroxychloroquine plus Sofosbuvir/Daclatasvir
arm group type: Experimental
description: 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
arm group label: Standard of care
arm group type: Active Comparator
description: Hydroxychloroquine 400 mg by mouth twice daily for 1 day, then 200 mg by mouth twice daily for 14 days
intervention type: Drug
intervention name: Hydroxychloroquine , Sofosbuvir, daclatasvir
description: 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.
arm group label: Hydroxychloroquine plus Sofosbuvir/Daclatasvir
intervention type: Drug
intervention name: Standard of care treatment
description: 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),
arm group label: Standard of care
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
responsible party type: Principal Investigator
investigator affiliation: Cairo University
investigator full name: Gamal Esmat
investigator title: Professor of Endemic Medicine
mesh term: COVID-19
mesh term: Hydroxychloroquine
mesh term: Sofosbuvir
sharing ipd: Undecided