<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/NCT04438850</url>
  </required_header>
  <id_info>
    <org_study_id>cover_1</org_study_id>
    <nct_id>NCT04438850</nct_id>
  </id_info>
  <brief_title>COVidIVERmectin: Ivermectin for Treatment of Covid-19</brief_title>
  <acronym>COVER</acronym>
  <official_title>Randomized, Double-blind, Multi Centre Phase II, Proof of Concept, Dose Finding Clinical Trial on Ivermectin for the Early Treatment of COVID-19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>IRCCS Sacro Cuore Don Calabria di Negrar</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Istituto Di Ricerche Farmacologiche Mario Negri</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>IRCCS Sacro Cuore Don Calabria di Negrar</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Prospective, multi-centre, randomized, double-blind trial to assess efficacy and safety of&#xD;
      ivermectin for the treatment of initial infection with SARS-CoV2 infection.&#xD;
&#xD;
      Study arms: A) placebo B) ivermectin 600 μg/kg daily for 5 consecutive days (I_600) +&#xD;
      placebo. C) ivermectin 1200 μg/kg daily at empty stomach with water for 5 consecutive days&#xD;
      (I_1200). Patients will be randomized at emergency room of hospitals as well as at outpatient&#xD;
      ambulatory care as well as at home, according to routine procedures of recruiting centres.&#xD;
&#xD;
      In arm A and B, the number of placebo tablets to be administered will be calculated by the&#xD;
      study dedicated pharmacist considering the number of tablets that should be taken in case a&#xD;
      patient with the same weight is assigned to arm C.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Primary objectives&#xD;
&#xD;
      The study is aimed:&#xD;
&#xD;
        1. at defining if ivermectin, administered at dosage of 600 μg/kg or 1200 μg/kg QD for five&#xD;
           consecutive days is safe in patients with initial, asymptomatic or oligosymptomatic&#xD;
           SARS_CoV-2 infection,&#xD;
&#xD;
        2. at defining if ivermectin, administered at the dosage(s) found to be safe decreases the&#xD;
           viral load of SARS-CoV-2 at Day 7.&#xD;
&#xD;
      Secondary objectives To assess&#xD;
&#xD;
        1. the temporal profile of viral load at baseline, day 7, 14 and 30&#xD;
&#xD;
        2. the time to clinical cure (for symptomatic patients)&#xD;
&#xD;
        3. the proportion of patients with virological clearance at day 14 and 30.&#xD;
&#xD;
        4. the hospitalization rate.&#xD;
&#xD;
        5. the COVID-19 Severity Score at day 14 and 30&#xD;
&#xD;
      STUDY DESIGN&#xD;
&#xD;
      This is a multicentre, prospective, randomized, double-blind, adaptive phase II dose finding&#xD;
      study.&#xD;
&#xD;
      Patients meeting the inclusion criteria will be asked to participate to the study and&#xD;
      randomized in a 1:1:1 ratio to either:&#xD;
&#xD;
        -  Placebo arm (arm A): placebo will be identical in appearance to ivermectin in order to&#xD;
           preserve blinding and will be administered p.o. at empty stomach with water once daily,&#xD;
           for 5 days&#xD;
&#xD;
        -  Intervention arms: a) Ivermectin, single dose 600 μg/kg, for 5 days (I_600) and placebo&#xD;
           (arm B) ; b) Ivermectin, single dose 1200 μg/kg, for 5 days (I_1200) (arm C) ); these&#xD;
           drugs will be administered p.o. once daily, for 5 days.&#xD;
&#xD;
      In arm A and B, the number of placebo tablets to be administered will be calculated by the&#xD;
      study dedicated pharmacist considering the number of tablets that should be taken in case a&#xD;
      patient with the same weight is assigned to arm C.&#xD;
&#xD;
      Patients will be randomized by a centralized computer system. At randomization a treatment ID&#xD;
      is assigned to the patient. Once a treatment ID is assigned this must not be re-assigned even&#xD;
      in cases of errors.&#xD;
&#xD;
      Enrolled subjects will be identified by a unique subject number (patient code) that will&#xD;
      remain consistent for the duration of the study.&#xD;
&#xD;
      Patients will be recruited at the emergency room of hospitals, and/or among asymptomatic&#xD;
      hospital workers found positive for SARS-CoV-2 at routine screening and/or in outpatient&#xD;
      ambulatory settings, and/or at home, if not meeting the clinical criteria for&#xD;
      hospitalization, according to the routine procedure of each participating site. The expected&#xD;
      duration of subject inclusion in the study is of 1 month, or until the planned number of&#xD;
      subjects to be enrolled will be reached.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Incidence has dramatically dropped and there is lack of eligible patients&#xD;
  </why_stopped>
  <start_date type="Actual">July 31, 2020</start_date>
  <completion_date type="Actual">June 8, 2021</completion_date>
  <primary_completion_date type="Actual">June 8, 2021</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Ivermectin and placebo treatment will be double blinded, i.e. the treatment will be unknown to both the subject and the treating physician. The hospital pharmacist will be unblinded to study treatment because in charge to prepare the study treatment according to randomization arm.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>SADR</measure>
    <time_frame>14 days</time_frame>
    <description>Number of serious adverse drug reaction</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Viral load</measure>
    <time_frame>Assessed at day 7</time_frame>
    <description>Quantitative viral load as measured by quantitative, digital droplet PCR.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Trend viral load</measure>
    <time_frame>Days 7 and 14 from baseline</time_frame>
    <description>1. Trend over time of quantitative viral load at Day 7 and 14 as measured by quantitative, digital droplet PCR.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical resolution</measure>
    <time_frame>Assessed on Day 30</time_frame>
    <description>Time to clinical resolution (for symptomatic patients).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Viral clearance</measure>
    <time_frame>assessed on days 14 and 30</time_frame>
    <description>Time from diagnosis to documented viral clearance</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Virological clearance</measure>
    <time_frame>Assessed at day 14 and 30</time_frame>
    <description>Proportion of patients with virological clearance</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>hospitalization rate</measure>
    <time_frame>Day 30</time_frame>
    <description>rate of hospitalization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Severity score</measure>
    <time_frame>Assessed at Day 14 and Day 30</time_frame>
    <description>COVID-19 Severity Score (Coronavirus Diseases 19 Severity Score) - min value 1 (&quot;no limitation of activities), max value 8 (&quot;death&quot;). Higher scores mean worse outcome</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">93</enrollment>
  <condition>Covid19</condition>
  <arm_group>
    <arm_group_label>I_600</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>ivermectin 600 μg/kg daily for 5 consecutive days (I_600) + placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>I_1200</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>ivermectin 1200 μg/kg daily at empty stomach with water for 5 consecutive days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ivermectin</intervention_name>
    <description>Patients will be administered a single oral daily dose of approximately 600 μg/Kg (486-679 μg/Kg as rounded to a whole number of tablets), or 1200 μg/Kg (1098-1286 μg/Kg).</description>
    <arm_group_label>I_1200</arm_group_label>
    <arm_group_label>I_600</arm_group_label>
    <other_name>Ivermectin 9 mg cp by Chemo group</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Patients should take placebo orally on an empty stomach with water</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Placebo supplied by chemo group</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age &gt;=18 years&#xD;
&#xD;
          -  Positivity at RT-PCR per SARS_CoV2 (nasopharyngeal swabs)&#xD;
&#xD;
          -  Consent to participation to the study and to the processing of personal data&#xD;
&#xD;
          -  COVID-19 Severity Score &lt; 3&#xD;
&#xD;
          -  Patient able to take oral drugs&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant or lactating women (pregnancy test not required, if doubt patient is&#xD;
             excluded)&#xD;
&#xD;
          -  Subjects suffering from known CNS diseases&#xD;
&#xD;
          -  Lack of (or inability to provide) informed consent&#xD;
&#xD;
          -  Patient under dialysis&#xD;
&#xD;
          -  Any severe medical condition with a prognosis of &lt; 6 months&#xD;
&#xD;
          -  Patients under warfarin treatment&#xD;
&#xD;
          -  Patients under antiviral treatment&#xD;
&#xD;
          -  Patients under chloroquine phosphate or hydroxychloroquine&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Zeno Bisoffi</last_name>
    <role>Principal Investigator</role>
    <affiliation>IRCCS Sacro Cuore Don Calabria hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>IRCCS Sacro Cuore Don Calabria hospital</name>
      <address>
        <city>Negrar</city>
        <state>Verona</state>
        <zip>37024</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Policlinico S. Orsola</name>
      <address>
        <city>Bologna</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale Luigi Sacco</name>
      <address>
        <city>Milan</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale di Rovereto</name>
      <address>
        <city>Rovereto</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale Amedeo di Savoia</name>
      <address>
        <city>Turin</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <removed_countries>
    <country>Spain</country>
  </removed_countries>
  <verification_date>June 2021</verification_date>
  <study_first_submitted>April 10, 2020</study_first_submitted>
  <study_first_submitted_qc>June 18, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 19, 2020</study_first_posted>
  <last_update_submitted>June 17, 2021</last_update_submitted>
  <last_update_submitted_qc>June 17, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">June 23, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>ivermectin</keyword>
  <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>Ivermectin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>The anonymized database will be uploaded into a public repository</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_time_frame>The database will be available upon publication of the results</ipd_time_frame>
    <ipd_access_criteria>The data will be available in a public repository</ipd_access_criteria>
  </patient_data>
  <pending_results>
    <submitted>May 17, 2022</submitted>
    <returned>February 20, 2023</returned>
    <submitted>April 17, 2023</submitted>
  </pending_results>
  <!-- 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/NCT04438850
org study id: cover_1
nct id: NCT04438850
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Prospective, multi-centre, randomized, double-blind trial to assess efficacy and safety of
      ivermectin for the treatment of initial infection with SARS-CoV2 infection.

      Study arms: A) placebo B) ivermectin 600 μg/kg daily for 5 consecutive days (I_600) +
      placebo. C) ivermectin 1200 μg/kg daily at empty stomach with water for 5 consecutive days
      (I_1200). Patients will be randomized at emergency room of hospitals as well as at outpatient
      ambulatory care as well as at home, according to routine procedures of recruiting centres.

      In arm A and B, the number of placebo tablets to be administered will be calculated by the
      study dedicated pharmacist considering the number of tablets that should be taken in case a
      patient with the same weight is assigned to arm C.
Primary objectives

      The study is aimed:

        1. at defining if ivermectin, administered at dosage of 600 μg/kg or 1200 μg/kg QD for five
           consecutive days is safe in patients with initial, asymptomatic or oligosymptomatic
           SARS_CoV-2 infection,

        2. at defining if ivermectin, administered at the dosage(s) found to be safe decreases the
           viral load of SARS-CoV-2 at Day 7.

      Secondary objectives To assess

        1. the temporal profile of viral load at baseline, day 7, 14 and 30

        2. the time to clinical cure (for symptomatic patients)

        3. the proportion of patients with virological clearance at day 14 and 30.

        4. the hospitalization rate.

        5. the COVID-19 Severity Score at day 14 and 30

      STUDY DESIGN

      This is a multicentre, prospective, randomized, double-blind, adaptive phase II dose finding
      study.

      Patients meeting the inclusion criteria will be asked to participate to the study and
      randomized in a 1:1:1 ratio to either:

        -  Placebo arm (arm A): placebo will be identical in appearance to ivermectin in order to
           preserve blinding and will be administered p.o. at empty stomach with water once daily,
           for 5 days

        -  Intervention arms: a) Ivermectin, single dose 600 μg/kg, for 5 days (I_600) and placebo
           (arm B) ; b) Ivermectin, single dose 1200 μg/kg, for 5 days (I_1200) (arm C) ); these
           drugs will be administered p.o. once daily, for 5 days.

      In arm A and B, the number of placebo tablets to be administered will be calculated by the
      study dedicated pharmacist considering the number of tablets that should be taken in case a
      patient with the same weight is assigned to arm C.

      Patients will be randomized by a centralized computer system. At randomization a treatment ID
      is assigned to the patient. Once a treatment ID is assigned this must not be re-assigned even
      in cases of errors.

      Enrolled subjects will be identified by a unique subject number (patient code) that will
      remain consistent for the duration of the study.

      Patients will be recruited at the emergency room of hospitals, and/or among asymptomatic
      hospital workers found positive for SARS-CoV-2 at routine screening and/or in outpatient
      ambulatory settings, and/or at home, if not meeting the clinical criteria for
      hospitalization, according to the routine procedure of each participating site. The expected
      duration of subject inclusion in the study is of 1 month, or until the planned number of
      subjects to be enrolled will be reached.
allocation: Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Ivermectin and placebo treatment will be double blinded, i.e. the treatment will be unknown to both the subject and the treating physician. The hospital pharmacist will be unblinded to study treatment because in charge to prepare the study treatment according to randomization arm.
measure: SADR
time frame: 14 days
description: Number of serious adverse drug reaction
measure: Viral load
time frame: Assessed at day 7
description: Quantitative viral load as measured by quantitative, digital droplet PCR.
measure: Trend viral load
time frame: Days 7 and 14 from baseline
description: 1. Trend over time of quantitative viral load at Day 7 and 14 as measured by quantitative, digital droplet PCR.
measure: Clinical resolution
time frame: Assessed on Day 30
description: Time to clinical resolution (for symptomatic patients).
measure: Viral clearance
time frame: assessed on days 14 and 30
description: Time from diagnosis to documented viral clearance
measure: Virological clearance
time frame: Assessed at day 14 and 30
description: Proportion of patients with virological clearance
measure: hospitalization rate
time frame: Day 30
description: rate of hospitalization
measure: Severity score
time frame: Assessed at Day 14 and Day 30
description: COVID-19 Severity Score (Coronavirus Diseases 19 Severity Score) - min value 1 ("no limitation of activities), max value 8 ("death"). Higher scores mean worse outcome
arm group label: I_600
arm group type: Experimental
description: ivermectin 600 μg/kg daily for 5 consecutive days (I_600) + placebo
arm group label: I_1200
arm group type: Experimental
description: ivermectin 1200 μg/kg daily at empty stomach with water for 5 consecutive days
arm group label: Placebo
arm group type: Placebo Comparator
description: placebo
intervention type: Drug
intervention name: Ivermectin
description: Patients will be administered a single oral daily dose of approximately 600 μg/Kg (486-679 μg/Kg as rounded to a whole number of tablets), or 1200 μg/Kg (1098-1286 μg/Kg).
arm group label: I_1200
arm group label: I_600
other name: Ivermectin 9 mg cp by Chemo group
intervention type: Other
intervention name: Placebo
description: Patients should take placebo orally on an empty stomach with water
arm group label: Placebo
other name: Placebo supplied by chemo group
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Zeno Bisoffi
role: Principal Investigator
affiliation: IRCCS Sacro Cuore Don Calabria hospital
facility: 
facility: 
facility: 
facility: 
facility: 
country: Italy
country: Spain
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Ivermectin
sharing ipd: Yes
ipd description: The anonymized database will be uploaded into a public repository
ipd info type: Study Protocol
ipd time frame: The database will be available upon publication of the results
ipd access criteria: The data will be available in a public repository
submitted: May 17, 2022
returned: February 20, 2023
submitted: April 17, 2023