<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/NCT04447235</url>
  </required_header>
  <id_info>
    <org_study_id>NP 1677/20</org_study_id>
    <nct_id>NCT04447235</nct_id>
  </id_info>
  <brief_title>Early Treatment With Ivermectin and LosarTAN for Cancer Patients With COVID-19 Infection</brief_title>
  <acronym>TITAN</acronym>
  <official_title>Randomized, Doubled-blind Phase II Trial Evaluating the Use of Ivermectin Plus Losartan for Prophylaxis of Severe Events in Cancer Patients With Recent Diagnosis of COVID-19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Instituto do Cancer do Estado de São Paulo</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Instituto do Cancer do Estado de São Paulo</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>
      Ivermectin plus losartan as prophilaxy to severe events in patients with cancer with recent&#xD;
      diagnosis of COVID-19&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a randomized, doubled-blind and placebo-controlled phase II study that will evaluate&#xD;
      the efficacy of the early use of ivermectin plus losartan in cancer patients who present with&#xD;
      recent diagnosis of COVID-19.&#xD;
&#xD;
      The trial will enroll 176 patients with previous diagnosis of active cancer (88 in each arm)&#xD;
      and the aim of the study is to assess the efficacy of these drugs combination to decrease the&#xD;
      incidence of COVID-19 severe complications. Patients will receive single dose ivermectin of&#xD;
      12mg after the confirmed diagnosis of COVID-19, followed by 15 days of losartan.&#xD;
&#xD;
      We believe that the association of anti-viral activity of the ivermectin plus the&#xD;
      extracellular blockade of the receptor used by the virus will decrease the overall viremia&#xD;
      and subsequently improve clinical outcomes.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    futility analysis has demonstrated no difference between arms&#xD;
  </why_stopped>
  <start_date type="Actual">July 23, 2020</start_date>
  <completion_date type="Actual">June 30, 2022</completion_date>
  <primary_completion_date type="Actual">June 30, 2022</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>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Care Provider)</masking>
    <masking_description>doubled-blind and placebo-controlled</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of severe complications due COVID-19 infection</measure>
    <time_frame>28 days</time_frame>
    <description>Incidence of severe complications due COVID-19 infection defined as need for ICU admission, need for mechanical ventilation, or death</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of Severe Acute Respiratory Syndrome</measure>
    <time_frame>28 days</time_frame>
    <description>Severe Acute Respiratory Syndrome defined as oxygen saturation less than 93%</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Severe Acute Respiratory Syndrome</measure>
    <time_frame>28 days</time_frame>
    <description>Severe Acute Respiratory Syndrome defined as respiratory rate higher than 24 incursion per minute</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events</measure>
    <time_frame>28 days</time_frame>
    <description>Incidence of hepatic toxicity (elevation of ALT, AST above the upper limit of normal, measured by U/L)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events</measure>
    <time_frame>28 days</time_frame>
    <description>Incidence of hepatic toxicity (elevation of bilirubin above the upper limit of normal, measured by mg/dL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events</measure>
    <time_frame>28 days</time_frame>
    <description>Incidence of renal toxicity (elevation of serum creatinine levels above the upper limit of normal, measured by mg/dL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events</measure>
    <time_frame>28 days</time_frame>
    <description>Incidence of symptomatic postural hypotension, diagnosed by clinical assessment of reduction of &gt; 20 mmHG of arterial systolic pressure after measurement in prone position and orthostatic position.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>28 days</time_frame>
    <description>Death of any cause since protocol enrollment</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">77</enrollment>
  <condition>Cancer</condition>
  <condition>COVID</condition>
  <condition>Coronavirus Infection</condition>
  <arm_group>
    <arm_group_label>ARM A: Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients will receive ivermectin-placebo single dose on the day of confirmed diagnosis of COVID-19, followed by losartan-placebo daily for 15 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ARM B: Ivermectin plus losartan</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will receive a single dose of 12mg of ivermectin on the day of the confirmed diagnosis of COVID-19, followed by losartan 50mg orally once daily for 15 consecutive days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Use of the combination of ivermectin-placebo plus losartan-placebo as early treatment for COVID-19 in cancer patients</description>
    <arm_group_label>ARM A: Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ivermectin</intervention_name>
    <description>Use of the combination of ivermectin plus losartan as early treatment for COVID-19 in cancer patients</description>
    <arm_group_label>ARM B: Ivermectin plus losartan</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Losartan</intervention_name>
    <description>Use of the combination of ivermectin plus losartan as early treatment for COVID-19 in cancer patients</description>
    <arm_group_label>ARM B: Ivermectin plus losartan</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age greater than or equal to 18 years of age&#xD;
&#xD;
          -  Ability to understand and sign informed consent&#xD;
&#xD;
          -  Biopsy-proven diagnosis of previous cancer (solid or hematologic disease)&#xD;
&#xD;
          -  Participants must be diagnosed with active malignancy, defined as the presence of&#xD;
             metastatic disease; or patient undergoing curative treatment during cancer treatment,&#xD;
             regardless of the therapeutic modality.&#xD;
&#xD;
          -  Confirmed diagnosis of COVID-19 by the presence of a positive PCR test or positive&#xD;
             serological test and / or diagnosis presumed by the presence of flu-like symptoms&#xD;
             associated to suggestive findings on CT scan.&#xD;
&#xD;
          -  ECOG performance status 0 to 2&#xD;
&#xD;
          -  Patients must have an assessment of adequate organ function within 28 days prior to&#xD;
             enrollment, evidenced by:&#xD;
&#xD;
               -  Hemoglobin ≥ 9.0 g / dL&#xD;
&#xD;
               -  Leukometry&gt; 2,000 / mm3&#xD;
&#xD;
               -  Absolute neutrophil count ≥ 1,500 / mm3&#xD;
&#xD;
               -  Platelet count ≥ 100,000 / mm3&#xD;
&#xD;
               -  Creatinine clearance ≥ 30 mL / min. Creatinine clearance (CrCl) should be&#xD;
                  calculated according to the Cockcroft-Gault formula.&#xD;
&#xD;
               -  Total bilirubin &lt;3 x the upper limit of normal (ULN), except for patients with&#xD;
                  known Gilbert's syndrome.&#xD;
&#xD;
               -  Aspartate aminotransaminase (AST) &lt;3.0 x LSN.&#xD;
&#xD;
               -  Alanine aminotransaminase (ALT) &lt;3.0 x ULN.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Currently taking an angiotensin converting enzyme inhibitor (ACEi) or Angiotensin&#xD;
             receptor blocker (ARB).&#xD;
&#xD;
          -  Patients who presents with severe conditions at the time of diagnosis requiring ICU&#xD;
             admission.&#xD;
&#xD;
          -  Prior reaction or intolerance to an ARB or ACE inhibitor.&#xD;
&#xD;
          -  Blood pressure less than 110/70 mmHg at presentation&#xD;
&#xD;
          -  Potassium greater than 5.0 mEq / L&#xD;
&#xD;
          -  Pregnancy or breastfeeding&#xD;
&#xD;
          -  Prior reaction to Ivermectin.&#xD;
&#xD;
          -  Patient currently enrolled in another research protocol&#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>Pedro Exman, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Instituto do Cancer do Estado de São Paulo</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Maria del Pilar Diz, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Instituto do Cancer do Estado de São Paulo</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Instituto do Cancer do Estado de Sao Paulo</name>
      <address>
        <city>SAo Paulo</city>
        <zip>01246-000</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>June 22, 2020</study_first_submitted>
  <study_first_submitted_qc>June 23, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 25, 2020</study_first_posted>
  <last_update_submitted>August 5, 2022</last_update_submitted>
  <last_update_submitted_qc>August 5, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 9, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>cancer</keyword>
  <keyword>covid-19</keyword>
  <keyword>losartan</keyword>
  <keyword>ivermectin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Coronavirus Infections</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ivermectin</mesh_term>
    <mesh_term>Losartan</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>no plan to share individual participant data</ipd_description>
  </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/NCT04447235
org study id: NP 1677/20
nct id: NCT04447235
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Ivermectin plus losartan as prophilaxy to severe events in patients with cancer with recent
      diagnosis of COVID-19
This is a randomized, doubled-blind and placebo-controlled phase II study that will evaluate
      the efficacy of the early use of ivermectin plus losartan in cancer patients who present with
      recent diagnosis of COVID-19.

      The trial will enroll 176 patients with previous diagnosis of active cancer (88 in each arm)
      and the aim of the study is to assess the efficacy of these drugs combination to decrease the
      incidence of COVID-19 severe complications. Patients will receive single dose ivermectin of
      12mg after the confirmed diagnosis of COVID-19, followed by 15 days of losartan.

      We believe that the association of anti-viral activity of the ivermectin plus the
      extracellular blockade of the receptor used by the virus will decrease the overall viremia
      and subsequently improve clinical outcomes.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Care Provider)
masking description: doubled-blind and placebo-controlled
measure: Incidence of severe complications due COVID-19 infection
time frame: 28 days
description: Incidence of severe complications due COVID-19 infection defined as need for ICU admission, need for mechanical ventilation, or death
measure: Incidence of Severe Acute Respiratory Syndrome
time frame: 28 days
description: Severe Acute Respiratory Syndrome defined as oxygen saturation less than 93%
measure: Incidence of Severe Acute Respiratory Syndrome
time frame: 28 days
description: Severe Acute Respiratory Syndrome defined as respiratory rate higher than 24 incursion per minute
measure: Adverse events
time frame: 28 days
description: Incidence of hepatic toxicity (elevation of ALT, AST above the upper limit of normal, measured by U/L)
measure: Adverse events
time frame: 28 days
description: Incidence of hepatic toxicity (elevation of bilirubin above the upper limit of normal, measured by mg/dL)
measure: Adverse events
time frame: 28 days
description: Incidence of renal toxicity (elevation of serum creatinine levels above the upper limit of normal, measured by mg/dL)
measure: Adverse events
time frame: 28 days
description: Incidence of symptomatic postural hypotension, diagnosed by clinical assessment of reduction of > 20 mmHG of arterial systolic pressure after measurement in prone position and orthostatic position.
measure: Overall survival
time frame: 28 days
description: Death of any cause since protocol enrollment
arm group label: ARM A: Placebo
arm group type: Placebo Comparator
description: Patients will receive ivermectin-placebo single dose on the day of confirmed diagnosis of COVID-19, followed by losartan-placebo daily for 15 days.
arm group label: ARM B: Ivermectin plus losartan
arm group type: Experimental
description: Patients will receive a single dose of 12mg of ivermectin on the day of the confirmed diagnosis of COVID-19, followed by losartan 50mg orally once daily for 15 consecutive days
intervention type: Drug
intervention name: Placebo
description: Use of the combination of ivermectin-placebo plus losartan-placebo as early treatment for COVID-19 in cancer patients
arm group label: ARM A: Placebo
intervention type: Drug
intervention name: Ivermectin
description: Use of the combination of ivermectin plus losartan as early treatment for COVID-19 in cancer patients
arm group label: ARM B: Ivermectin plus losartan
intervention type: Drug
intervention name: Losartan
description: Use of the combination of ivermectin plus losartan as early treatment for COVID-19 in cancer patients
arm group label: ARM B: Ivermectin plus losartan
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Pedro Exman, MD
role: Principal Investigator
affiliation: Instituto do Cancer do Estado de São Paulo
last name: Maria del Pilar Diz, MD, PhD
role: Study Director
affiliation: Instituto do Cancer do Estado de São Paulo
facility: 
country: Brazil
responsible party type: Sponsor
mesh term: Infections
mesh term: COVID-19
mesh term: Coronavirus Infections
mesh term: Ivermectin
mesh term: Losartan
sharing ipd: No
ipd description: no plan to share individual participant data