<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/NCT03791593</url>
  </required_header>
  <id_info>
    <org_study_id>ICOR-2016-05</org_study_id>
    <secondary_id>2017-004656-30</secondary_id>
    <nct_id>NCT03791593</nct_id>
  </id_info>
  <brief_title>EVOlocumab in Stable Heart Failure With Reduced Ejection Fraction of Ischemic Etiology: EVO-HF Pilot</brief_title>
  <acronym>EVO-HF</acronym>
  <official_title>EVOlocumab in Stable Heart Failure With Reduced Ejection Fraction of Ischemic Etiology: EVO-HF Pilot</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fundació Institut Germans Trias i Pujol</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Fundació Institut Germans Trias i Pujol</source>
  <oversight_info>
    <has_dmc>No</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>
      Evolocumab has been able to reduce the incidence of cardiovascular events in patients that&#xD;
      had at least one cardiovascular risk factor [28]. In patients with chronic HFrEF, as we&#xD;
      mentioned before, treatment with statins is not recommended as it has not shown benefits in&#xD;
      improving its prognosis. However, CAD control stands as an approach that could improve the&#xD;
      course of the disease by preventing microlesions that further weaken the heart. A recent&#xD;
      multicenter study, the BIOSTAT-CHF [3436], was performed to determine whether the PCSK9-LDLR&#xD;
      axis could predict risk in patients with HF. A multivariate analysis, which included BIOSTAT&#xD;
      risk scores, LDLR, and statin treatment as covariates, revealed a positive linear association&#xD;
      between PCSK9 levels and the risk of mortality and the composite endpoint (death or&#xD;
      HF-related hospitalization). A similar analysis for LDLR revealed a negative association with&#xD;
      mortality and the composite endpoint. Future studies must assess whether PCSK9 inhibition&#xD;
      will result in better outcomes in HF.&#xD;
&#xD;
      There is an unmet clinical need: blockade of the neurohormonal activation has provided&#xD;
      advances in patients with HFrEF, yet mortality and morbidity remain unacceptably high.&#xD;
      Approaching a strict control of lipid levels and CAD with evolocumab in stable HFrEF of&#xD;
      ischemic ethology may represent a complementary pathophysiological pathway to reduce&#xD;
      mortality and morbidity. The burden of CAD provides a solid rationale for testing the value&#xD;
      of evolocumab in HF patients.&#xD;
&#xD;
      Therefore, a pilot trial is proposed to evaluate the beneficial effect of evolocumab by&#xD;
      surrogate biological markers before considering an event analysis study.&#xD;
&#xD;
      Evolocumab reduces the risk of cardiovascular events in patients with established&#xD;
      atherosclerotic disease, so this drug could play a role in HFrEF of ischemic etiology, by&#xD;
      limiting macro- and micro-vascular coronary disease progression. In HFrEF patients due to&#xD;
      ischemic etiology, there is a continuous troponin release due to persistent myocyte injury,&#xD;
      which has been associated with adverse outcomes. Our hypothesis is that evolocumab may have&#xD;
      the potential to reduce circulating hs-TnT levels, as a surrogate of myocyte injury due to&#xD;
      atheroma progression in HFrEF. A positive result in this EVO-HF Pilot study may lead to the&#xD;
      set-up of a large-scale multicenter prospective and randomized events study analyzing the&#xD;
      role of lipid-lowering treatment by means of evolocumab in HFrEF of ischemic etiology&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Evolocumab has been able to reduce the incidence of cardiovascular events in patients that&#xD;
      had at least one cardiovascular risk factor [28]. In patients with chronic HFrEF, as we&#xD;
      mentioned before, treatment with statins is not recommended as it has not shown benefits in&#xD;
      improving its prognosis. However, CAD control stands as an approach that could improve the&#xD;
      course of the disease by preventing microlesions that further weaken the heart. A recent&#xD;
      multicenter study, the BIOSTAT-CHF [3436], was performed to determine whether the PCSK9-LDLR&#xD;
      axis could predict risk in patients with HF. A multivariate analysis, which included BIOSTAT&#xD;
      risk scores, LDLR, and statin treatment as covariates, revealed a positive linear association&#xD;
      between PCSK9 levels and the risk of mortality and the composite endpoint (death or&#xD;
      HF-related hospitalization). A similar analysis for LDLR revealed a negative association with&#xD;
      mortality and the composite endpoint. Future studies must assess whether PCSK9 inhibition&#xD;
      will result in better outcomes in HF.&#xD;
&#xD;
      There is an unmet clinical need: blockade of the neurohormonal activation has provided&#xD;
      advances in patients with HFrEF, yet mortality and morbidity remain unacceptably high.&#xD;
      Approaching a strict control of lipid levels and CAD with evolocumab in stable HFrEF of&#xD;
      ischemic ethology may represent a complementary pathophysiological pathway to reduce&#xD;
      mortality and morbidity. The burden of CAD provides a solid rationale for testing the value&#xD;
      of evolocumab in HF patients.&#xD;
&#xD;
      Evolocumab reduces the risk of cardiovascular events in patients with established&#xD;
      atherosclerotic disease, so this drug could play a role in HFrEF of ischemic etiology, by&#xD;
      limiting macro- and micro-vascular coronary disease progression. In HFrEF patients due to&#xD;
      ischemic etiology, there is a continuous troponin release due to persistent myocyte injury,&#xD;
      which has been associated with adverse outcomes. Our hypothesis is that evolocumab may have&#xD;
      the potential to reduce circulating hs-TnT levels, as a surrogate of myocyte injury due to&#xD;
      atheroma progression in HFrEF. A positive result in this EVO-HF Pilot study may lead to the&#xD;
      set-up of a large-scale multicenter prospective and randomized events study analyzing the&#xD;
      role of lipid-lowering treatment by means of evolocumab in HFrEF of ischemic etiology.&#xD;
&#xD;
      Therefore, a pilot trial is proposed to evaluate the beneficial effect of evolocumab by&#xD;
      surrogate biological markers before considering an event analysis study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 3, 2018</start_date>
  <completion_date type="Actual">July 20, 2022</completion_date>
  <primary_completion_date type="Actual">June 30, 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>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
    <masking_description>Investigators will be blinded for the biomarkers results.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in hs-TnT levels at 1 year</measure>
    <time_frame>at 12 months of follow-up</time_frame>
    <description>Change of high-sensitivity troponin T (hs-TnT) levels from baseline to 1 year.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">46</enrollment>
  <condition>Heart Failure With Reduced Ejection Fraction</condition>
  <arm_group>
    <arm_group_label>Experimental group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The patient will receive evolocumab 420 mg/month on top of guideline-driven medical treatment</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>The patient will continue guideline-driven medical treatment</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Evolocumab</intervention_name>
    <description>Evolocumab is a human IgG2 monoclonal antibody, it will add to patient treatment during 12 months.</description>
    <arm_group_label>Experimental group</arm_group_label>
    <other_name>Repatha</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Signing of the informed consent&#xD;
&#xD;
          2. Patient ≥18 years and ≤80 years of age&#xD;
&#xD;
          3. LVEF &lt;40%&#xD;
&#xD;
          4. Ischemic etiology (evidence of at least one acute coronary event and/or CAD by&#xD;
             coronary angiography or multi slice CT)&#xD;
&#xD;
          5. New York Heart Association (NYHA) class II&#xD;
&#xD;
          6. NT-proBNP ≥ 400 pg/mL&#xD;
&#xD;
          7. Hs-TnT &gt;10 pg/mL&#xD;
&#xD;
          8. LDL ≥ 70 mg/dL&#xD;
&#xD;
          9. Stable CAD (last ACS before the last 3 months)&#xD;
&#xD;
         10. GDMT according to 2016 ESC HF guidelines for at least the last 3 months.&#xD;
&#xD;
         11. Statin treatment, whichever dose the patient receives at the time of enrolment, stable&#xD;
             for at least 1 month, without need to statin uptitration.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Extracardiac disease with estimated life expectancy less than 1 year&#xD;
&#xD;
          2. Contraindication to receiving evolocumab&#xD;
&#xD;
          3. Hypersensitivity to the active substance or to any of the excipients&#xD;
&#xD;
          4. Female subject who has not used an acceptable method of birth control for at least 1&#xD;
             month prior to screening and/or is not willing to inform her partner of her&#xD;
             participation in this clinical trial and to use an acceptable method of effective&#xD;
             birth control during treatment with evolocumab and for an additional 15 weeks after&#xD;
             the end of treatment with evolocumab, unless the female subject is permanently&#xD;
             sterilized or postmenopausal:&#xD;
&#xD;
             A female is considered of childbearing potential unless permanently sterilized&#xD;
             (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or postmenopausal&#xD;
             with menopause defined as:&#xD;
&#xD;
               -  Age ≥55 years and ≥12 months of spontaneous and continuous amenorrhea, or&#xD;
&#xD;
               -  Age &lt;55 years but no spontaneous menses for ≥2 years, or&#xD;
&#xD;
               -  Age &lt;55 years and spontaneous menses within the past 1 year, but currently&#xD;
                  amenorrheic, AND with follicle-stimulating hormone (FSH) levels &gt;40 IU/L or&#xD;
                  estradiol levels &lt;5 ng/dL or according to the definition of &quot;postmenopausal&#xD;
                  range&quot; for the laboratory involved.&#xD;
&#xD;
          5. Patient &lt;18 or ≥ 81 years&#xD;
&#xD;
          6. Liver dysfunction (AST or ALT&gt; 3 times the upper limit of normal value).&#xD;
&#xD;
          7. Severe renal dysfunction (estimated glomerular filtration rate [eGFR] &lt; 30&#xD;
             ml/min/1.73m²) or renal replacement therapy at screening (CKD-EPI equation).&#xD;
&#xD;
          8. Coronary revascularization in the 3 months prior to randomization or pending coronary&#xD;
             revascularization.&#xD;
&#xD;
          9. Previous haemorrhagic stroke&#xD;
&#xD;
         10. Uncontrolled hypertension (systolic blood pressure ≥ 140 or/and diastolic blood&#xD;
             pressure ≥ 90 mmHg) either on or off therapy at screening or at baseline&#xD;
&#xD;
         11. Uncontrolled hypothyroidism or hyperthyroidism&#xD;
&#xD;
         12. Type 1 diabetes; newly diagnosed or poorly controlled type 2 diabetes (HbA1c &gt; 8.5%)&#xD;
&#xD;
         13. Uncontrolled cardiac arrhythmia&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Antoni Bayes-Genís, MD,PhD,FESC</last_name>
    <role>Principal Investigator</role>
    <affiliation>HUGTIP</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital Universitari Germans Trias i Pujol</name>
      <address>
        <city>Badalona</city>
        <state>Barcelona</state>
        <zip>08916</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Virgen del Rocío</name>
      <address>
        <city>Sevilla</city>
        <zip>41013</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clínico de Valencia</name>
      <address>
        <city>Valencia</city>
        <zip>46010</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>December 30, 2018</study_first_submitted>
  <study_first_submitted_qc>December 30, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">January 2, 2019</study_first_posted>
  <last_update_submitted>February 14, 2023</last_update_submitted>
  <last_update_submitted_qc>February 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Evolocumab</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03791593
org study id: ICOR-2016-05
secondary id: 2017-004656-30
nct id: NCT03791593
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Evolocumab has been able to reduce the incidence of cardiovascular events in patients that
      had at least one cardiovascular risk factor [28]. In patients with chronic HFrEF, as we
      mentioned before, treatment with statins is not recommended as it has not shown benefits in
      improving its prognosis. However, CAD control stands as an approach that could improve the
      course of the disease by preventing microlesions that further weaken the heart. A recent
      multicenter study, the BIOSTAT-CHF [3436], was performed to determine whether the PCSK9-LDLR
      axis could predict risk in patients with HF. A multivariate analysis, which included BIOSTAT
      risk scores, LDLR, and statin treatment as covariates, revealed a positive linear association
      between PCSK9 levels and the risk of mortality and the composite endpoint (death or
      HF-related hospitalization). A similar analysis for LDLR revealed a negative association with
      mortality and the composite endpoint. Future studies must assess whether PCSK9 inhibition
      will result in better outcomes in HF.

      There is an unmet clinical need: blockade of the neurohormonal activation has provided
      advances in patients with HFrEF, yet mortality and morbidity remain unacceptably high.
      Approaching a strict control of lipid levels and CAD with evolocumab in stable HFrEF of
      ischemic ethology may represent a complementary pathophysiological pathway to reduce
      mortality and morbidity. The burden of CAD provides a solid rationale for testing the value
      of evolocumab in HF patients.

      Therefore, a pilot trial is proposed to evaluate the beneficial effect of evolocumab by
      surrogate biological markers before considering an event analysis study.

      Evolocumab reduces the risk of cardiovascular events in patients with established
      atherosclerotic disease, so this drug could play a role in HFrEF of ischemic etiology, by
      limiting macro- and micro-vascular coronary disease progression. In HFrEF patients due to
      ischemic etiology, there is a continuous troponin release due to persistent myocyte injury,
      which has been associated with adverse outcomes. Our hypothesis is that evolocumab may have
      the potential to reduce circulating hs-TnT levels, as a surrogate of myocyte injury due to
      atheroma progression in HFrEF. A positive result in this EVO-HF Pilot study may lead to the
      set-up of a large-scale multicenter prospective and randomized events study analyzing the
      role of lipid-lowering treatment by means of evolocumab in HFrEF of ischemic etiology
Evolocumab has been able to reduce the incidence of cardiovascular events in patients that
      had at least one cardiovascular risk factor [28]. In patients with chronic HFrEF, as we
      mentioned before, treatment with statins is not recommended as it has not shown benefits in
      improving its prognosis. However, CAD control stands as an approach that could improve the
      course of the disease by preventing microlesions that further weaken the heart. A recent
      multicenter study, the BIOSTAT-CHF [3436], was performed to determine whether the PCSK9-LDLR
      axis could predict risk in patients with HF. A multivariate analysis, which included BIOSTAT
      risk scores, LDLR, and statin treatment as covariates, revealed a positive linear association
      between PCSK9 levels and the risk of mortality and the composite endpoint (death or
      HF-related hospitalization). A similar analysis for LDLR revealed a negative association with
      mortality and the composite endpoint. Future studies must assess whether PCSK9 inhibition
      will result in better outcomes in HF.

      There is an unmet clinical need: blockade of the neurohormonal activation has provided
      advances in patients with HFrEF, yet mortality and morbidity remain unacceptably high.
      Approaching a strict control of lipid levels and CAD with evolocumab in stable HFrEF of
      ischemic ethology may represent a complementary pathophysiological pathway to reduce
      mortality and morbidity. The burden of CAD provides a solid rationale for testing the value
      of evolocumab in HF patients.

      Evolocumab reduces the risk of cardiovascular events in patients with established
      atherosclerotic disease, so this drug could play a role in HFrEF of ischemic etiology, by
      limiting macro- and micro-vascular coronary disease progression. In HFrEF patients due to
      ischemic etiology, there is a continuous troponin release due to persistent myocyte injury,
      which has been associated with adverse outcomes. Our hypothesis is that evolocumab may have
      the potential to reduce circulating hs-TnT levels, as a surrogate of myocyte injury due to
      atheroma progression in HFrEF. A positive result in this EVO-HF Pilot study may lead to the
      set-up of a large-scale multicenter prospective and randomized events study analyzing the
      role of lipid-lowering treatment by means of evolocumab in HFrEF of ischemic etiology.

      Therefore, a pilot trial is proposed to evaluate the beneficial effect of evolocumab by
      surrogate biological markers before considering an event analysis study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Outcomes Assessor)
masking description: Investigators will be blinded for the biomarkers results.
measure: Change in hs-TnT levels at 1 year
time frame: at 12 months of follow-up
description: Change of high-sensitivity troponin T (hs-TnT) levels from baseline to 1 year.
arm group label: Experimental group
arm group type: Experimental
description: The patient will receive evolocumab 420 mg/month on top of guideline-driven medical treatment
arm group label: Control group
arm group type: No Intervention
description: The patient will continue guideline-driven medical treatment
intervention type: Drug
intervention name: Evolocumab
description: Evolocumab is a human IgG2 monoclonal antibody, it will add to patient treatment during 12 months.
arm group label: Experimental group
other name: Repatha
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Antoni Bayes-Genís, MD,PhD,FESC
role: Principal Investigator
affiliation: HUGTIP
facility: 
facility: 
facility: 
country: Spain
responsible party type: Sponsor
mesh term: Heart Failure
mesh term: Evolocumab