<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/NCT03271879</url>
  </required_header>
  <id_info>
    <org_study_id>605-16</org_study_id>
    <nct_id>NCT03271879</nct_id>
  </id_info>
  <brief_title>Empagliflozin Versus Placebo on the Rate of Arrhythmic Events in Heart Failure Patients</brief_title>
  <acronym>ERA-HF</acronym>
  <official_title>The Effect of Empagliflozin Versus Placebo on the Rate of Arrhythmic Events in Heart Failure Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Rambam Health Care Campus</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Rambam Health Care Campus</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Empagliflozin treatment in high cardiovascular risk patients has been shown to have a&#xD;
      relatively rapid powerful capability in reducing cardiovascular mortality. Among the&#xD;
      suggested mechanisms mediating this effect of empagliflozin, anti-arrhythmic effect (AAE) has&#xD;
      the highest potential to translate into a rapid clinical beneficial effect on cardiovascular&#xD;
      mortality, while other mechanisms are known to have a lag in their clinical effect based on&#xD;
      data from previous studies. Based on this assumption, the study driving hypothesis is that&#xD;
      the effect of empagliflozin on the rate of cardiovascular death may be mediated by a direct&#xD;
      effect on the risk for arrhythmic events (via a direct or an indirect effect on the&#xD;
      myocardium). The current study aims at assessing the effect of empagliflozin on arrhythmias&#xD;
      in diabetic patients with HF with reduced ejection fraction and relatively high arrhythmic&#xD;
      burden. The objective of the current study is to demonstrate the effect of empagliflozin&#xD;
      compared to placebo on the rate of ventricular arrhythmic events in type 2 diabetes patients&#xD;
      with heart failure with reduced ejection fraction and high risk arrhythmic profile.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background and rationale: Empagliflozin is an orally available inhibitor of the&#xD;
      sodium-glucose co-transporter 2 (SGLT-2), that promotes enhanced glucose excretion in the&#xD;
      urine, thereby lowering blood glucose concentrations in patients with type 2 diabetes&#xD;
      mellitus (T2DM). The EMPA-REG OUTCOME study demonstrated a significant reduction in both&#xD;
      heart failure hospitalization and cardiovascular death in type 2 diabetes patients with high&#xD;
      risk for cardiovascular events. A potential mechanism underlying the pleiotropic and&#xD;
      explaining the remarkable early reduction in cardiovascular mortality may be related to the&#xD;
      effect of empagliflozin on arrhythmic events.&#xD;
&#xD;
      Multiple potential mechanisms have been suggested to mediate the positive cardiovascular&#xD;
      effect of empagliflozin (altered cardiomyocyte metabolism, anti-arrhythmic effect, improved&#xD;
      glycemic control, positive effect on myocardial contractility).&#xD;
&#xD;
      Ventricular arrhythmias and the associated sudden cardiac death (SCD) is the leading cause of&#xD;
      mortality in patients with heart failure. The risk for the occurrence of SCD in heart failure&#xD;
      patients is closely related to the etiology (ischemic versus non-ischemic) and the left&#xD;
      ventricular EF. The introduction of defibrillation therapy for primary prevention of SCD in&#xD;
      HF patients has revolutionized the field during the last 2 decades. Nevertheless, ventricular&#xD;
      arrhythmias remain a major cause of mortality for HF patients given the limited ability for&#xD;
      risk stratification, and the dreadful prognosis associated with ventricular arrhythmias&#xD;
      treated by defibrillation therapy. The burden of premature ventricular Complexes (PVCs) has&#xD;
      been shown as an independent risk factor for ventricular tachyarrhythmia and SCD for healthy,&#xD;
      ischemic and heart failure patients (with and without resynchronization and/or defibrillator&#xD;
      therapy). Anti-arrhythmic drugs (AAD) are efficient in suppressing the occurrence of PVCs but&#xD;
      for certain drugs, the associated with profile of adverse events and cardiotoxicity may&#xD;
      paradoxically increase the rate of sudden cardiac death as learned by the remarkable CAST&#xD;
      study. Be that as it may, easily suppressed PVC burden (without the associated adverse&#xD;
      profile of AADs) has been suggested to correlate with reduction of the likelihood for SCD.&#xD;
      Furthermore, the growing field of PVC ablation has been shown to have beneficial effect on&#xD;
      cardiac function and the risk for ventricular arrhythmia. In summary, PVC suppression, a once&#xD;
      neglected strategy, is now considered a promising strategy for evaluating the effect of&#xD;
      therapeutic strategies on the risk for SCD.&#xD;
&#xD;
      Empagliflozin treatment in high cardiovascular risk patients has been shown to have a&#xD;
      relatively rapid powerful capability in reducing cardiovascular mortality. Among the&#xD;
      suggested mechanisms mediating this effect of empagliflozin, anti-arrhythmic effect (AAE) has&#xD;
      the highest potential to translate into a rapid clinical beneficial effect on cardiovascular&#xD;
      mortality, while other mechanisms are known to have a lag in their clinical effect based on&#xD;
      data from previous studies. Based on this assumption, the study driving hypothesis is that&#xD;
      the effect of empagliflozin on the rate of cardiovascular death may be mediated by a direct&#xD;
      effect on the risk for arrhythmic events (via a direct or an indirect effect on the&#xD;
      myocardium). The current study aims at assessing the effect of empagliflozin on arrhythmias&#xD;
      in diabetic patients with HF with reduced EF and relatively high arrhythmic burden.&#xD;
&#xD;
      Study Objectives The objective of the current study is to demonstrate the effect of&#xD;
      empagliflozin compared to placebo on the rate of ventricular arrhythmic events in type 2&#xD;
      diabetes patients with heart failure with reduced ejection fraction and high risk arrhythmic&#xD;
      profile.&#xD;
&#xD;
      Primary endpoint:&#xD;
&#xD;
      The primary endpoint is the burden of premature ventricular complexes, defined as the PVCs&#xD;
      percentage of all beats in a pre-specified period captured on implantable&#xD;
      cardioverter-defibrillator ( ICD ) or CRTD/P device.&#xD;
&#xD;
      Secondary endpoint:&#xD;
&#xD;
        1. The number of non-sustained ventricular tachycardia (NSVT) episodes.&#xD;
&#xD;
        2. A composite cumulative endpoint of ventricular arrhythmia load (number of: sustained&#xD;
           ventricular tachycardia, ventricular fibrillation, antitachycardia pacing (ATP) or&#xD;
           delivery of shock therapy episodes.&#xD;
&#xD;
        3. The change in blood level of NT-Pro Brain Natriuretic peptide (BNP) from baseline to the&#xD;
           end of any of the treatment periods.&#xD;
&#xD;
        4. The change in Left ventricular end diastolic diameter on echocardiography from baseline&#xD;
           to the end of any of the treatment periods.&#xD;
&#xD;
        5. The change in left ventricular ejection fraction (EF) on echocardiography from baseline&#xD;
           to the end of any of the treatment periods.&#xD;
&#xD;
        6. Safety endpoints (as detailed bellow).&#xD;
&#xD;
      Study Design:&#xD;
&#xD;
      The present study is a randomized, prospective, controlled, double blind, cross-over,&#xD;
      pairwise, add on standard therapy, event driven study, comparing empagliflozin versus placebo&#xD;
      on the ventricular arrhythmia burden in a blocked randomization stratified by ischemic versus&#xD;
      non-ischemic cardiomyopathy and PVC burden at screening of&lt; or &gt; to 4%. Potential study&#xD;
      subjects will sign an informed consent prior to undergoing any study related procedure.&#xD;
      Number of patients to be enrolled is 128.&#xD;
&#xD;
      This study encompass 4 periods for each study subject: screening period of 8 weeks, first&#xD;
      treatment period of 8 weeks, washout period of 4 weeks and a second treatment period of 8&#xD;
      weeks. Expected duration of subject participation is 6-7 months.&#xD;
&#xD;
      Duration of study:&#xD;
&#xD;
      The duration of the treatment period is approximately 6 months. This time span is required&#xD;
      for completing the therapy and determining the safety profile of the drug combination and the&#xD;
      response rate.&#xD;
&#xD;
      Estimated accrual duration: 12 months. Estimated total trial duration: 18 months (for each&#xD;
      center).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">February 15, 2018</start_date>
  <completion_date type="Anticipated">June 1, 2020</completion_date>
  <primary_completion_date type="Anticipated">September 1, 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <intervention_model_description>Patients will receive study drug: empagliflozin or placebo for an exposure period of up to 16 weeks - at the two treatment periods in a crossover design.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The primary endpoint is the burden of premature ventricular complexes, defined as the PVCs percentage of all beats in a pre-specified period captured on ICD or CRTD/P device</measure>
    <time_frame>Time frames include the time frame between visit 2 (on day 56) and visit 3 (on day 112) and that between visit 4 (on day 140) to visit 5 (on day 196)- each period between visits 2 and 3 and visit 4 and 5 contain a time frame of 56 days</time_frame>
    <description>PVCs burden is defined as the PVCs percentage of all beats in a pre-specified period captured on ICD or CRTD/P device. The change in PVC burden between time on treatment arm versus time on placebo will be calculated and serve as the primary endpoint.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Non-sustained ventricular tachycardia (NSVT)</measure>
    <time_frame>Time frames include the time frame between visit 2 (on day 56) and visit 3 (on day 112) and that between visit 4 (on day 140) to visit 5 (on day 196)- each period between visits 2 and 3 and visit 4 and 5 contain a time frame of 56 days</time_frame>
    <description>This is defined as the number of sustained ventricular tachycardia, and/or ventricular fibrillation, and/or tachycardia pacing (ATP) and/or delivery of shock therapy. All the four parameters will be captured on ICD or CRTD/P device interrogation. Sustained VT and NSVT will be captured as a backup information (in case of ICD or CRTD/P malfunction) on Holter ECG.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>NT-Pro-BNP</measure>
    <time_frame>Time frames include NT-Pro-BNP measurement on the end of visit 3 (on day 112) versus NT-Pro-BNP level at the end of visit 5 (on day 196).</time_frame>
    <description>NT-Pro-BNP Is a plasma level of B-type Natriuretic Peptide used as a blood test for diagnosing and evaluation the presence/severity of heart failure. The change in NT-Pro-BNP will be evaluated as a marker of heart failure severity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left ventricular end diastolic diameter</measure>
    <time_frame>Time frames include left ventricular diastolic diameter measured on the end of visit 3 (on day 112) versus that measured at the end of visit 5 (on day 196).</time_frame>
    <description>End diastolic diameter is defined as the cross-sectional diameter of the left ventricle, including the septum and the posterior thicknesses in diastole.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left ventricular ejection fraction (EF)</measure>
    <time_frame>Time frames include EF measured on visit 3 (on day 112) versus that measured at the end of visit 5 (on day 196).</time_frame>
    <description>Ejection fraction is defined as the ratio of the stroke volume to the end-diastolic volume in the left ventricle as performed by echocardiography and expressed by percentage.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">128</enrollment>
  <condition>Heart Failure</condition>
  <condition>Diabetes Mellitus</condition>
  <condition>Arrythmia</condition>
  <arm_group>
    <arm_group_label>Empagliflozin at a dose of 10 mg/day</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients will be treated with 10mg Empagliflozin once daily for 8 weeks. Patient glucose levels will be monitored based on home monitoring during the treatment period.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients will be treated with Placebo once daily for 8 weeks. Patient glucose levels will be monitored based on home monitoring during the treatment period.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Empagliflozin at a dose of 10 mg/day</intervention_name>
    <description>Comparing empagliflozin versus placebo on the ventricular arrhythmia burden. This study encompass 4 periods for each study subject: screening period of 8 weeks, first treatment period of 8 weeks, washout period of 4 weeks and a second treatment period of 8 weeks in a cross-over design</description>
    <arm_group_label>Empagliflozin at a dose of 10 mg/day</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>JARDIANCE at a dose of 10mg/day</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Heart failure patients with reduced ejection fraction (EF≤40%) as assessed by&#xD;
             echocardiographist least 6 months prior to recruitment and NYHA Class≥2&#xD;
&#xD;
          2. Patients implanted with ICD, CRTD/S or CRTP devices that are capable of recording the&#xD;
             PVC burden and implanted ≥ 2 months prior to recruitment.&#xD;
&#xD;
          3. High risk for arrhythmic events at baseline identified by either PVC burden ≥0.5% or&#xD;
             ≥2 events of non sustained VT or ≥1 event of sustained ventricular tachycardia or need&#xD;
             for anti-tachycardia pacing or defibrillation therapy, during a period of 2 months&#xD;
             prior to recruitment.&#xD;
&#xD;
          4. Diagnosis of type 2 diabetes mellitus prior to informed consent&#xD;
&#xD;
          5. HbA1c≥7% and ≤12%.&#xD;
&#xD;
          6. Signed and dated written informed consent by date of Visit 1 in accordance with GCP&#xD;
             legislation&#xD;
&#xD;
             -&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Evidence of ICD malfunction.&#xD;
&#xD;
          2. Past exposure to SGLT2 inhibitors.&#xD;
&#xD;
          3. Uncontrolled diabetes with HbA1c&gt;12% or glucose &gt;240 mg/dL after an overnight fast.&#xD;
&#xD;
          4. Liver abnormalities defined by serum levels of alanine aminotransferase, aspartate&#xD;
             aminotransferase, or alkaline phosphatase above 3 x upper limit of normal.&#xD;
&#xD;
          5. Planned cardiac procedure within 3 months.&#xD;
&#xD;
          6. Prior MI in the last 40 days.&#xD;
&#xD;
          7. Calculated eGFR&lt; 45ml/min/1.73m2 as determined by the MDRD formula GFR (mL/min/1.73&#xD;
             m2) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African&#xD;
             American)&#xD;
&#xD;
          8. BMI&gt;50&#xD;
&#xD;
          9. Medical History of active cancer in the last 2 years. Exceptions include the&#xD;
             following: Basal cell carcinoma of the skin, Squamous cell carcinoma of the skin,&#xD;
             Carcinoma in situ of the cervix, Carcinoma in situ of the breast, Incidental&#xD;
             histologic finding of prostate cancer (TNM stage of T1a or T1b).&#xD;
&#xD;
         10. History of recurrent UTIs or genital infections&#xD;
&#xD;
         11. Systolic blood pressure&lt; 90 mmHg.&#xD;
&#xD;
         12. Alcohol or drug abuse within 3 months of informed consent.&#xD;
&#xD;
         13. Pre-menopausal women (last menstruation &lt;+ 1 year prior to informed consent) who:&#xD;
&#xD;
               -  - are nursing or pregnant or&#xD;
&#xD;
               -  - are of child-bearing potential and are not practicing an acceptable method of&#xD;
                  birth control, or do not plan to continue using this method throughout the study&#xD;
                  and do not agree to submit to periodic pregnancy testing during participation in&#xD;
                  the trial. Acceptable methods of birth control include tubal ligation,&#xD;
                  transdermal patch, intra uterine devices/systems, oral, implantable or injectable&#xD;
                  contraceptives, sexual abstinence, double barrier method and vasectomised&#xD;
                  partner.&#xD;
&#xD;
         14. Intake of an investigational drug in another trial within 30 days prior to intake of&#xD;
             study medication in this trial or participating in another trial involving an&#xD;
             investigational drug and/or follow-up&#xD;
&#xD;
             -&#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>Oren Caspi, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Rambam MC</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Oren Caspi, MD</last_name>
    <phone>97247772180</phone>
    <email>orencaspi@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Shmuel Rispler, MD</last_name>
    <phone>97247772180</phone>
    <email>s_rispler@rambam.health.gov.il</email>
  </overall_contact_backup>
  <verification_date>January 2018</verification_date>
  <study_first_submitted>July 30, 2017</study_first_submitted>
  <study_first_submitted_qc>August 31, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 5, 2017</study_first_posted>
  <last_update_submitted>January 24, 2018</last_update_submitted>
  <last_update_submitted_qc>January 24, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">January 25, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Diabetes</keyword>
  <keyword>Heart</keyword>
  <keyword>Arrhythmia</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
    <mesh_term>Arrhythmias, Cardiac</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Empagliflozin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>IPD will be shared following approval of the submitted research proposal by the researcher applying.</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>May 14, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/79/NCT03271879/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT03271879
org study id: 605-16
nct id: NCT03271879
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
Empagliflozin treatment in high cardiovascular risk patients has been shown to have a
      relatively rapid powerful capability in reducing cardiovascular mortality. Among the
      suggested mechanisms mediating this effect of empagliflozin, anti-arrhythmic effect (AAE) has
      the highest potential to translate into a rapid clinical beneficial effect on cardiovascular
      mortality, while other mechanisms are known to have a lag in their clinical effect based on
      data from previous studies. Based on this assumption, the study driving hypothesis is that
      the effect of empagliflozin on the rate of cardiovascular death may be mediated by a direct
      effect on the risk for arrhythmic events (via a direct or an indirect effect on the
      myocardium). The current study aims at assessing the effect of empagliflozin on arrhythmias
      in diabetic patients with HF with reduced ejection fraction and relatively high arrhythmic
      burden. The objective of the current study is to demonstrate the effect of empagliflozin
      compared to placebo on the rate of ventricular arrhythmic events in type 2 diabetes patients
      with heart failure with reduced ejection fraction and high risk arrhythmic profile.
Background and rationale: Empagliflozin is an orally available inhibitor of the
      sodium-glucose co-transporter 2 (SGLT-2), that promotes enhanced glucose excretion in the
      urine, thereby lowering blood glucose concentrations in patients with type 2 diabetes
      mellitus (T2DM). The EMPA-REG OUTCOME study demonstrated a significant reduction in both
      heart failure hospitalization and cardiovascular death in type 2 diabetes patients with high
      risk for cardiovascular events. A potential mechanism underlying the pleiotropic and
      explaining the remarkable early reduction in cardiovascular mortality may be related to the
      effect of empagliflozin on arrhythmic events.

      Multiple potential mechanisms have been suggested to mediate the positive cardiovascular
      effect of empagliflozin (altered cardiomyocyte metabolism, anti-arrhythmic effect, improved
      glycemic control, positive effect on myocardial contractility).

      Ventricular arrhythmias and the associated sudden cardiac death (SCD) is the leading cause of
      mortality in patients with heart failure. The risk for the occurrence of SCD in heart failure
      patients is closely related to the etiology (ischemic versus non-ischemic) and the left
      ventricular EF. The introduction of defibrillation therapy for primary prevention of SCD in
      HF patients has revolutionized the field during the last 2 decades. Nevertheless, ventricular
      arrhythmias remain a major cause of mortality for HF patients given the limited ability for
      risk stratification, and the dreadful prognosis associated with ventricular arrhythmias
      treated by defibrillation therapy. The burden of premature ventricular Complexes (PVCs) has
      been shown as an independent risk factor for ventricular tachyarrhythmia and SCD for healthy,
      ischemic and heart failure patients (with and without resynchronization and/or defibrillator
      therapy). Anti-arrhythmic drugs (AAD) are efficient in suppressing the occurrence of PVCs but
      for certain drugs, the associated with profile of adverse events and cardiotoxicity may
      paradoxically increase the rate of sudden cardiac death as learned by the remarkable CAST
      study. Be that as it may, easily suppressed PVC burden (without the associated adverse
      profile of AADs) has been suggested to correlate with reduction of the likelihood for SCD.
      Furthermore, the growing field of PVC ablation has been shown to have beneficial effect on
      cardiac function and the risk for ventricular arrhythmia. In summary, PVC suppression, a once
      neglected strategy, is now considered a promising strategy for evaluating the effect of
      therapeutic strategies on the risk for SCD.

      Empagliflozin treatment in high cardiovascular risk patients has been shown to have a
      relatively rapid powerful capability in reducing cardiovascular mortality. Among the
      suggested mechanisms mediating this effect of empagliflozin, anti-arrhythmic effect (AAE) has
      the highest potential to translate into a rapid clinical beneficial effect on cardiovascular
      mortality, while other mechanisms are known to have a lag in their clinical effect based on
      data from previous studies. Based on this assumption, the study driving hypothesis is that
      the effect of empagliflozin on the rate of cardiovascular death may be mediated by a direct
      effect on the risk for arrhythmic events (via a direct or an indirect effect on the
      myocardium). The current study aims at assessing the effect of empagliflozin on arrhythmias
      in diabetic patients with HF with reduced EF and relatively high arrhythmic burden.

      Study Objectives The objective of the current study is to demonstrate the effect of
      empagliflozin compared to placebo on the rate of ventricular arrhythmic events in type 2
      diabetes patients with heart failure with reduced ejection fraction and high risk arrhythmic
      profile.

      Primary endpoint:

      The primary endpoint is the burden of premature ventricular complexes, defined as the PVCs
      percentage of all beats in a pre-specified period captured on implantable
      cardioverter-defibrillator ( ICD ) or CRTD/P device.

      Secondary endpoint:

        1. The number of non-sustained ventricular tachycardia (NSVT) episodes.

        2. A composite cumulative endpoint of ventricular arrhythmia load (number of: sustained
           ventricular tachycardia, ventricular fibrillation, antitachycardia pacing (ATP) or
           delivery of shock therapy episodes.

        3. The change in blood level of NT-Pro Brain Natriuretic peptide (BNP) from baseline to the
           end of any of the treatment periods.

        4. The change in Left ventricular end diastolic diameter on echocardiography from baseline
           to the end of any of the treatment periods.

        5. The change in left ventricular ejection fraction (EF) on echocardiography from baseline
           to the end of any of the treatment periods.

        6. Safety endpoints (as detailed bellow).

      Study Design:

      The present study is a randomized, prospective, controlled, double blind, cross-over,
      pairwise, add on standard therapy, event driven study, comparing empagliflozin versus placebo
      on the ventricular arrhythmia burden in a blocked randomization stratified by ischemic versus
      non-ischemic cardiomyopathy and PVC burden at screening of< or > to 4%. Potential study
      subjects will sign an informed consent prior to undergoing any study related procedure.
      Number of patients to be enrolled is 128.

      This study encompass 4 periods for each study subject: screening period of 8 weeks, first
      treatment period of 8 weeks, washout period of 4 weeks and a second treatment period of 8
      weeks. Expected duration of subject participation is 6-7 months.

      Duration of study:

      The duration of the treatment period is approximately 6 months. This time span is required
      for completing the therapy and determining the safety profile of the drug combination and the
      response rate.

      Estimated accrual duration: 12 months. Estimated total trial duration: 18 months (for each
      center).
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: Patients will receive study drug: empagliflozin or placebo for an exposure period of up to 16 weeks - at the two treatment periods in a crossover design.
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: The primary endpoint is the burden of premature ventricular complexes, defined as the PVCs percentage of all beats in a pre-specified period captured on ICD or CRTD/P device
time frame: Time frames include the time frame between visit 2 (on day 56) and visit 3 (on day 112) and that between visit 4 (on day 140) to visit 5 (on day 196)- each period between visits 2 and 3 and visit 4 and 5 contain a time frame of 56 days
description: PVCs burden is defined as the PVCs percentage of all beats in a pre-specified period captured on ICD or CRTD/P device. The change in PVC burden between time on treatment arm versus time on placebo will be calculated and serve as the primary endpoint.
measure: Non-sustained ventricular tachycardia (NSVT)
time frame: Time frames include the time frame between visit 2 (on day 56) and visit 3 (on day 112) and that between visit 4 (on day 140) to visit 5 (on day 196)- each period between visits 2 and 3 and visit 4 and 5 contain a time frame of 56 days
description: This is defined as the number of sustained ventricular tachycardia, and/or ventricular fibrillation, and/or tachycardia pacing (ATP) and/or delivery of shock therapy. All the four parameters will be captured on ICD or CRTD/P device interrogation. Sustained VT and NSVT will be captured as a backup information (in case of ICD or CRTD/P malfunction) on Holter ECG.
measure: NT-Pro-BNP
time frame: Time frames include NT-Pro-BNP measurement on the end of visit 3 (on day 112) versus NT-Pro-BNP level at the end of visit 5 (on day 196).
description: NT-Pro-BNP Is a plasma level of B-type Natriuretic Peptide used as a blood test for diagnosing and evaluation the presence/severity of heart failure. The change in NT-Pro-BNP will be evaluated as a marker of heart failure severity.
measure: Left ventricular end diastolic diameter
time frame: Time frames include left ventricular diastolic diameter measured on the end of visit 3 (on day 112) versus that measured at the end of visit 5 (on day 196).
description: End diastolic diameter is defined as the cross-sectional diameter of the left ventricle, including the septum and the posterior thicknesses in diastole.
measure: Left ventricular ejection fraction (EF)
time frame: Time frames include EF measured on visit 3 (on day 112) versus that measured at the end of visit 5 (on day 196).
description: Ejection fraction is defined as the ratio of the stroke volume to the end-diastolic volume in the left ventricle as performed by echocardiography and expressed by percentage.
arm group label: Empagliflozin at a dose of 10 mg/day
arm group type: Active Comparator
description: Patients will be treated with 10mg Empagliflozin once daily for 8 weeks. Patient glucose levels will be monitored based on home monitoring during the treatment period.
arm group label: Placebo
arm group type: Placebo Comparator
description: Patients will be treated with Placebo once daily for 8 weeks. Patient glucose levels will be monitored based on home monitoring during the treatment period.
intervention type: Drug
intervention name: Empagliflozin at a dose of 10 mg/day
description: Comparing empagliflozin versus placebo on the ventricular arrhythmia burden. This study encompass 4 periods for each study subject: screening period of 8 weeks, first treatment period of 8 weeks, washout period of 4 weeks and a second treatment period of 8 weeks in a cross-over design
arm group label: Empagliflozin at a dose of 10 mg/day
arm group label: Placebo
other name: JARDIANCE at a dose of 10mg/day
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Oren Caspi, MD
role: Principal Investigator
affiliation: Rambam MC
last name: Oren Caspi, MD
phone: 97247772180
email: orencaspi@gmail.com
last name: Shmuel Rispler, MD
phone: 97247772180
email: s_rispler@rambam.health.gov.il
responsible party type: Sponsor
mesh term: Heart Failure
mesh term: Arrhythmias, Cardiac
mesh term: Empagliflozin
sharing ipd: Undecided
ipd description: IPD will be shared following approval of the submitted research proposal by the researcher applying.
provided document: 