<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/NCT04409119</url>
  </required_header>
  <id_info>
    <org_study_id>HIS alternative 2</org_study_id>
    <nct_id>NCT04409119</nct_id>
  </id_info>
  <brief_title>Direct HIS/LBB Pacing as an Alternative to Biventricular Pacing in Patients With HFrEF and a Typical LBBB.</brief_title>
  <acronym>HIS-alt_2</acronym>
  <official_title>Direct HIS/LBB Pacing as an Alternative to Biventricular Pacing in Patients With Symptomatic Heart Failure Despite Optimal Medical Treatment and an ECG With a Typical Left Bundle Branch Block Pattern.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Rigshospitalet, Denmark</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Rigshospitalet, Denmark</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>
      The study will investigate the feasibility of using direct HIS pacing or left bundle branch&#xD;
      pacing (LBB pacing) as an alternative to biventricular pacing in patients with symptomatic&#xD;
      heart failure and an ECG with a typical left bundle branch block pattern.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Biventricular pacing has for more than a decade been standard of care for patients with&#xD;
      HFrEF, LVEF &lt; 35%, NYHA II-IV despite optimal medical treatment and an ECG with left bundle&#xD;
      branch block (LBBB). However, it is not always ideal because of several drawbacks such as&#xD;
      phrenic nerve capture, inability to reach late activated areas and many more. Direct HIS&#xD;
      pacing can in many cases capture the left bundle and provide normal electrical activation of&#xD;
      the left ventricle but sometimes with high pacing thresholds. Recently direct left bundle&#xD;
      branch pacing has shown promise with synchronous activation of the left ventricle at low&#xD;
      pacing thresholds.&#xD;
&#xD;
      In the present study we randomize 125 patients in one center to either conventional CRT (45&#xD;
      patients) or HIS/LBB pacing (80 patients). In the HIS/LBB arm, direct HIS-pacing is attempted&#xD;
      first but if its not possible or the pacing threshold for capturing the left bundle branch is&#xD;
      &gt; 2.5 V at 1 ms we switch to placing a LBB-lead.&#xD;
&#xD;
      Power calculation for non-inferiority: With the 50 patients in the first His Alternative&#xD;
      study (25 Biv-CRT og 25 His-CRT) we observed a fall in systolic volumes of 34% and 46% with a&#xD;
      standard deviation of 13-16%. Using these numbers it would take at least 108 patients to be&#xD;
      90% sure that the lower limit of a one-sided 97.5% confidence interval (equal to a 95%&#xD;
      two-sided confidence interval) would be over the non-inferiority limit of -10%.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 1, 2020</start_date>
  <completion_date type="Anticipated">January 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 1, 2023</primary_completion_date>
  <phase>N/A</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, Outcomes Assessor)</masking>
    <masking_description>The patient and the staff performing and evaluating echocardiography and hall-walk tests are blinded to the treatment arm</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Left ventricular end-systolic volume</measure>
    <time_frame>6 months</time_frame>
    <description>Echocardiographic response after 6 months defined as decrease in left ventricular systolic volume of ≥ 15% of baseline</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Success rate of implanting a HIS-bundle lead with capture of the left bundle branch or a LBB-lead with narrowing of QRS</measure>
    <time_frame>6 months</time_frame>
    <description>The success rate of implanting a pacing lead to the HIS-bundle with capture of the left bundle at a threshold &lt; 2.5 V at 1 ms or implantation of a LBB lead with narrowing of the QRS duration and maintaining this effect at 6 month follow-up</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in LVEF and left ventricular chamber dimensions</measure>
    <time_frame>6 months</time_frame>
    <description>Echocardiographic response assessed by chamber dimensions and LVEF on a continuous scale</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in 6-min hall-walk test</measure>
    <time_frame>6 months</time_frame>
    <description>Functional response after 6 months defined as an increase in 6-min walking distance of ≥ 20% of the initial value</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in NYHA class</measure>
    <time_frame>6 months</time_frame>
    <description>Symptomatic response after 6 months defined as a fall in NYHA class of ≥ 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Minnesota Living with Heart Failure score</measure>
    <time_frame>6 months</time_frame>
    <description>Change in well-being after 6 months defined as a decrease in Minnesota Living With Heart Failure score of ≥ 15% of baseline</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Shortening of QRS duration</measure>
    <time_frame>6 months</time_frame>
    <description>Shortening the duration of the QRS complex defined as the widest paced QRS complex rated at 12-lead ECG after 6 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in NT-pro BNP value</measure>
    <time_frame>6 months</time_frame>
    <description>Change in NT-pro BNP value</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complications</measure>
    <time_frame>6 months</time_frame>
    <description>Device-related complications (periprocedural: electrode reoperation, pneumothorax, hemothorax, pericardial bleeding/tamponade and later (after 30 days post implantation): LV/HIS electrode reoperation, change of device due to battery depletion and infection requiring extraction).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">125</enrollment>
  <condition>Heart Failure</condition>
  <condition>Left Bundle-Branch Block</condition>
  <arm_group>
    <arm_group_label>HIS/LBB pacing</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>In this arm a right ventricular (RV) lead or implantable cardioverter defibrillator (ICD) lead is placed first and then implantation of a HIS-pacing lead is attempted. If it is not possible to find and pace HIS, to correct the LBBB or the threshold for correcting the LBBB is &gt; 2.5 V at 1 ms, implantation of a LBB-pacing lead is attempted instead. If that is not possible either, a left ventricular (LV) lead is implanted.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>LV pacing</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>In this arm an RV-lead or ICD-lead is placed first and then implantation of a LV-pacing lead is attempted. If this is not possible due to anatomical difficulties (no coronary sinus (CS) access, no available branches other than v cordis anterior or v cordis media) or electrical difficulties (no capture below 4 V at 1.0 msec or phrenic nerve stimulation &lt; 2x pacing threshold), implantation of a HIS-pacing lead is attempted instead. If that is not possible or the threshold for correcting the LBBB is &gt; 2.5 V at 1 ms, implantation of a LBB-pacing lead is attempted instead.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>HIS/LBB pacing</intervention_name>
    <description>3830 lead to HIS or LBB</description>
    <arm_group_label>HIS/LBB pacing</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>LV pacing</intervention_name>
    <description>LV lead in a CS branch</description>
    <arm_group_label>LV pacing</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients over 18 years of age, ischemic or non-ischemic cardiomyopathy with LVEF ≤ 35%&#xD;
             assessed by echocardiography, NYHA class II-IV heart failure symptoms despite optimal&#xD;
             medical treatment and&#xD;
&#xD;
               -  Either planned new implantation of a biventricular pacing system (CRT-P or&#xD;
                  CRT-D), where the ECG is with sinus rhythm and a typical left bundle branch block&#xD;
                  (see definition below)&#xD;
&#xD;
               -  Or planned upgrade of an existing pacemaker or ICD to a biventricular pacing&#xD;
                  system (CRT-P or CRT-D), where the ECG is with sinus rhythm and a typical left&#xD;
                  bundle branch block or there has been&gt; 90% right ventricular pacing from an&#xD;
                  existing pacemaker for at least 2 months prior to enrollment&#xD;
&#xD;
          -  Signed informed consent&#xD;
&#xD;
        Typical left bundle branch block:&#xD;
&#xD;
        QRS width &gt; 130 msec for women and &gt; 140 msec for men QS or rS pattern in leads V1 and V2,&#xD;
        and mid-QRS plateau phase with or without extras in at least 2 of leads V1, V2, V5, V6, I,&#xD;
        and aVL&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Existing biventricular pacing system&#xD;
&#xD;
          -  Permanent atrial fibrillation&#xD;
&#xD;
          -  Severe renal failure with eGFR &lt; 30 ml/min&#xD;
&#xD;
          -  AMI or CABG within the last three months&#xD;
&#xD;
          -  The patient does not want to participate&#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>Michael Vinther, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Rigshospitalet, Denmark</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Berit Th Philbert, MD PhD</last_name>
    <phone>+4535451410</phone>
    <email>berit.thornvig.philbert@regionh.dk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Niels Risum, MD PhD</last_name>
    <phone>+4535456995</phone>
    <email>niels.risum.01@regionh.dk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Rigshospitalet</name>
      <address>
        <city>Copenhagen</city>
        <state>Hovedstaden</state>
        <zip>2100</zip>
        <country>Denmark</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michael Vinther, MD PhD</last_name>
      <phone>+4535456994</phone>
      <email>michael.vinther@regionh.dk</email>
    </contact>
    <contact_backup>
      <last_name>Anne-Sofie Ellekilde, RN</last_name>
      <phone>+4535450923</phone>
      <email>Anne-sofie.ellekilde@regionh.dk</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>May 26, 2020</study_first_submitted>
  <study_first_submitted_qc>May 26, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 1, 2020</study_first_posted>
  <last_update_submitted>March 28, 2023</last_update_submitted>
  <last_update_submitted_qc>March 28, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 29, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Rigshospitalet, Denmark</investigator_affiliation>
    <investigator_full_name>Michael Vinther</investigator_full_name>
    <investigator_title>Chief Physician Electrophysiology</investigator_title>
  </responsible_party>
  <keyword>left bundle branch block</keyword>
  <keyword>HIS-pacing</keyword>
  <keyword>LBB-pacing</keyword>
  <keyword>left bundle branch pacing</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
    <mesh_term>Bundle-Branch Block</mesh_term>
    <mesh_term>Heart Block</mesh_term>
  </condition_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/NCT04409119
org study id: HIS alternative 2
nct id: NCT04409119
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The study will investigate the feasibility of using direct HIS pacing or left bundle branch
      pacing (LBB pacing) as an alternative to biventricular pacing in patients with symptomatic
      heart failure and an ECG with a typical left bundle branch block pattern.
Biventricular pacing has for more than a decade been standard of care for patients with
      HFrEF, LVEF < 35%, NYHA II-IV despite optimal medical treatment and an ECG with left bundle
      branch block (LBBB). However, it is not always ideal because of several drawbacks such as
      phrenic nerve capture, inability to reach late activated areas and many more. Direct HIS
      pacing can in many cases capture the left bundle and provide normal electrical activation of
      the left ventricle but sometimes with high pacing thresholds. Recently direct left bundle
      branch pacing has shown promise with synchronous activation of the left ventricle at low
      pacing thresholds.

      In the present study we randomize 125 patients in one center to either conventional CRT (45
      patients) or HIS/LBB pacing (80 patients). In the HIS/LBB arm, direct HIS-pacing is attempted
      first but if its not possible or the pacing threshold for capturing the left bundle branch is
      > 2.5 V at 1 ms we switch to placing a LBB-lead.

      Power calculation for non-inferiority: With the 50 patients in the first His Alternative
      study (25 Biv-CRT og 25 His-CRT) we observed a fall in systolic volumes of 34% and 46% with a
      standard deviation of 13-16%. Using these numbers it would take at least 108 patients to be
      90% sure that the lower limit of a one-sided 97.5% confidence interval (equal to a 95%
      two-sided confidence interval) would be over the non-inferiority limit of -10%.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Outcomes Assessor)
masking description: The patient and the staff performing and evaluating echocardiography and hall-walk tests are blinded to the treatment arm
measure: Change in Left ventricular end-systolic volume
time frame: 6 months
description: Echocardiographic response after 6 months defined as decrease in left ventricular systolic volume of ≥ 15% of baseline
measure: Success rate of implanting a HIS-bundle lead with capture of the left bundle branch or a LBB-lead with narrowing of QRS
time frame: 6 months
description: The success rate of implanting a pacing lead to the HIS-bundle with capture of the left bundle at a threshold < 2.5 V at 1 ms or implantation of a LBB lead with narrowing of the QRS duration and maintaining this effect at 6 month follow-up
measure: Change in LVEF and left ventricular chamber dimensions
time frame: 6 months
description: Echocardiographic response assessed by chamber dimensions and LVEF on a continuous scale
measure: Change in 6-min hall-walk test
time frame: 6 months
description: Functional response after 6 months defined as an increase in 6-min walking distance of ≥ 20% of the initial value
measure: Change in NYHA class
time frame: 6 months
description: Symptomatic response after 6 months defined as a fall in NYHA class of ≥ 1
measure: Change in Minnesota Living with Heart Failure score
time frame: 6 months
description: Change in well-being after 6 months defined as a decrease in Minnesota Living With Heart Failure score of ≥ 15% of baseline
measure: Shortening of QRS duration
time frame: 6 months
description: Shortening the duration of the QRS complex defined as the widest paced QRS complex rated at 12-lead ECG after 6 months
measure: Change in NT-pro BNP value
time frame: 6 months
description: Change in NT-pro BNP value
measure: Complications
time frame: 6 months
description: Device-related complications (periprocedural: electrode reoperation, pneumothorax, hemothorax, pericardial bleeding/tamponade and later (after 30 days post implantation): LV/HIS electrode reoperation, change of device due to battery depletion and infection requiring extraction).
arm group label: HIS/LBB pacing
arm group type: Experimental
description: In this arm a right ventricular (RV) lead or implantable cardioverter defibrillator (ICD) lead is placed first and then implantation of a HIS-pacing lead is attempted. If it is not possible to find and pace HIS, to correct the LBBB or the threshold for correcting the LBBB is > 2.5 V at 1 ms, implantation of a LBB-pacing lead is attempted instead. If that is not possible either, a left ventricular (LV) lead is implanted.
arm group label: LV pacing
arm group type: Active Comparator
description: In this arm an RV-lead or ICD-lead is placed first and then implantation of a LV-pacing lead is attempted. If this is not possible due to anatomical difficulties (no coronary sinus (CS) access, no available branches other than v cordis anterior or v cordis media) or electrical difficulties (no capture below 4 V at 1.0 msec or phrenic nerve stimulation < 2x pacing threshold), implantation of a HIS-pacing lead is attempted instead. If that is not possible or the threshold for correcting the LBBB is > 2.5 V at 1 ms, implantation of a LBB-pacing lead is attempted instead.
intervention type: Device
intervention name: HIS/LBB pacing
description: 3830 lead to HIS or LBB
arm group label: HIS/LBB pacing
intervention type: Device
intervention name: LV pacing
description: LV lead in a CS branch
arm group label: LV pacing
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Michael Vinther, MD PhD
role: Principal Investigator
affiliation: Rigshospitalet, Denmark
last name: Berit Th Philbert, MD PhD
phone: +4535451410
email: berit.thornvig.philbert@regionh.dk
last name: Niels Risum, MD PhD
phone: +4535456995
email: niels.risum.01@regionh.dk
facility: 
status: Recruiting
contact: 
contact backup: 
country: Denmark
responsible party type: Principal Investigator
investigator affiliation: Rigshospitalet, Denmark
investigator full name: Michael Vinther
investigator title: Chief Physician Electrophysiology
mesh term: Heart Failure
mesh term: Bundle-Branch Block
mesh term: Heart Block