<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/NCT03768804</url>
  </required_header>
  <id_info>
    <org_study_id>13808</org_study_id>
    <nct_id>NCT03768804</nct_id>
  </id_info>
  <brief_title>SyncAV Study: Investigation of the Efficacy of the SyncAV Fusion Pacing Algorithm on Exercise</brief_title>
  <official_title>Assessing the Effect of the SyncAV Algorithm in Cardiac Resynchronization Therapy on Exercise Capacity and QRS Duration on Exercise</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Oxford</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Oxford</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>
      In patients with weak pumping function of the heart, uncoordinated contraction of the&#xD;
      chambers can be corrected using a cardiac resynchronization therapy (&quot;CRT&quot;) pacemaker. These&#xD;
      devices make patients live longer by improving how the heart pumps and reducing symptoms such&#xD;
      as breathlessness. However, not all patients benefit from CRT and programming devices&#xD;
      optimally can greatly influence success. Predicting the correct timings of contraction&#xD;
      between the atria (top chambers of the heart) and the ventricles (bottom chambers), as well&#xD;
      as between the left and right ventricles, especially when heart rate increases during&#xD;
      exercises, is challenging.&#xD;
&#xD;
      A new approach to optimizing CRT programming has been proposed known as 'fusion-pacing'. This&#xD;
      allows the electrical wave from the heart's own conduction system to merge or fuse with the&#xD;
      impulse from the pacemaker in the left ventricle. The timing of the pacemaker's impulse is&#xD;
      continuously adjusted to measurements the device makes of the hearts natural conduction. What&#xD;
      is not clear is how effective 'fusion-pacing' is during exercise when the hearts natural&#xD;
      conduction changes rapidly and unpredictably. We plan to investigate this by monitoring the&#xD;
      electrocardiogram (&quot;ECG&quot;) whilst accurately measuring exercise performance and ability during&#xD;
      a cardiopulmonary exercise test (&quot;CPET&quot;) on an exercise bike. We will also ask participants&#xD;
      to rate their perceived exercise intensity to see whether fusion pacing improves ECG&#xD;
      resynchronization, exercise performance, and patients' symptoms compared to standard&#xD;
      programming.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Heart failure represents a significant health problem, with the last national heart failure&#xD;
      audit demonstrating prevalence in the United Kingdom of 900,000 patients, accounting for 5%&#xD;
      of all acute hospital admissions. This is expected to increase with an ageing population.&#xD;
      Despite improvements in medical therapy, prognosis remains poor, with an in- hospital&#xD;
      mortality of 9.6%, and an estimated mortality of 30-40% at 1 year after diagnosis.&#xD;
&#xD;
      Multiple randomised controlled trials have demonstrated that cardiac resynchronization&#xD;
      therapy pacemaker devices (&quot;CRT&quot;) are an effective therapy for patients with poor pumping&#xD;
      function and altered electrical conduction of the heart (left bundle branch block, &quot;LBBB&quot;),&#xD;
      improving both morbidity and mortality. However, only 60-70% of patients notice a symptomatic&#xD;
      improvement with CRT and even in patients who do respond, response can often be improved&#xD;
      further by optimising how the device is programmed.&#xD;
&#xD;
      CRT devices improve coordination of heart pumping by pacing both ventricles of the heart. A&#xD;
      key function of this is to coordinate the timing of contraction of the the atria and the&#xD;
      ventricles (atrio-ventricular, or &quot;AV&quot;, optimisation). This allows maximal filling of the&#xD;
      left ventricle with blood. More recently, it has become important not only in standard&#xD;
      bi-ventricular (&quot;BiV&quot;) pacing, but to allow left ventricular pacing to be timed with&#xD;
      intrinsic conduction to the right ventricle to provide CRT (so called 'fusion' pacing).&#xD;
&#xD;
      Multiple methods have been described to assess AV optimisation, including echocardiographic&#xD;
      measurements. However, echo based methods are labour intensive, and their value is uncertain.&#xD;
      Device algorithms utilising analysis of the intra-cardiac electrogram (&quot;IEGM&quot;) have become an&#xD;
      attractive alternative due to their rapid and automated nature, although evidence suggests&#xD;
      that they may not have clinical benefit over using fixed AV delays. In addition, intrinsic AV&#xD;
      conduction is known to alter with exercise, normally becoming shorter. Optimisation of AV&#xD;
      delays in CRT on exercise has been shown to improve cardiac output. Device algorithms can&#xD;
      therefore allow dynamic adjustment of AV delays as they change with exercise and heart rate&#xD;
      (rate-adaptive AV delay or &quot;RAAVD&quot;). Indeed, use of individually tailored RAAVD in CRT&#xD;
      patients has demonstrated an increase in exercise capacity.&#xD;
&#xD;
      Patients with heart failure and LBBB often have normal intrinsic right ventricular activation&#xD;
      through the right bundle. Utilization of timed left ventricular (&quot;LV&quot;) pacing to merge (or&#xD;
      fuse) with this intrinsic conduction may confer benefits over standard BiV pacing, but&#xD;
      requires relatively normal intrinsic AV conduction as well as correct timing of LV pacing to&#xD;
      right ventricular (&quot;RV&quot;) activation. Algorithms now exist which allow dynamic reassessment of&#xD;
      intrinsic conduction and so adjustment of the optimal AV delay. They can therefore compensate&#xD;
      for changes in the intrinsic AV delay on exercising, and so maintain adequate fusion pacing&#xD;
      and CRT optimisation. One such software algorithm is SyncAV, developed by Abbott (Abbott&#xD;
      Vascular, 3200 Lakeside Drive, Santa Clara, California 95054-2807). SyncAVTM assesses&#xD;
      intrinsic AV conduction every 256 beats. It then sets a shorter programmed AV delay by&#xD;
      subtracting a set period (known as the &quot;delta&quot; - adjustable but nominally set to 50ms) from&#xD;
      the intrinsic time.&#xD;
&#xD;
      There is some evidence that fusion pacing gives benefit in terms of both acute pumping&#xD;
      function of the heart and long term response to CRT. However, what remains unclear is whether&#xD;
      the effect of dynamic AV optimisation and fusion pacing is maintained on exercise. Firstly,&#xD;
      the re-analysis and adjustment intervals may be insufficient to allow effective fusion&#xD;
      throughout exercise. It is therefore possible that with rapidly changing heart rates this&#xD;
      coordinated timing is lost, leading to inefficient conduction of electricity through the&#xD;
      heart. This could result in large periods of time on exercising without effective CRT and so&#xD;
      poor exercise tolerance. Secondly, there is evidence that in patients with heart failure AV&#xD;
      intervals do not alter with change in heart rate in a similar way to healthy controls. One&#xD;
      study found that the degree of change is greater on exercise, whilst one demonstrated that in&#xD;
      a CRT population only a third of patients had shorter optimal AV delay intervals on exercise,&#xD;
      with a third being unchanged and a third longer. The use of a fixed &quot;delta&quot; in SyncAVTM may&#xD;
      therefore result in incorrect adjustment of AV intervals as intrinsic conduction changes,&#xD;
      with the effectiveness of SyncAV therefore depending on how the intrinsic interval changes.&#xD;
&#xD;
      We will use a prospective single-centre randomized single-blind crossover study to&#xD;
      investigate the effectiveness of SyncAV on exercise, by randomising participants to either&#xD;
      use of SyncAV or fixed AV delays, and then carrying out cardiopulmonary exercise testing&#xD;
      (&quot;CPET&quot;).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Enrolling by invitation</last_known_status>
  <start_date type="Actual">May 31, 2019</start_date>
  <completion_date type="Anticipated">December 2021</completion_date>
  <primary_completion_date type="Anticipated">December 2021</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>Crossover Assignment</intervention_model>
    <intervention_model_description>Double blind, randomised crossover study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Exercise capacity</measure>
    <time_frame>1 Year</time_frame>
    <description>Exercise capacity as measured by cardiopulmonary exercise testing (&quot;CPET&quot;) including blood sampling</description>
  </primary_outcome>
  <primary_outcome>
    <measure>BORG-RPE rating</measure>
    <time_frame>1 Year</time_frame>
    <description>Borg rating of perceived exertion (&quot;Borg-RPE&quot;) during CPET</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>QRS duration</measure>
    <time_frame>1 Year</time_frame>
    <description>QRS duration during exercise, compared to at rest</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exercise duration</measure>
    <time_frame>1 Year</time_frame>
    <description>Exercise duration as measured by cardiopulmonary exercise testing (&quot;CPET&quot;)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PR duration</measure>
    <time_frame>1 Year</time_frame>
    <description>Intrinsic PR duration during exercise when fusion pacing is on</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">22</enrollment>
  <condition>Heart Failure, Systolic</condition>
  <arm_group>
    <arm_group_label>SyncAV algorithm on</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Device randomised to have SyncAV on, with delta programmed to the value which gives the narrowest QRS duration at rest and pseudo left ventricular (&quot;LV&quot;) only pacing</description>
  </arm_group>
  <arm_group>
    <arm_group_label>SyncAV algorithm off</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Device randomised to have SyncAV off, with a fixed sensed atrioventricular (&quot;AV&quot;) delay of 120ms or shorter if necessary to prevent fusion, and biventricular (&quot;BiV&quot;) pacing</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>SyncAV algorithm on</intervention_name>
    <description>Cardiac Resynchronisation Device will be set to have the SyncAV algorithm on for the duration of the cardiopulmonary exercise test (&quot;CPET&quot;), before being reset to pre-existing settings</description>
    <arm_group_label>SyncAV algorithm on</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>SyncAV algorithm off</intervention_name>
    <description>ardiac Resynchronisation Device will be set to have the SyncAV algorithm off and a fixed AV delay, for the duration of the CPET, before being reset to pre-existing settings</description>
    <arm_group_label>SyncAV algorithm off</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥18 and able to give informed consent.&#xD;
&#xD;
          -  Patients with existing cardiac resynchronization therapy (&quot;CRT&quot;) devices able to&#xD;
             utilise the SyncAV algorithm, implanted ≥6 months and under follow up at Oxford&#xD;
             University Hospitals National Health Service (&quot;NHS&quot;) Foundation Trust.&#xD;
&#xD;
          -  Evidence of response to CRT, defined as functional improvement or left ventricular&#xD;
             (&quot;LV&quot;) remodelling on imaging.&#xD;
&#xD;
          -  Sinus rhythm and PR interval &lt;250ms.&#xD;
&#xD;
          -  Able to exercise to perform cardiopulmonary exercise testing (&quot;CPET&quot;).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnancy or breast feeding.&#xD;
&#xD;
          -  Atrial fibrillation or atrial tachycardia.&#xD;
&#xD;
          -  Underlying 2nd or 3rd degree heart block.&#xD;
&#xD;
          -  PR interval ≥250ms.&#xD;
&#xD;
          -  Chronotropic incompetence, defined as use of rate-response algorithm or ≥80% atrial&#xD;
             pacing.&#xD;
&#xD;
          -  Any concurrent condition contraindicating use of CPET.&#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>Neil Herring, BMBCh MRCP</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Oxford</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Physiology, Anatomy and Genetics, University of Oxford</name>
      <address>
        <city>Oxford</city>
        <state>Oxfordshire</state>
        <zip>OX1 3PT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>December 3, 2018</study_first_submitted>
  <study_first_submitted_qc>December 6, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 7, 2018</study_first_posted>
  <last_update_submitted>November 16, 2020</last_update_submitted>
  <last_update_submitted_qc>November 16, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 17, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Cardiac resynchronisation therapy</keyword>
  <keyword>Fusion pacing</keyword>
  <keyword>SyncAV</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure, Systolic</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>No IPD to be shared</ipd_description>
  </patient_data>
  <pending_results>
    <submitted>March 28, 2023</submitted>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03768804
org study id: 13808
nct id: NCT03768804
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
In patients with weak pumping function of the heart, uncoordinated contraction of the
      chambers can be corrected using a cardiac resynchronization therapy ("CRT") pacemaker. These
      devices make patients live longer by improving how the heart pumps and reducing symptoms such
      as breathlessness. However, not all patients benefit from CRT and programming devices
      optimally can greatly influence success. Predicting the correct timings of contraction
      between the atria (top chambers of the heart) and the ventricles (bottom chambers), as well
      as between the left and right ventricles, especially when heart rate increases during
      exercises, is challenging.

      A new approach to optimizing CRT programming has been proposed known as 'fusion-pacing'. This
      allows the electrical wave from the heart's own conduction system to merge or fuse with the
      impulse from the pacemaker in the left ventricle. The timing of the pacemaker's impulse is
      continuously adjusted to measurements the device makes of the hearts natural conduction. What
      is not clear is how effective 'fusion-pacing' is during exercise when the hearts natural
      conduction changes rapidly and unpredictably. We plan to investigate this by monitoring the
      electrocardiogram ("ECG") whilst accurately measuring exercise performance and ability during
      a cardiopulmonary exercise test ("CPET") on an exercise bike. We will also ask participants
      to rate their perceived exercise intensity to see whether fusion pacing improves ECG
      resynchronization, exercise performance, and patients' symptoms compared to standard
      programming.
Heart failure represents a significant health problem, with the last national heart failure
      audit demonstrating prevalence in the United Kingdom of 900,000 patients, accounting for 5%
      of all acute hospital admissions. This is expected to increase with an ageing population.
      Despite improvements in medical therapy, prognosis remains poor, with an in- hospital
      mortality of 9.6%, and an estimated mortality of 30-40% at 1 year after diagnosis.

      Multiple randomised controlled trials have demonstrated that cardiac resynchronization
      therapy pacemaker devices ("CRT") are an effective therapy for patients with poor pumping
      function and altered electrical conduction of the heart (left bundle branch block, "LBBB"),
      improving both morbidity and mortality. However, only 60-70% of patients notice a symptomatic
      improvement with CRT and even in patients who do respond, response can often be improved
      further by optimising how the device is programmed.

      CRT devices improve coordination of heart pumping by pacing both ventricles of the heart. A
      key function of this is to coordinate the timing of contraction of the the atria and the
      ventricles (atrio-ventricular, or "AV", optimisation). This allows maximal filling of the
      left ventricle with blood. More recently, it has become important not only in standard
      bi-ventricular ("BiV") pacing, but to allow left ventricular pacing to be timed with
      intrinsic conduction to the right ventricle to provide CRT (so called 'fusion' pacing).

      Multiple methods have been described to assess AV optimisation, including echocardiographic
      measurements. However, echo based methods are labour intensive, and their value is uncertain.
      Device algorithms utilising analysis of the intra-cardiac electrogram ("IEGM") have become an
      attractive alternative due to their rapid and automated nature, although evidence suggests
      that they may not have clinical benefit over using fixed AV delays. In addition, intrinsic AV
      conduction is known to alter with exercise, normally becoming shorter. Optimisation of AV
      delays in CRT on exercise has been shown to improve cardiac output. Device algorithms can
      therefore allow dynamic adjustment of AV delays as they change with exercise and heart rate
      (rate-adaptive AV delay or "RAAVD"). Indeed, use of individually tailored RAAVD in CRT
      patients has demonstrated an increase in exercise capacity.

      Patients with heart failure and LBBB often have normal intrinsic right ventricular activation
      through the right bundle. Utilization of timed left ventricular ("LV") pacing to merge (or
      fuse) with this intrinsic conduction may confer benefits over standard BiV pacing, but
      requires relatively normal intrinsic AV conduction as well as correct timing of LV pacing to
      right ventricular ("RV") activation. Algorithms now exist which allow dynamic reassessment of
      intrinsic conduction and so adjustment of the optimal AV delay. They can therefore compensate
      for changes in the intrinsic AV delay on exercising, and so maintain adequate fusion pacing
      and CRT optimisation. One such software algorithm is SyncAV, developed by Abbott (Abbott
      Vascular, 3200 Lakeside Drive, Santa Clara, California 95054-2807). SyncAVTM assesses
      intrinsic AV conduction every 256 beats. It then sets a shorter programmed AV delay by
      subtracting a set period (known as the "delta" - adjustable but nominally set to 50ms) from
      the intrinsic time.

      There is some evidence that fusion pacing gives benefit in terms of both acute pumping
      function of the heart and long term response to CRT. However, what remains unclear is whether
      the effect of dynamic AV optimisation and fusion pacing is maintained on exercise. Firstly,
      the re-analysis and adjustment intervals may be insufficient to allow effective fusion
      throughout exercise. It is therefore possible that with rapidly changing heart rates this
      coordinated timing is lost, leading to inefficient conduction of electricity through the
      heart. This could result in large periods of time on exercising without effective CRT and so
      poor exercise tolerance. Secondly, there is evidence that in patients with heart failure AV
      intervals do not alter with change in heart rate in a similar way to healthy controls. One
      study found that the degree of change is greater on exercise, whilst one demonstrated that in
      a CRT population only a third of patients had shorter optimal AV delay intervals on exercise,
      with a third being unchanged and a third longer. The use of a fixed "delta" in SyncAVTM may
      therefore result in incorrect adjustment of AV intervals as intrinsic conduction changes,
      with the effectiveness of SyncAV therefore depending on how the intrinsic interval changes.

      We will use a prospective single-centre randomized single-blind crossover study to
      investigate the effectiveness of SyncAV on exercise, by randomising participants to either
      use of SyncAV or fixed AV delays, and then carrying out cardiopulmonary exercise testing
      ("CPET").
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: Double blind, randomised crossover study
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Exercise capacity
time frame: 1 Year
description: Exercise capacity as measured by cardiopulmonary exercise testing ("CPET") including blood sampling
measure: BORG-RPE rating
time frame: 1 Year
description: Borg rating of perceived exertion ("Borg-RPE") during CPET
measure: QRS duration
time frame: 1 Year
description: QRS duration during exercise, compared to at rest
measure: Exercise duration
time frame: 1 Year
description: Exercise duration as measured by cardiopulmonary exercise testing ("CPET")
measure: PR duration
time frame: 1 Year
description: Intrinsic PR duration during exercise when fusion pacing is on
arm group label: SyncAV algorithm on
arm group type: Other
description: Device randomised to have SyncAV on, with delta programmed to the value which gives the narrowest QRS duration at rest and pseudo left ventricular ("LV") only pacing
arm group label: SyncAV algorithm off
arm group type: Other
description: Device randomised to have SyncAV off, with a fixed sensed atrioventricular ("AV") delay of 120ms or shorter if necessary to prevent fusion, and biventricular ("BiV") pacing
intervention type: Other
intervention name: SyncAV algorithm on
description: Cardiac Resynchronisation Device will be set to have the SyncAV algorithm on for the duration of the cardiopulmonary exercise test ("CPET"), before being reset to pre-existing settings
arm group label: SyncAV algorithm on
intervention type: Other
intervention name: SyncAV algorithm off
description: ardiac Resynchronisation Device will be set to have the SyncAV algorithm off and a fixed AV delay, for the duration of the CPET, before being reset to pre-existing settings
arm group label: SyncAV algorithm off
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Neil Herring, BMBCh MRCP
role: Principal Investigator
affiliation: University of Oxford
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Heart Failure, Systolic
sharing ipd: No
ipd description: No IPD to be shared
submitted: March 28, 2023