xml: <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/NCT05993585</url>
    </required_header>
    <id_info>
      <org_study_id>318500</org_study_id>
      <nct_id>NCT05993585</nct_id>
    </id_info>
    <brief_title>The Effect of CRT on the Frank Starling Mechanism</brief_title>
    <acronym>CRT</acronym>
    <official_title>The Effects of Cardiac Resynchronisation Therapy on the Frank Starling Mechanism in Patients With Heart Failure</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Guy's and St Thomas' NHS Foundation Trust</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>King's College London</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Guy's and St Thomas' NHS Foundation Trust</source>
    <oversight_info>
      <has_dmc>Yes</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        The investigators are examining a scientific principle called the Frank Starling Mechanism&#xD;
        and how it relates to Cardiac Resynchronisation Therapy (CRT), a form of pacemaker therapy&#xD;
        used in the treatment of heart failure.&#xD;
  &#xD;
        The Frank Starling Mechanism is an established biological principle. The law states that the&#xD;
        stroke volume of the heart increases in response to an increase in the volume of blood in the&#xD;
        ventricles, before contraction, when all other factors remain constant. In other words, the&#xD;
        law states that the more blood enters the heart, the more blood is pumped out of the heart&#xD;
        with any given beat.&#xD;
  &#xD;
        There is some evidence that in some patients with chronic heart conditions, the Frank&#xD;
        Starling Mechanism is LESS EFFECTIVE, meaning that the heart is less able to cope with a&#xD;
        reduction in heart pumping function over time. There is also evidence that treatment with CRT&#xD;
        may IMPROVE the Frank Starling Mechanism - evidence for this has been shown in dog and mice&#xD;
        hearts, however, has never been shown in humans.&#xD;
  &#xD;
        The investigators aim to conduct a study where subjects undergo an ultrasound scan of the&#xD;
        heart (echocardiogram) whilst the participants pacemaker settings are temporarily changed.&#xD;
        This allows the investigators to measure the pumping function of the heart as more blood&#xD;
        enters the heart. The investigators will perform this test on 20 participants before and&#xD;
        after CRT, as well as 20 participants who have pacemakers, but no heart failure. This study&#xD;
        aims to test 3 hypotheses.&#xD;
  &#xD;
          1. In participants with pacemakers, a REDUCED Frank Starling Mechanism predicts which&#xD;
             participants go on to develop heart failure.&#xD;
  &#xD;
          2. Treatment with CRT IMPROVES the Frank Starling Mechanism in participants with pacemakers&#xD;
             and heart failure.&#xD;
  &#xD;
          3. The degree of improvement of the Frank Starling Mechanism after treatment with CRT&#xD;
             predicts which participants will respond to this treatment.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        The primary research investigation in this study is a non-invasive test of the Frank Starling&#xD;
        mechanism, which involves performing a transthoracic echocardiogram (ultrasound scan of the&#xD;
        heart) whilst temporarily changing pacemaker settings to mimic conditions such as faster&#xD;
        heart rates or increased blood flow to the heart. Measurements taken from the echocardiogram&#xD;
        during these changes in pacemaker settings will be used to determine the effectiveness of the&#xD;
        heart's Starling Mechanism. This test will last between 20-40 minutes. No special preparation&#xD;
        is needed and participants will be able to go home immediately afterwards. Pacemaker settings&#xD;
        will be returned to normal once the test is completed.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">August 4, 2023</start_date>
    <completion_date type="Anticipated">June 2, 2025</completion_date>
    <primary_completion_date type="Anticipated">June 2, 2025</primary_completion_date>
    <phase>N/A</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Non-Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <intervention_model_description>Single centre trial - observational cohort study</intervention_model_description>
      <primary_purpose>Basic Science</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Difference in starling mechanism</measure>
      <time_frame>Prior to pacing test (starling mechanism test) and after six months</time_frame>
      <description>1. Difference in maximum change in stroke volume (SV) in millilitres with AV delay modification &quot;Starling mechanics&quot; pre-CRT versus post-CRT (difference between lowest and highest SV).</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Left ventricular end-systolic volume (ml)</measure>
      <time_frame>Prior to pacing test (starling mechanism test) and after six months</time_frame>
      <description>Difference in left ventricular end-systolic volume in millimetres recorded on echocardiogram</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Left ventricular ejection fraction (%)</measure>
      <time_frame>Prior to pacing test (starling mechanism test) and after six months</time_frame>
      <description>Difference in Left ventricular ejection fraction in percent measured on echocardiogram</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Quality of life with heart failure symptoms</measure>
      <time_frame>Prior to pacing test (starling mechanism test) and after six months</time_frame>
      <description>Quality of life in heart failure assessed by Minnesota Living with Heart Failure Questionnaire</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Heart failure symptoms</measure>
      <time_frame>Prior to pacing test (starling mechanism test) and after six months</time_frame>
      <description>New York Heart Association ( NYHA) class - breathlessness on different levels of exercise - from walking on the flat (NYHA 2) up to limited by breathlessness on little movement (NYHA 4)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Packer's clinical composite score</measure>
      <time_frame>Prior to pacing test (starling mechanism test) and at six months</time_frame>
      <description>Difference in patient outcome measured by the clinical composite score - the score ranges from improved to unchanged or worsened</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Difference in baseline Starling mechanics between CRT group and control group</measure>
      <time_frame>Prior to pacing test (starling mechanism test) and at six months</time_frame>
      <description>Difference in stroke volume in millilitres during the pacing test (starling mechanism test) between the CRT and control group</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">40</enrollment>
    <condition>Pacemaker</condition>
    <condition>Heartfailure</condition>
    <arm_group>
      <arm_group_label>CRT Group</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>CRT group: We will include patients with symptomatic heart failure (LV ejection fraction &lt;35% on TTE, NYHA II-IV) and an RV pacing percentage of &gt;40%, thus meeting ESC Criteria for CRT upgrade.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Control Group</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Control group: patients with an existing dual chamber pacemaker and with preserved ejection fraction</description>
    </arm_group>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Test Of The Frank Starling Mechanism - Adjustment Of Av Delay And Measurement Of Pre-load -Control</intervention_name>
      <description>(Control Group): One test of the Starling mechanism Visit 1: Sign consent form, doctor assessment, electrocardiogram (ECG), Starling Test. If patients are in this category, this will be their only research visit</description>
      <arm_group_label>CRT Group</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Other: Test Of The Frank Starling Mechanism - Adjustment Of Av Delay And Measurement Of Pre-load -CRT</intervention_name>
      <description>(CRT Group): Two tests of the Starling mechanisms Visit 1: Sign consent form, assessment by doctor, electrocardiogram (ECG), Test of the Starling mechanism Visit 2: CRT upgrade procedure - your Cardiologist will explain this procedure to you. Visit 3: CRT pacing check at 6 weeks post-procedure Visit 4: Assessment by doctor, ECG, Echocardiogram, Test of the Starling mechanism at 6 months post-procedure.</description>
      <arm_group_label>Control Group</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  • Ability to provide informed consent to participate and willing to comply with the&#xD;
               clinical investigation plan and follow-up schedule.&#xD;
  &#xD;
                 -  Existing dual chamber pacemaker or ICD including atrial lead and RV lead.&#xD;
  &#xD;
                 -  RV pacing percentage &gt;40%.&#xD;
  &#xD;
                 -  CRT group - Severe left ventricular systolic impairment (LVEF≤35%). Clinical&#xD;
                    symptoms of heart failure despite optimum medical therapy (NYHA class II-IV).&#xD;
  &#xD;
                 -  Control group - LVEF &gt;50%.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  • Previous treated with CRT (existing LV lead/His-Bundle lead/Left Bundle Branch Area&#xD;
               lead).&#xD;
  &#xD;
                 -  Persistent atrial fibrillation&#xD;
  &#xD;
                 -  Female participants who are pregnant, lactating or planning pregnancy during the&#xD;
                    course of the study.&#xD;
  &#xD;
                 -  Participation in other studies with active treatment / investigational arm&#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>Christopher Aldo Rinaldi/Professor, MD, FHRS</last_name>
      <role>Principal Investigator</role>
      <affiliation>Guy's and St Thomas' NHS Trust</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Steven Niederer/Professor, PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>King's College London</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Sandra N Howell/Dr, Med State Exam, MSc, MSc</last_name>
      <phone>44 020 7188 9257</phone>
      <email>sandra.howell@kcl.ac.uk</email>
    </overall_contact>
    <location>
      <facility>
        <name>Guy's and St Thomas' NHS Trust</name>
        <address>
          <city>London</city>
          <zip>SE1 7EH</zip>
          <country>United Kingdom</country>
        </address>
      </facility>
      <contact>
        <last_name>Sandra N Howell/Dr, Med State Exam, MSc, MSc</last_name>
        <phone>020 7188 9257</phone>
        <email>sandra.howell@kcl.ac.uk</email>
      </contact>
      <investigator>
        <last_name>Christopher Aldo Rinaldi/Professor, MD, FHRS</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>United Kingdom</country>
    </location_countries>
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      <citation>Glikson M, Nielsen JC, Kronborg MB, Michowitz Y, Auricchio A, Barbash IM, Barrabes JA, Boriani G, Braunschweig F, Brignole M, Burri H, Coats AJS, Deharo JC, Delgado V, Diller GP, Israel CW, Keren A, Knops RE, Kotecha D, Leclercq C, Merkely B, Starck C, Thylen I, Tolosana JM; ESC Scientific Document Group. 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J. 2021 Sep 14;42(35):3427-3520. doi: 10.1093/eurheartj/ehab364. No abstract available. Erratum In: Eur Heart J. 2022 May 1;43(17):1651.</citation>
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    <verification_date>July 2023</verification_date>
    <study_first_submitted>July 31, 2023</study_first_submitted>
    <study_first_submitted_qc>August 8, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 15, 2023</study_first_posted>
    <last_update_submitted>August 8, 2023</last_update_submitted>
    <last_update_submitted_qc>August 8, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 15, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>Frank Starling Mechanism</keyword>
    <keyword>CRT</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Heart Failure</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>Yes</sharing_ipd>
      <ipd_description>Non-identifiable data will be shared upon request</ipd_description>
      <ipd_info_type>Study Protocol</ipd_info_type>
      <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
      <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
      <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
      <ipd_time_frame>Non-identifiable data will only be available after the end of the study</ipd_time_frame>
      <ipd_access_criteria>Fully anonymised data available upon request via email</ipd_access_criteria>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05993585
  org study id: 318500
  nct id: NCT05993585
  lead sponsor: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  The investigators are examining a scientific principle called the Frank Starling Mechanism
        and how it relates to Cardiac Resynchronisation Therapy (CRT), a form of pacemaker therapy
        used in the treatment of heart failure.
  
        The Frank Starling Mechanism is an established biological principle. The law states that the
        stroke volume of the heart increases in response to an increase in the volume of blood in the
        ventricles, before contraction, when all other factors remain constant. In other words, the
        law states that the more blood enters the heart, the more blood is pumped out of the heart
        with any given beat.
  
        There is some evidence that in some patients with chronic heart conditions, the Frank
        Starling Mechanism is LESS EFFECTIVE, meaning that the heart is less able to cope with a
        reduction in heart pumping function over time. There is also evidence that treatment with CRT
        may IMPROVE the Frank Starling Mechanism - evidence for this has been shown in dog and mice
        hearts, however, has never been shown in humans.
  
        The investigators aim to conduct a study where subjects undergo an ultrasound scan of the
        heart (echocardiogram) whilst the participants pacemaker settings are temporarily changed.
        This allows the investigators to measure the pumping function of the heart as more blood
        enters the heart. The investigators will perform this test on 20 participants before and
        after CRT, as well as 20 participants who have pacemakers, but no heart failure. This study
        aims to test 3 hypotheses.
  
          1. In participants with pacemakers, a REDUCED Frank Starling Mechanism predicts which
             participants go on to develop heart failure.
  
          2. Treatment with CRT IMPROVES the Frank Starling Mechanism in participants with pacemakers
             and heart failure.
  
          3. The degree of improvement of the Frank Starling Mechanism after treatment with CRT
             predicts which participants will respond to this treatment.
  The primary research investigation in this study is a non-invasive test of the Frank Starling
        mechanism, which involves performing a transthoracic echocardiogram (ultrasound scan of the
        heart) whilst temporarily changing pacemaker settings to mimic conditions such as faster
        heart rates or increased blood flow to the heart. Measurements taken from the echocardiogram
        during these changes in pacemaker settings will be used to determine the effectiveness of the
        heart's Starling Mechanism. This test will last between 20-40 minutes. No special preparation
        is needed and participants will be able to go home immediately afterwards. Pacemaker settings
        will be returned to normal once the test is completed.
  allocation: Non-Randomized
  intervention model: Parallel Assignment
  intervention model description: Single centre trial - observational cohort study
  primary purpose: Basic Science
  masking: None (Open Label)
  measure: Difference in starling mechanism
  time frame: Prior to pacing test (starling mechanism test) and after six months
  description: 1. Difference in maximum change in stroke volume (SV) in millilitres with AV delay modification "Starling mechanics" pre-CRT versus post-CRT (difference between lowest and highest SV).
  measure: Left ventricular end-systolic volume (ml)
  time frame: Prior to pacing test (starling mechanism test) and after six months
  description: Difference in left ventricular end-systolic volume in millimetres recorded on echocardiogram
  measure: Left ventricular ejection fraction (%)
  time frame: Prior to pacing test (starling mechanism test) and after six months
  description: Difference in Left ventricular ejection fraction in percent measured on echocardiogram
  measure: Quality of life with heart failure symptoms
  time frame: Prior to pacing test (starling mechanism test) and after six months
  description: Quality of life in heart failure assessed by Minnesota Living with Heart Failure Questionnaire
  measure: Heart failure symptoms
  time frame: Prior to pacing test (starling mechanism test) and after six months
  description: New York Heart Association ( NYHA) class - breathlessness on different levels of exercise - from walking on the flat (NYHA 2) up to limited by breathlessness on little movement (NYHA 4)
  measure: Packer's clinical composite score
  time frame: Prior to pacing test (starling mechanism test) and at six months
  description: Difference in patient outcome measured by the clinical composite score - the score ranges from improved to unchanged or worsened
  measure: Difference in baseline Starling mechanics between CRT group and control group
  time frame: Prior to pacing test (starling mechanism test) and at six months
  description: Difference in stroke volume in millilitres during the pacing test (starling mechanism test) between the CRT and control group
  arm group label: CRT Group
  arm group type: Experimental
  description: CRT group: We will include patients with symptomatic heart failure (LV ejection fraction <35% on TTE, NYHA II-IV) and an RV pacing percentage of >40%, thus meeting ESC Criteria for CRT upgrade.
  arm group label: Control Group
  arm group type: Active Comparator
  description: Control group: patients with an existing dual chamber pacemaker and with preserved ejection fraction
  intervention type: Other
  intervention name: Test Of The Frank Starling Mechanism - Adjustment Of Av Delay And Measurement Of Pre-load -Control
  description: (Control Group): One test of the Starling mechanism Visit 1: Sign consent form, doctor assessment, electrocardiogram (ECG), Starling Test. If patients are in this category, this will be their only research visit
  arm group label: CRT Group
  intervention type: Other
  intervention name: Other: Test Of The Frank Starling Mechanism - Adjustment Of Av Delay And Measurement Of Pre-load -CRT
  description: (CRT Group): Two tests of the Starling mechanisms Visit 1: Sign consent form, assessment by doctor, electrocardiogram (ECG), Test of the Starling mechanism Visit 2: CRT upgrade procedure - your Cardiologist will explain this procedure to you. Visit 3: CRT pacing check at 6 weeks post-procedure Visit 4: Assessment by doctor, ECG, Echocardiogram, Test of the Starling mechanism at 6 months post-procedure.
  arm group label: Control Group
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Christopher Aldo Rinaldi/Professor, MD, FHRS
  role: Principal Investigator
  affiliation: Guy's and St Thomas' NHS Trust
  last name: Steven Niederer/Professor, PhD
  role: Principal Investigator
  affiliation: King's College London
  last name: Sandra N Howell/Dr, Med State Exam, MSc, MSc
  phone: 44 020 7188 9257
  email: sandra.howell@kcl.ac.uk
  facility: 
  contact: 
  investigator: 
  country: United Kingdom
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  PMID: 34455430
  responsible party type: Sponsor
  mesh term: Heart Failure
  sharing ipd: Yes
  ipd description: Non-identifiable data will be shared upon request
  ipd info type: Study Protocol
  ipd info type: Statistical Analysis Plan (SAP)
  ipd info type: Informed Consent Form (ICF)
  ipd info type: Clinical Study Report (CSR)
  ipd time frame: Non-identifiable data will only be available after the end of the study
  ipd access criteria: Fully anonymised data available upon request via email