<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/NCT03755570</url>
  </required_header>
  <id_info>
    <org_study_id>251230</org_study_id>
    <nct_id>NCT03755570</nct_id>
  </id_info>
  <brief_title>How is COGNItive Function Affected by Cardiac Resynchronisation Therapy?</brief_title>
  <acronym>COGNI-CRT</acronym>
  <official_title>How is COGNItive Function Affected by Cardiac Resynchronisation Therapy?</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Royal Cornwall Hospitals Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Royal Cornwall Hospitals Trust</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary objective of COGNI-CRT is to assess whether Cardiac Resynchronisation Therapy&#xD;
      (CRT) can improve cognitive function in patients with systolic HF (LVEF ≤35%), when compared&#xD;
      to a control group of patients implanted with an Implantable Cardioverter-Defibrillator (ICD)&#xD;
      or a permanent pacemaker (PPM) with systolic HF (LVEF ≤35%).&#xD;
&#xD;
      This clinical investigation is a prospective, single-centre cohort study. Each participant&#xD;
      will be followed for 6 months. The study will collect data over 3 years; 2.5 years for&#xD;
      enrolment and 6 months until the last participant completes the last 6-month follow-up visit.&#xD;
&#xD;
      N.B: COGNI-CRT does NOT affect the patient's care pathway - the patients who will be selected&#xD;
      for participation are those who have already been referred for the device implant. The ONLY&#xD;
      difference to the patient's care pathway caused by COGNI-CRT is the addition of a battery of&#xD;
      cognitive function tests, which involves asking the patient questions and asking them to&#xD;
      complete questionnaire-like cognitive tests.&#xD;
&#xD;
      NTpro-BNP levels, NYHA classification and LVEF will be measured prior to device implantation&#xD;
      and at 6-months post-implant to assess the device's impact on the participant's heart failure&#xD;
      (and CRT response). N.B: NT-proBNP, NYHA classification and LVEF are all parts of the&#xD;
      patient's standard care pathway, COGNI-CRT is just utilising the data collected as part of&#xD;
      the investigation.&#xD;
&#xD;
      The main study arm and control group allows COGNI-CRT to assess 3 potential outcomes for&#xD;
      patients with severe HF (LVEF &lt;35%):&#xD;
&#xD;
        1. Cognitive function is not improved by CRT, ICDs or PPMs&#xD;
&#xD;
        2. Cognitive function can be improved by the assurance of rate control offered by CRT, ICDs&#xD;
           and PPMs&#xD;
&#xD;
        3. Cognitive function can be improved by the assurance of ventricular synchronisation and&#xD;
           rate control provided by the additional left ventricular lead in CRT devices.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Purpose:&#xD;
&#xD;
      The purpose of this clinical investigation is to assess whether cardiac resynchronisation&#xD;
      therapy (CRT) can improve cognitive function in patients with systolic heart failure (Left&#xD;
      Ventricular Ejection Fraction (LVEF) ≤35%), when compared to a control group of patients&#xD;
      implanted with an implantable cardioverter-defibrillator (ICD) or permanent pacemaker (PPM)&#xD;
      with systolic heart failure (LVEF ≤35%).&#xD;
&#xD;
      Design:&#xD;
&#xD;
      This clinical investigation is a prospective, single-centre cohort study. The study will be&#xD;
      conducted at the Royal Cornwall Hospital Trust (RCHT) in Cornwall, England. Subjects will be&#xD;
      followed for 6 months.&#xD;
&#xD;
      Cognitive performance will be assessed in patients pre- and post-CRT implant (Group A). An&#xD;
      ICD and PPM control group (Group B) will also be assessed using the same battery of cognitive&#xD;
      function tests to ensure any difference in cognitive function which is identified between&#xD;
      pre- and post- CRT implant is due to the CRT therapy, and not due to a placebo effect (which&#xD;
      can be especially powerful with implanted devices) or due to a learning effect (i.e. patients&#xD;
      tested on the second occasion might improve their scores because they have had more&#xD;
      practice).&#xD;
&#xD;
      N.B: COGNI-CRT does NOT affect the patient's care pathway - the patients who will be selected&#xD;
      for participation are those who have already been referred for the device implant. The ONLY&#xD;
      difference to the patient's care pathway caused by COGNI-CRT is the addition of a battery of&#xD;
      cognitive function tests, which involves asking the patient questions and asking them to&#xD;
      complete questionnaire-like cognitive tests.&#xD;
&#xD;
      LVEF, NT-proBNP and New York Heart Association (NYHA) classification data which is collected&#xD;
      prior to device implantation and at 6-months post-implant will be utilised for analysis to&#xD;
      measure response to CRT and to assess difference between the main arm and control group.&#xD;
&#xD;
      Arms in the study will be:&#xD;
&#xD;
        -  Group A: Participants implanted with a CRT who are eligible according to the inclusion/&#xD;
           exclusion criteria&#xD;
&#xD;
        -  Group B: Participants implanted with an ICD or a PPM who are eligible according to the&#xD;
           inclusion / exclusion criteria&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      Primary objective: To assess whether CRT can improve cognitive function in patients with&#xD;
      systolic heart failure (LVEF ≤35%), when compared to a control group of patients implanted&#xD;
      with an ICD or PPM with systolic heart failure (LVEF ≤35%).&#xD;
&#xD;
      Secondary Objectives:&#xD;
&#xD;
        -  To assess whether CRT can improve cognitive function&#xD;
&#xD;
        -  To assess whether ICD and PPM therapy can improve cognitive function&#xD;
&#xD;
        -  To assess if the level of improvement in cognitive function correlates to LVEF&#xD;
           improvement / stability and/or NYHA improvement /stability and/or NT-proBNP level&#xD;
           reduction (CRT response).&#xD;
&#xD;
      Subject Population:&#xD;
&#xD;
      The subject population enrolled in this investigation will comprise of male and female&#xD;
      patients aged 20-89 years old. These subjects are patients who are willing to provide&#xD;
      informed consent and meet the specific eligibility criteria. A minimum of 198 participants&#xD;
      will be enrolled in this investigation.&#xD;
&#xD;
      Data for this study will be collected at:&#xD;
&#xD;
        -  Enrolment&#xD;
&#xD;
        -  Pre-Assessment for CRT, ICD or PPM Implantation&#xD;
&#xD;
        -  Cardiac Implantable Electronic Device (CIED) Implant&#xD;
&#xD;
        -  Post-Implant 6-Week Device Check (For device optimisation)&#xD;
&#xD;
        -  Post-Implant 6-Month Device Follow-Up Visit After completing the Post-Implant 6-Month&#xD;
           Device Follow-Up Visit, the patient will have completed his/her participation in the&#xD;
           study.&#xD;
&#xD;
      Devices Used:&#xD;
&#xD;
      Implanted CRT-P, CRT-D, ICD and PPM devices may include Biotronik, Boston Scientific,&#xD;
      Medtronic and St Jude Medical.&#xD;
&#xD;
      Patient Screening:&#xD;
&#xD;
      Patients who are referred to RCHT for CRT, ICD or PPM implantation with systolic heart&#xD;
      failure (LVEF ≤35%) will be screened prior to Pre-Assessment by the clinical team.&#xD;
      Prospective patients will be afforded sufficient time to consider participation in COGNI-CRT.&#xD;
&#xD;
      Cognitive Tests Used to Evaluate Cognitive Function:&#xD;
&#xD;
      To be Performed Only At Pre-Assessment:&#xD;
&#xD;
        1. Test of Premorbid Functioning (TOPF): TOPF provides the participant with a list of 70&#xD;
           words that have atypical grapheme to phoneme translations. The participant must attempt&#xD;
           to read the list aloud so pronunciation of the words can be assessed. This tests IQ and&#xD;
           memory as the participant must be familiar with the words, rather than being able to&#xD;
           spell out a word they do not know. It takes approximately 10 minutes to complete&#xD;
&#xD;
           To be Performed at Pre-Assessment and at the Post-Implant 6-Month Device Follow-Up&#xD;
           Visit:&#xD;
&#xD;
        2. Hospital Anxiety and Depression Scale (HADS): The test consists of 14 multiple-choice&#xD;
           questions, each attempting to ascertain about the frequency the participant has felt a&#xD;
           certain symptom within the last 7 days. There are 4 answers to choose from which range&#xD;
           from suffering from the symptom &quot;nearly all the time&quot; to &quot;not at all&quot; and are graded 0-3&#xD;
           depending on the participant's answer.&#xD;
&#xD;
        3. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): Consisting&#xD;
           of 12 sections, to evaluate 5 types of cognitive function: immediate memory;&#xD;
           visuospatial/ constructional; attention; language and delayed memory.&#xD;
&#xD;
        4. Frontal Assessment Battery (FAB): The test has 6 neuropsychological tasks which involve&#xD;
           asking the participant questions, for example &quot;In what way are a banana and an orange&#xD;
           alike?&quot;, and learning simple actions in response to hand taps or movements.&#xD;
&#xD;
        5. Trail Making Test (TMT) Parts A &amp; B: Both parts of TMT involve circles dotted over a&#xD;
           piece of paper, the circles for Part A are marked with the numbers 1 - 25 and the&#xD;
           patient must draw a line connecting the numbers in ascending order, i.e. &quot;1-2-3-4-5-6…&quot;&#xD;
           etc. Part B involves numbers and letters dotted around the page, from 1-13 and from A-L.&#xD;
           The patient must connect the numbers and letters in ascending order, alternating between&#xD;
           numbers and letters, i.e. &quot;1-A-2-B-3-C…&quot; etc&#xD;
&#xD;
      Response to CRT Measures will be measured prior to device implantation and at the 6-month&#xD;
      follow-up device follow-up clinic:&#xD;
&#xD;
      LVEF: LVEF will be measured prior to device implant to assess the patient's heart function,&#xD;
      and at the Post-Implant 6-Month Device Follow-Up Visit.&#xD;
&#xD;
      NT-proBNP: NT-proBNP levels from the patient's routine blood tests prior to device&#xD;
      implantation and at the Post-Implant 6-Month Device Follow-Up Visit where blood testing is&#xD;
      routine for heart failure patients every 6 months.&#xD;
&#xD;
      NYHA: A NYHA scale assessment will be performed during the screening clinics prior to device&#xD;
      implant, and at the Post-Implant 6-Month Device Follow-Up Visit using the standardised NYHA&#xD;
      questions designed for the purpose of this trial.&#xD;
&#xD;
      N.B: The above 3 tests (LVEF, NT-proBNP and NYHA classification) are performed routinely as&#xD;
      part of the patient standard care pathway for heart failure, and this data will be utilised&#xD;
      for analysis in this trial. The tests are NOT performed for the purpose of COGNI-CRT.&#xD;
&#xD;
      Device Optimisation:&#xD;
&#xD;
      At the post-implant 6-week device follow-up check, all efforts will be made to ensure the&#xD;
      device is optimised as much as is possible, and the patient listed for MDT if problems are&#xD;
      encountered to attempt to resolve problems.&#xD;
&#xD;
      Data Analysis:&#xD;
&#xD;
      Data will be tested for normality. Tests for group differences will be used to compare&#xD;
      cognitive function between patients before and after CRT implant, and in the control group&#xD;
      before and after ICD or PPM implant. Tests for group differences will also be used in&#xD;
      comparison of the LVEF values, BNP results, NYHA classification, QRS duration, percentage&#xD;
      biventricular pacing and BP measurements. Sample size calculations have estimated the&#xD;
      required CRT sample size to power the study to be 99 participants (with a 95% confidence&#xD;
      interval and a 5% margin of error). The expectation is for 99 patients to sign the informed&#xD;
      consent and complete follow-up = 99 CRT participants. The control group will aim to enrol a&#xD;
      similar figure to the main study group, a further 99 ICD and PPM participants. 99 CRT&#xD;
      patients + 99 ICD or PPM patients = 198 patients are expected to be enrolled and complete the&#xD;
      study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Suspended</overall_status>
  <why_stopped>
    PI request&#xD;
  </why_stopped>
  <start_date type="Actual">June 21, 2019</start_date>
  <completion_date type="Anticipated">January 14, 2024</completion_date>
  <primary_completion_date type="Anticipated">January 14, 2024</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Change in cognitive function at 6 months post-implant</measure>
    <time_frame>6 months</time_frame>
    <description>Measured by the use of a 5-stage cognitive battery test</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in left ventricular ejection fraction (LVEF) at 6 months</measure>
    <time_frame>6 months</time_frame>
    <description>Measured by transthoracic echocardiogram (TTE)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) Test at 6 months</measure>
    <time_frame>6 months</time_frame>
    <description>Measured by a NT-proBNP blood test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in New York Heart Association (NYHA) Functional Classification</measure>
    <time_frame>6 months</time_frame>
    <description>Measured via standardised assessment for all participants</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">198</enrollment>
  <condition>Cognitive Impairment</condition>
  <condition>Cognitive Change</condition>
  <condition>Heart Failure, Systolic</condition>
  <condition>Heart Failure</condition>
  <condition>Cognitive Impairment, Mild</condition>
  <condition>Left Ventricular Dysfunction</condition>
  <condition>Left Ventricular Systolic Dysfunction</condition>
  <condition>Systolic Dysfunction</condition>
  <condition>Systolic Heart Failure</condition>
  <arm_group>
    <arm_group_label>CRT: Main Arm</arm_group_label>
    <description>Cardiac Resynchronisation Therapy (CRT): Main Arm ~98 participants&#xD;
Prior to CRT Implantation &amp; Post-Implant 6-Month Device Follow-Up Clinic:&#xD;
- Battery of 5 questionnaire-based cognitive tests, including the Test of Premorbid Functioning, Repeatable Battery for the Assessment of Neuropsychological Status, Hospital Anxiety and Depression Scale, Frontal Assessment Battery and Trail Making Test Part A and B&#xD;
Please note, the Test of Premorbid Functioning will only be performed ONCE at Pre-Assessment as results reflect IQ prior to disease onset.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ICD and PPM: Control Arm</arm_group_label>
    <description>Implantable Cardioverter-Defibrillator (ICD) and Permanent Pacemaker (PPM): Control Arm ~98 participants&#xD;
Prior to ICD or PPM Implantation &amp; Post-Implant 6-Month Device Follow-Up Clinic:&#xD;
- Battery of 5 questionnaire-based cognitive tests, including the Test of Premorbid Functioning Repeatable Battery for the Assessment of Neuropsychological Status, Hospital Anxiety and Depression Scale, Frontal Assessment Battery and Trail Making Test Part A and B&#xD;
Please note, the Test of Premorbid Functioning will only be performed ONCE at Pre-Assessment as results reflect IQ prior to disease onset.</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Repeatable Assessment of Neuropsychological Status</intervention_name>
    <description>Cognitive Function Test (Questionnaire-based)</description>
    <arm_group_label>CRT: Main Arm</arm_group_label>
    <arm_group_label>ICD and PPM: Control Arm</arm_group_label>
    <other_name>RBANS</other_name>
    <other_name>Repeatable Battery for Assessment Neuropsychological Status</other_name>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Hospital Anxiety and Depression Scale</intervention_name>
    <description>Cognitive Function Test (Questionnaire-based)</description>
    <arm_group_label>CRT: Main Arm</arm_group_label>
    <arm_group_label>ICD and PPM: Control Arm</arm_group_label>
    <other_name>HADS</other_name>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Frontal Assessment Battery</intervention_name>
    <description>Cognitive Function Test (Questionnaire-based)</description>
    <arm_group_label>CRT: Main Arm</arm_group_label>
    <arm_group_label>ICD and PPM: Control Arm</arm_group_label>
    <other_name>FAB</other_name>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Trail Making Test Part A and B</intervention_name>
    <description>Cognitive Function Test (Questionnaire-based)</description>
    <arm_group_label>CRT: Main Arm</arm_group_label>
    <arm_group_label>ICD and PPM: Control Arm</arm_group_label>
    <other_name>TMT</other_name>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Test of Premorbid Functioning</intervention_name>
    <description>Cognitive Function Test (Questionnaire-based)</description>
    <arm_group_label>CRT: Main Arm</arm_group_label>
    <arm_group_label>ICD and PPM: Control Arm</arm_group_label>
    <other_name>TOPF</other_name>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Heart failure patients (left ventricular ejection fraction (LVEF) &lt;35%) receiving an&#xD;
        Cardiac Implantable Electronic Device (CIED), including Cardiac Resynchronisation Therapy&#xD;
        (CRT), an Implantable Cardioverter Defibrillator (ICD) or a Permanent Pacemaker (PPM).&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Undergoing implant of a CRT system with an LVEF of ≤35% (main group), or ICD or PPM&#xD;
             system with an LVEF of ≤35% (control group)&#xD;
&#xD;
          -  Are 20 - 89 years of age&#xD;
&#xD;
          -  Be able to provide written informed consent prior to investigational related&#xD;
             procedure, and be willing and able to comply with the described protocols and&#xD;
             follow-up schedules listed in the PIS&#xD;
&#xD;
          -  Be literate to a level in which the cognitive function tests can be completed&#xD;
             effectively&#xD;
&#xD;
          -  Mental capacity to provide informed consent and undertake cognitive function tests&#xD;
&#xD;
          -  Geographically stable and able to return for the Post-Implant 6-Month Device Follow-Up&#xD;
             Visit&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Are ≤19 years of age (due to specifications outlined in cognitive function test&#xD;
             requirements)&#xD;
&#xD;
          -  Are ≥90 years of age (due to specifications outlined in cognitive function test&#xD;
             requirements)&#xD;
&#xD;
          -  Are pregnant at time of enrolment&#xD;
&#xD;
          -  Is participating in an investigational drug investigation&#xD;
&#xD;
          -  Be experiencing a condition at the time of data collection which affects mental&#xD;
             capacity (lack capacitiy), such as dementia, Alzheimer's, psychosis, schizophrenia&#xD;
             (excluding depression and anxiety).&#xD;
&#xD;
          -  Recent Cerebral Vascular Event (CVE) which may have affected cognitive function&#xD;
&#xD;
          -  Heavy substance abuse, drugs or alcohol&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>89 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Hannah Ford, BSc (Hons)</last_name>
    <role>Principal Investigator</role>
    <affiliation>Royal Cornwall Hospital NHS Trust</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Royal Cornwall Hospital NHS Trust</name>
      <address>
        <city>Truro</city>
        <state>Cornwall</state>
        <zip>TR13LQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>November 21, 2018</study_first_submitted>
  <study_first_submitted_qc>November 26, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 28, 2018</study_first_posted>
  <last_update_submitted>July 29, 2022</last_update_submitted>
  <last_update_submitted_qc>July 29, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 2, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Cognitive Impairment</keyword>
  <keyword>Left Ventricular Systolic Dysfunction</keyword>
  <keyword>Heart Failure</keyword>
  <keyword>Cardiac Resynchronisation Therapy</keyword>
  <keyword>Implantable Cardioverter-Defibrillator</keyword>
  <keyword>Pacemaker</keyword>
  <keyword>CRT</keyword>
  <keyword>ICD</keyword>
  <keyword>PPM</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
    <mesh_term>Ventricular Dysfunction</mesh_term>
    <mesh_term>Ventricular Dysfunction, Left</mesh_term>
    <mesh_term>Heart Failure, Systolic</mesh_term>
    <mesh_term>Systolic Murmurs</mesh_term>
    <mesh_term>Cognitive Dysfunction</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03755570
org study id: 251230
nct id: NCT03755570
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: Yes
is us export: Yes
The primary objective of COGNI-CRT is to assess whether Cardiac Resynchronisation Therapy
      (CRT) can improve cognitive function in patients with systolic HF (LVEF ≤35%), when compared
      to a control group of patients implanted with an Implantable Cardioverter-Defibrillator (ICD)
      or a permanent pacemaker (PPM) with systolic HF (LVEF ≤35%).

      This clinical investigation is a prospective, single-centre cohort study. Each participant
      will be followed for 6 months. The study will collect data over 3 years; 2.5 years for
      enrolment and 6 months until the last participant completes the last 6-month follow-up visit.

      N.B: COGNI-CRT does NOT affect the patient's care pathway - the patients who will be selected
      for participation are those who have already been referred for the device implant. The ONLY
      difference to the patient's care pathway caused by COGNI-CRT is the addition of a battery of
      cognitive function tests, which involves asking the patient questions and asking them to
      complete questionnaire-like cognitive tests.

      NTpro-BNP levels, NYHA classification and LVEF will be measured prior to device implantation
      and at 6-months post-implant to assess the device's impact on the participant's heart failure
      (and CRT response). N.B: NT-proBNP, NYHA classification and LVEF are all parts of the
      patient's standard care pathway, COGNI-CRT is just utilising the data collected as part of
      the investigation.

      The main study arm and control group allows COGNI-CRT to assess 3 potential outcomes for
      patients with severe HF (LVEF <35%):

        1. Cognitive function is not improved by CRT, ICDs or PPMs

        2. Cognitive function can be improved by the assurance of rate control offered by CRT, ICDs
           and PPMs

        3. Cognitive function can be improved by the assurance of ventricular synchronisation and
           rate control provided by the additional left ventricular lead in CRT devices.
Purpose:

      The purpose of this clinical investigation is to assess whether cardiac resynchronisation
      therapy (CRT) can improve cognitive function in patients with systolic heart failure (Left
      Ventricular Ejection Fraction (LVEF) ≤35%), when compared to a control group of patients
      implanted with an implantable cardioverter-defibrillator (ICD) or permanent pacemaker (PPM)
      with systolic heart failure (LVEF ≤35%).

      Design:

      This clinical investigation is a prospective, single-centre cohort study. The study will be
      conducted at the Royal Cornwall Hospital Trust (RCHT) in Cornwall, England. Subjects will be
      followed for 6 months.

      Cognitive performance will be assessed in patients pre- and post-CRT implant (Group A). An
      ICD and PPM control group (Group B) will also be assessed using the same battery of cognitive
      function tests to ensure any difference in cognitive function which is identified between
      pre- and post- CRT implant is due to the CRT therapy, and not due to a placebo effect (which
      can be especially powerful with implanted devices) or due to a learning effect (i.e. patients
      tested on the second occasion might improve their scores because they have had more
      practice).

      N.B: COGNI-CRT does NOT affect the patient's care pathway - the patients who will be selected
      for participation are those who have already been referred for the device implant. The ONLY
      difference to the patient's care pathway caused by COGNI-CRT is the addition of a battery of
      cognitive function tests, which involves asking the patient questions and asking them to
      complete questionnaire-like cognitive tests.

      LVEF, NT-proBNP and New York Heart Association (NYHA) classification data which is collected
      prior to device implantation and at 6-months post-implant will be utilised for analysis to
      measure response to CRT and to assess difference between the main arm and control group.

      Arms in the study will be:

        -  Group A: Participants implanted with a CRT who are eligible according to the inclusion/
           exclusion criteria

        -  Group B: Participants implanted with an ICD or a PPM who are eligible according to the
           inclusion / exclusion criteria

      Objectives:

      Primary objective: To assess whether CRT can improve cognitive function in patients with
      systolic heart failure (LVEF ≤35%), when compared to a control group of patients implanted
      with an ICD or PPM with systolic heart failure (LVEF ≤35%).

      Secondary Objectives:

        -  To assess whether CRT can improve cognitive function

        -  To assess whether ICD and PPM therapy can improve cognitive function

        -  To assess if the level of improvement in cognitive function correlates to LVEF
           improvement / stability and/or NYHA improvement /stability and/or NT-proBNP level
           reduction (CRT response).

      Subject Population:

      The subject population enrolled in this investigation will comprise of male and female
      patients aged 20-89 years old. These subjects are patients who are willing to provide
      informed consent and meet the specific eligibility criteria. A minimum of 198 participants
      will be enrolled in this investigation.

      Data for this study will be collected at:

        -  Enrolment

        -  Pre-Assessment for CRT, ICD or PPM Implantation

        -  Cardiac Implantable Electronic Device (CIED) Implant

        -  Post-Implant 6-Week Device Check (For device optimisation)

        -  Post-Implant 6-Month Device Follow-Up Visit After completing the Post-Implant 6-Month
           Device Follow-Up Visit, the patient will have completed his/her participation in the
           study.

      Devices Used:

      Implanted CRT-P, CRT-D, ICD and PPM devices may include Biotronik, Boston Scientific,
      Medtronic and St Jude Medical.

      Patient Screening:

      Patients who are referred to RCHT for CRT, ICD or PPM implantation with systolic heart
      failure (LVEF ≤35%) will be screened prior to Pre-Assessment by the clinical team.
      Prospective patients will be afforded sufficient time to consider participation in COGNI-CRT.

      Cognitive Tests Used to Evaluate Cognitive Function:

      To be Performed Only At Pre-Assessment:

        1. Test of Premorbid Functioning (TOPF): TOPF provides the participant with a list of 70
           words that have atypical grapheme to phoneme translations. The participant must attempt
           to read the list aloud so pronunciation of the words can be assessed. This tests IQ and
           memory as the participant must be familiar with the words, rather than being able to
           spell out a word they do not know. It takes approximately 10 minutes to complete

           To be Performed at Pre-Assessment and at the Post-Implant 6-Month Device Follow-Up
           Visit:

        2. Hospital Anxiety and Depression Scale (HADS): The test consists of 14 multiple-choice
           questions, each attempting to ascertain about the frequency the participant has felt a
           certain symptom within the last 7 days. There are 4 answers to choose from which range
           from suffering from the symptom "nearly all the time" to "not at all" and are graded 0-3
           depending on the participant's answer.

        3. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): Consisting
           of 12 sections, to evaluate 5 types of cognitive function: immediate memory;
           visuospatial/ constructional; attention; language and delayed memory.

        4. Frontal Assessment Battery (FAB): The test has 6 neuropsychological tasks which involve
           asking the participant questions, for example "In what way are a banana and an orange
           alike?", and learning simple actions in response to hand taps or movements.

        5. Trail Making Test (TMT) Parts A & B: Both parts of TMT involve circles dotted over a
           piece of paper, the circles for Part A are marked with the numbers 1 - 25 and the
           patient must draw a line connecting the numbers in ascending order, i.e. "1-2-3-4-5-6…"
           etc. Part B involves numbers and letters dotted around the page, from 1-13 and from A-L.
           The patient must connect the numbers and letters in ascending order, alternating between
           numbers and letters, i.e. "1-A-2-B-3-C…" etc

      Response to CRT Measures will be measured prior to device implantation and at the 6-month
      follow-up device follow-up clinic:

      LVEF: LVEF will be measured prior to device implant to assess the patient's heart function,
      and at the Post-Implant 6-Month Device Follow-Up Visit.

      NT-proBNP: NT-proBNP levels from the patient's routine blood tests prior to device
      implantation and at the Post-Implant 6-Month Device Follow-Up Visit where blood testing is
      routine for heart failure patients every 6 months.

      NYHA: A NYHA scale assessment will be performed during the screening clinics prior to device
      implant, and at the Post-Implant 6-Month Device Follow-Up Visit using the standardised NYHA
      questions designed for the purpose of this trial.

      N.B: The above 3 tests (LVEF, NT-proBNP and NYHA classification) are performed routinely as
      part of the patient standard care pathway for heart failure, and this data will be utilised
      for analysis in this trial. The tests are NOT performed for the purpose of COGNI-CRT.

      Device Optimisation:

      At the post-implant 6-week device follow-up check, all efforts will be made to ensure the
      device is optimised as much as is possible, and the patient listed for MDT if problems are
      encountered to attempt to resolve problems.

      Data Analysis:

      Data will be tested for normality. Tests for group differences will be used to compare
      cognitive function between patients before and after CRT implant, and in the control group
      before and after ICD or PPM implant. Tests for group differences will also be used in
      comparison of the LVEF values, BNP results, NYHA classification, QRS duration, percentage
      biventricular pacing and BP measurements. Sample size calculations have estimated the
      required CRT sample size to power the study to be 99 participants (with a 95% confidence
      interval and a 5% margin of error). The expectation is for 99 patients to sign the informed
      consent and complete follow-up = 99 CRT participants. The control group will aim to enrol a
      similar figure to the main study group, a further 99 ICD and PPM participants. 99 CRT
      patients + 99 ICD or PPM patients = 198 patients are expected to be enrolled and complete the
      study.
observational model: Cohort
time perspective: Prospective
measure: Change in cognitive function at 6 months post-implant
time frame: 6 months
description: Measured by the use of a 5-stage cognitive battery test
measure: Change in left ventricular ejection fraction (LVEF) at 6 months
time frame: 6 months
description: Measured by transthoracic echocardiogram (TTE)
measure: Change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) Test at 6 months
time frame: 6 months
description: Measured by a NT-proBNP blood test.
measure: Change in New York Heart Association (NYHA) Functional Classification
time frame: 6 months
description: Measured via standardised assessment for all participants
arm group label: CRT: Main Arm
description: Cardiac Resynchronisation Therapy (CRT): Main Arm ~98 participants
Prior to CRT Implantation & Post-Implant 6-Month Device Follow-Up Clinic:
- Battery of 5 questionnaire-based cognitive tests, including the Test of Premorbid Functioning, Repeatable Battery for the Assessment of Neuropsychological Status, Hospital Anxiety and Depression Scale, Frontal Assessment Battery and Trail Making Test Part A and B
Please note, the Test of Premorbid Functioning will only be performed ONCE at Pre-Assessment as results reflect IQ prior to disease onset.
arm group label: ICD and PPM: Control Arm
description: Implantable Cardioverter-Defibrillator (ICD) and Permanent Pacemaker (PPM): Control Arm ~98 participants
Prior to ICD or PPM Implantation & Post-Implant 6-Month Device Follow-Up Clinic:
- Battery of 5 questionnaire-based cognitive tests, including the Test of Premorbid Functioning Repeatable Battery for the Assessment of Neuropsychological Status, Hospital Anxiety and Depression Scale, Frontal Assessment Battery and Trail Making Test Part A and B
Please note, the Test of Premorbid Functioning will only be performed ONCE at Pre-Assessment as results reflect IQ prior to disease onset.
intervention type: Diagnostic Test
intervention name: Repeatable Assessment of Neuropsychological Status
description: Cognitive Function Test (Questionnaire-based)
arm group label: CRT: Main Arm
arm group label: ICD and PPM: Control Arm
other name: RBANS
other name: Repeatable Battery for Assessment Neuropsychological Status
intervention type: Diagnostic Test
intervention name: Hospital Anxiety and Depression Scale
description: Cognitive Function Test (Questionnaire-based)
arm group label: CRT: Main Arm
arm group label: ICD and PPM: Control Arm
other name: HADS
intervention type: Diagnostic Test
intervention name: Frontal Assessment Battery
description: Cognitive Function Test (Questionnaire-based)
arm group label: CRT: Main Arm
arm group label: ICD and PPM: Control Arm
other name: FAB
intervention type: Diagnostic Test
intervention name: Trail Making Test Part A and B
description: Cognitive Function Test (Questionnaire-based)
arm group label: CRT: Main Arm
arm group label: ICD and PPM: Control Arm
other name: TMT
intervention type: Diagnostic Test
intervention name: Test of Premorbid Functioning
description: Cognitive Function Test (Questionnaire-based)
arm group label: CRT: Main Arm
arm group label: ICD and PPM: Control Arm
other name: TOPF
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 20 Years
maximum age: 89 Years
healthy volunteers: No
last name: Hannah Ford, BSc (Hons)
role: Principal Investigator
affiliation: Royal Cornwall Hospital NHS Trust
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Heart Failure
mesh term: Ventricular Dysfunction
mesh term: Ventricular Dysfunction, Left
mesh term: Heart Failure, Systolic
mesh term: Systolic Murmurs
mesh term: Cognitive Dysfunction
sharing ipd: No