<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/NCT03305250</url>
  </required_header>
  <id_info>
    <org_study_id>FD-ILR-001</org_study_id>
    <nct_id>NCT03305250</nct_id>
  </id_info>
  <brief_title>Arrhythmia Burden, Risk of Sudden Cardiac Death and Stroke in Patients With Fabry Disease</brief_title>
  <acronym>RaILRoAD</acronym>
  <official_title>Arrhythmia Burden, Risk of Sudden Cardiac Death and Stroke in Patients With Fabry Disease: the Role of Implantable Loop Recorders</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital Birmingham NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Royal Free Hospital NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Northern Care Alliance NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Sydney</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Cambridge University Hospitals NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital Birmingham 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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Fabry disease (FD) is a genetic disorder that leads to progressive accumulation of fat or&#xD;
      'sphingolipid' within the tissues, including the heart muscle and conductive tissue.&#xD;
      Improvements in the detection of FD, together with more organised clinical services for rare&#xD;
      diseases, has led to a rapid growth in the disease prevalence. Earlier and more frequent&#xD;
      diagnosis of asymptomatic individuals before development of the disease itself has focused&#xD;
      attention on early detection of organ involvement and closer monitoring of disease&#xD;
      progression. Moreover, the introduction of enzyme replacement therapy within the last two&#xD;
      decades has changed the natural history of FD as follows: a) increased life expectancy; b)&#xD;
      improved morbidity; c) modification of the main cause of morbidity and mortality from renal&#xD;
      (kidney) to cardiovascular (heart) events, including heart failure, abnormal heart rhythms,&#xD;
      stroke and sudden death. Although symptoms such as palpitations and blackouts are extremely&#xD;
      common, information on the frequency of proven abnormal heart rhythms is limited. In&#xD;
      addition, the rate and appropriateness of implantation of life-saving devices is very&#xD;
      variable, including pacemakers to boost the heart when too slow and cardio-defibrillators&#xD;
      that stop the heart when too fast. The main markers of risk in similar diseases such as&#xD;
      hypertrophic cardiomyopathy cannot be used in FD. While patients are routinely followed up in&#xD;
      clinic with heart tracings and echocardiography (ultrasound of the heart), a recent small&#xD;
      study has emphasised that these tests under-estimate the burden of abnormal heart rhythms in&#xD;
      patients with advanced FD. The use of continuous heart monitoring with an implantable loop&#xD;
      recorder (ILR) has led to a significant change in treatment in 13 out of 15 of FD patients.&#xD;
      The investigators believe that more frequent use of ILRs will identify a greater need for&#xD;
      change in therapy in many more patients than currently treated, with the aim of reducing&#xD;
      morbidity and mortality in this patient cohort. In addition this will provide valuable data&#xD;
      to inform an estimate of future risk for these patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a 3-year open-label multicentre randomised controlled trial assessing arrhythmia&#xD;
      burden in patients with Fabry cardiac disease. This is an observational study, but with&#xD;
      implantable loop recorder (ILR) insertion at recruitment and removal at end of trial for the&#xD;
      intervention arm.&#xD;
&#xD;
      Null hypothesis: There will be no difference in the identification of arrhythmia between&#xD;
      patients following standard care compared to patients following standard care but with the&#xD;
      addition of ILR monitoring.&#xD;
&#xD;
      Beyond the proposed hypothesis, data collected will be used to inform whether ILR in FD will:&#xD;
&#xD;
        1. Reveal a high burden of unrecognised arrhythmia&#xD;
&#xD;
        2. Lead to frequent treatment modification (anti-coagulation, pacemaker and ICD&#xD;
           implantation, ablation)&#xD;
&#xD;
        3. Enable the development of FD specific risk prediction algorithms&#xD;
&#xD;
        4. Identify predictive power of new (Troponin, BNP, lysoGB3, T1 and T2 mapping) and&#xD;
           traditional biomarkers&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">September 18, 2019</start_date>
  <completion_date type="Anticipated">August 2024</completion_date>
  <primary_completion_date type="Anticipated">January 2024</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>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>First occurrence of atrial fibrillation (AF) requiring anticoagulation</measure>
    <time_frame>Total monitoring time period in study - 3 years</time_frame>
    <description>This will include all descriptions of AF, which can be defined as:&#xD;
paroxysmal - self-terminating episodes lasting between 48 hours to 7 days&#xD;
persistent - intermittent episodes lasting between 7 days to 1 year&#xD;
permanent - episodes lasting longer than 1 year</description>
  </primary_outcome>
  <primary_outcome>
    <measure>First occurrence of bradyarrhythmia requiring cardiac pacing</measure>
    <time_frame>Total monitoring time period in study - 3 years</time_frame>
    <description>This would include:&#xD;
Symptomatic significant AV block.&#xD;
Mobitz type 2 AV block or complete heart block irrespective of symptoms.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>First occurrence of supraventricular arrhythmia requiring drug treatment or ablation.</measure>
    <time_frame>Total monitoring time period in study - 3 years</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>First occurrence of non-sustained ventricular tachyarrhythmia requiring drug treatment, ICD implantation or ablation</measure>
    <time_frame>Total monitoring time period in study - 3 years</time_frame>
    <description>This is classified as three or more ventricular beats at a rate &gt;120bpm, for a duration of less than 30 seconds.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Frequency of arrhythmia in patients with and without late gadolinium enhancement (LGE)</measure>
    <time_frame>3 years</time_frame>
    <description>The study will aim at quantifying the extent of LGE deposited with myocardial tissue on cardiac MRI scanning. This will subsequently be correlated with the burden of arrhythmia detected to assess for potential risk factors.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency of arrhythmia according to location of myocardial fibrosis (inferolateral vs. non-inferolateral)</measure>
    <time_frame>3 years</time_frame>
    <description>The study will aim to correlate the location of myocardial fibrosis with the presence or absence of cardiac arrhythmia to define location of fibrosis as a potential risk factor for arrhythmia.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency of arrhythmia in those patients with a QRS duration greater or less than 120ms</measure>
    <time_frame>3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency of arrhythmia in those with an atrial size above or below indexed normal range for age and sex</measure>
    <time_frame>3 years</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">164</enrollment>
  <condition>Fabry Disease</condition>
  <arm_group>
    <arm_group_label>Interventional Arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Using an Implantable Loop Recorder fo continuous rhythm monitoring and home follow-up. This will be combined with standard care procedure, which will include annual ECG, 24 hour Holter/5 day ECG monitoring and further investigation dependent on symptom status.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard of Care Arm</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>The standard of care with annual ECG, 24 hour Holter/5 day ECG monitoring and further investigation dependent on symptom status.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Implantable Loop Recorder</intervention_name>
    <description>An implantable loop recorder (ILR), also known as an insertable cardiac monitor, is a small device (smaller than a AAA battery) that is inserted under the skin on the front of the chest. The ILR is inserted using local anesthetic as an out-patient procedure and lasts approximately 30 minutes. The ILR captures a continuous ECG of your heart activity, which allows doctors to detect any abnormal heart rhythms at any point. If you have the ILR, you will have the device for 3 years, after which it will be removed under local anesthetic during an out-patient procedure, again lasting approximately 30 minutes. The ILR device is completely safe and shouldn't affect your day to day living.</description>
    <arm_group_label>Interventional Arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with genotypically or enzymatically confirmed FD&#xD;
&#xD;
          -  Adults &gt; 18 years of age&#xD;
&#xD;
          -  Evidence of cardiac involvement from FD involving either:&#xD;
&#xD;
          -  Any ECG abnormality associated with FD&#xD;
&#xD;
          -  Low T1 on CMR (below centre-specific normal range according to sex)&#xD;
&#xD;
          -  LVH on transthoracic echo (defined as MWT &gt;12mm)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patient with an existing cardiac device (PPM, ICD or ILR).&#xD;
&#xD;
          -  Known dual pathology:&#xD;
&#xD;
          -  Known coronary artery disease (positive non-invasive imaging, confirmed myocardial&#xD;
             infarction, percutaneous or surgical revascularisation). Patients &gt;40 years old with&#xD;
             symptoms that could be from coronary artery disease will have this excluded&#xD;
&#xD;
          -  Known cardiomyopathy disease causing mutation (e.g. SCN5, MYBPC3)&#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>Richard Steeds, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Hospital Birmingham NHS Foundation Trust</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Ashwin Roy, MD</last_name>
    <phone>01213714042</phone>
    <email>ashwinroy@nhs.net</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Shaun Bolton, BSc</last_name>
    <phone>01213716795</phone>
    <email>shaun.bolton@uhb.nhs.uk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University of Sydney</name>
      <address>
        <city>Sydney</city>
        <country>Australia</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Rebecca Kozor</last_name>
      <email>rebeccakozor@gmail.com</email>
    </contact>
    <investigator>
      <last_name>Rebecca Kozor, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University Hospitals Birmingham NHS Foundation Trust</name>
      <address>
        <city>Birmingham</city>
        <state>West Midlands</state>
        <zip>B15 2TH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ashwin Roy, MD</last_name>
      <phone>01213714042</phone>
      <email>ashwinroy@nhs.net</email>
    </contact>
    <contact_backup>
      <last_name>Shaun Bolton, BSc</last_name>
      <phone>01213716795</phone>
      <email>shaun.bolton@uhb.nhs.uk</email>
    </contact_backup>
    <investigator>
      <last_name>Richard Steeds, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Tarekegn Hiwot, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Cambridge University Hospitals NHS Foundation Trust</name>
      <address>
        <city>Cambridge</city>
        <zip>CB2 0QQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Rosemary Rusk</last_name>
      <email>rosemary.rusk@nhs.net</email>
    </contact>
    <investigator>
      <last_name>Rosemary Rusk, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Royal Free NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <zip>NW3 2QG</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Derralynn Hughes, MD</last_name>
      <email>derralynnhughes@nhs.net</email>
    </contact>
    <investigator>
      <last_name>Derralynn Hughes, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Salford Royal NHS Foundation Trust</name>
      <address>
        <city>Manchester</city>
        <zip>M6 8HD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ana Jovanovic, MD</last_name>
      <email>Ana.Jovanovic@srft.nhs.uk</email>
    </contact>
    <investigator>
      <last_name>Ana Jovanovic, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Sheffield Teaching Hospitals NHS Foundation Trust</name>
      <address>
        <city>Sheffield</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Nigel Lewis, MD</last_name>
      <phone>01142266587</phone>
      <email>nigel.lewis1@nhs.net</email>
    </contact>
    <investigator>
      <last_name>Nigel Lewis, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>September 21, 2017</study_first_submitted>
  <study_first_submitted_qc>October 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 9, 2017</study_first_posted>
  <last_update_submitted>May 27, 2022</last_update_submitted>
  <last_update_submitted_qc>May 27, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 31, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Hospital Birmingham NHS Foundation Trust</investigator_affiliation>
    <investigator_full_name>Dr Richard Steeds</investigator_full_name>
    <investigator_title>Consultant in Cardiology</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fabry Disease</mesh_term>
    <mesh_term>Death, Sudden, Cardiac</mesh_term>
    <mesh_term>Death</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>There is no plan to make individual participant data available to other researchers. Data analysis conducted using anonymised patient data will be shared through publications.</ipd_description>
  </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/NCT03305250
org study id: FD-ILR-001
nct id: NCT03305250
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Fabry disease (FD) is a genetic disorder that leads to progressive accumulation of fat or
      'sphingolipid' within the tissues, including the heart muscle and conductive tissue.
      Improvements in the detection of FD, together with more organised clinical services for rare
      diseases, has led to a rapid growth in the disease prevalence. Earlier and more frequent
      diagnosis of asymptomatic individuals before development of the disease itself has focused
      attention on early detection of organ involvement and closer monitoring of disease
      progression. Moreover, the introduction of enzyme replacement therapy within the last two
      decades has changed the natural history of FD as follows: a) increased life expectancy; b)
      improved morbidity; c) modification of the main cause of morbidity and mortality from renal
      (kidney) to cardiovascular (heart) events, including heart failure, abnormal heart rhythms,
      stroke and sudden death. Although symptoms such as palpitations and blackouts are extremely
      common, information on the frequency of proven abnormal heart rhythms is limited. In
      addition, the rate and appropriateness of implantation of life-saving devices is very
      variable, including pacemakers to boost the heart when too slow and cardio-defibrillators
      that stop the heart when too fast. The main markers of risk in similar diseases such as
      hypertrophic cardiomyopathy cannot be used in FD. While patients are routinely followed up in
      clinic with heart tracings and echocardiography (ultrasound of the heart), a recent small
      study has emphasised that these tests under-estimate the burden of abnormal heart rhythms in
      patients with advanced FD. The use of continuous heart monitoring with an implantable loop
      recorder (ILR) has led to a significant change in treatment in 13 out of 15 of FD patients.
      The investigators believe that more frequent use of ILRs will identify a greater need for
      change in therapy in many more patients than currently treated, with the aim of reducing
      morbidity and mortality in this patient cohort. In addition this will provide valuable data
      to inform an estimate of future risk for these patients.
This is a 3-year open-label multicentre randomised controlled trial assessing arrhythmia
      burden in patients with Fabry cardiac disease. This is an observational study, but with
      implantable loop recorder (ILR) insertion at recruitment and removal at end of trial for the
      intervention arm.

      Null hypothesis: There will be no difference in the identification of arrhythmia between
      patients following standard care compared to patients following standard care but with the
      addition of ILR monitoring.

      Beyond the proposed hypothesis, data collected will be used to inform whether ILR in FD will:

        1. Reveal a high burden of unrecognised arrhythmia

        2. Lead to frequent treatment modification (anti-coagulation, pacemaker and ICD
           implantation, ablation)

        3. Enable the development of FD specific risk prediction algorithms

        4. Identify predictive power of new (Troponin, BNP, lysoGB3, T1 and T2 mapping) and
           traditional biomarkers
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: First occurrence of atrial fibrillation (AF) requiring anticoagulation
time frame: Total monitoring time period in study - 3 years
description: This will include all descriptions of AF, which can be defined as:
paroxysmal - self-terminating episodes lasting between 48 hours to 7 days
persistent - intermittent episodes lasting between 7 days to 1 year
permanent - episodes lasting longer than 1 year
measure: First occurrence of bradyarrhythmia requiring cardiac pacing
time frame: Total monitoring time period in study - 3 years
description: This would include:
Symptomatic significant AV block.
Mobitz type 2 AV block or complete heart block irrespective of symptoms.
measure: First occurrence of supraventricular arrhythmia requiring drug treatment or ablation.
time frame: Total monitoring time period in study - 3 years
measure: First occurrence of non-sustained ventricular tachyarrhythmia requiring drug treatment, ICD implantation or ablation
time frame: Total monitoring time period in study - 3 years
description: This is classified as three or more ventricular beats at a rate >120bpm, for a duration of less than 30 seconds.
measure: Frequency of arrhythmia in patients with and without late gadolinium enhancement (LGE)
time frame: 3 years
description: The study will aim at quantifying the extent of LGE deposited with myocardial tissue on cardiac MRI scanning. This will subsequently be correlated with the burden of arrhythmia detected to assess for potential risk factors.
measure: Frequency of arrhythmia according to location of myocardial fibrosis (inferolateral vs. non-inferolateral)
time frame: 3 years
description: The study will aim to correlate the location of myocardial fibrosis with the presence or absence of cardiac arrhythmia to define location of fibrosis as a potential risk factor for arrhythmia.
measure: Frequency of arrhythmia in those patients with a QRS duration greater or less than 120ms
time frame: 3 years
measure: Frequency of arrhythmia in those with an atrial size above or below indexed normal range for age and sex
time frame: 3 years
arm group label: Interventional Arm
arm group type: Active Comparator
description: Using an Implantable Loop Recorder fo continuous rhythm monitoring and home follow-up. This will be combined with standard care procedure, which will include annual ECG, 24 hour Holter/5 day ECG monitoring and further investigation dependent on symptom status.
arm group label: Standard of Care Arm
arm group type: No Intervention
description: The standard of care with annual ECG, 24 hour Holter/5 day ECG monitoring and further investigation dependent on symptom status.
intervention type: Device
intervention name: Implantable Loop Recorder
description: An implantable loop recorder (ILR), also known as an insertable cardiac monitor, is a small device (smaller than a AAA battery) that is inserted under the skin on the front of the chest. The ILR is inserted using local anesthetic as an out-patient procedure and lasts approximately 30 minutes. The ILR captures a continuous ECG of your heart activity, which allows doctors to detect any abnormal heart rhythms at any point. If you have the ILR, you will have the device for 3 years, after which it will be removed under local anesthetic during an out-patient procedure, again lasting approximately 30 minutes. The ILR device is completely safe and shouldn't affect your day to day living.
arm group label: Interventional Arm
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Richard Steeds, MD
role: Principal Investigator
affiliation: University Hospital Birmingham NHS Foundation Trust
last name: Ashwin Roy, MD
phone: 01213714042
email: ashwinroy@nhs.net
last name: Shaun Bolton, BSc
phone: 01213716795
email: shaun.bolton@uhb.nhs.uk
facility: 
status: Not yet recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
facility: 
status: Not yet recruiting
contact: 
investigator: 
facility: 
status: Not yet recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
country: Australia
country: United Kingdom
responsible party type: Principal Investigator
investigator affiliation: University Hospital Birmingham NHS Foundation Trust
investigator full name: Dr Richard Steeds
investigator title: Consultant in Cardiology
mesh term: Fabry Disease
mesh term: Death, Sudden, Cardiac
mesh term: Death
sharing ipd: No
ipd description: There is no plan to make individual participant data available to other researchers. Data analysis conducted using anonymised patient data will be shared through publications.