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Arrhythmia Burden, Risk of Sudden Cardiac Death and Stroke in Patients With Fabry Disease (RaILRoAD)

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ClinicalTrials.gov Identifier: NCT03305250
Recruitment Status : Not yet recruiting
First Posted : October 9, 2017
Last Update Posted : April 17, 2019
Sponsor:
Collaborators:
Royal Free Hospital NHS Foundation Trust
Salford Royal NHS Foundation Trust
University of Sydney
Cambridge University Hospitals NHS Foundation Trust
Information provided by (Responsible Party):
Dr Richard Steeds, University Hospital Birmingham NHS Foundation Trust

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Fabry Disease Device: Implantable Loop Recorder Not Applicable

Detailed Description:

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 164 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Arrhythmia Burden, Risk of Sudden Cardiac Death and Stroke in Patients With Fabry Disease: the Role of Implantable Loop Recorders
Estimated Study Start Date : July 2019
Estimated Primary Completion Date : January 2022
Estimated Study Completion Date : August 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Interventional Arm
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.
Device: Implantable Loop Recorder
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.

No Intervention: Standard of Care Arm
The standard of care with annual ECG, 24 hour Holter/5 day ECG monitoring and further investigation dependent on symptom status.



Primary Outcome Measures :
  1. First occurrence of atrial fibrillation (AF) requiring anticoagulation [ Time Frame: Total monitoring time period in study - 3 years ]

    This will include all descriptions of AF, which can be defined as:

    1. paroxysmal - self-terminating episodes lasting between 48 hours to 7 days
    2. persistent - intermittent episodes lasting between 7 days to 1 year
    3. permanent - episodes lasting longer than 1 year

  2. First occurrence of bradyarrhythmia requiring cardiac pacing [ Time Frame: Total monitoring time period in study - 3 years ]

    This would include:

    1. Symptomatic significant AV block.
    2. Mobitz type 2 AV block or complete heart block irrespective of symptoms.

  3. First occurrence of supraventricular arrhythmia requiring drug treatment or ablation. [ Time Frame: Total monitoring time period in study - 3 years ]
  4. First occurrence of non-sustained ventricular tachyarrhythmia requiring drug treatment, ICD implantation or ablation [ Time Frame: Total monitoring time period in study - 3 years ]
    This is classified as three or more ventricular beats at a rate >120bpm, for a duration of less than 30 seconds.


Secondary Outcome Measures :
  1. Frequency of arrhythmia in patients with and without late gadolinium enhancement (LGE) [ Time Frame: 3 years ]
    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.

  2. Frequency of arrhythmia according to location of myocardial fibrosis (inferolateral vs. non-inferolateral) [ Time Frame: 3 years ]
    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.

  3. Frequency of arrhythmia in those patients with a QRS duration greater or less than 120ms [ Time Frame: 3 years ]
  4. Frequency of arrhythmia in those with an atrial size above or below indexed normal range for age and sex [ Time Frame: 3 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with genotypically or enzymatically confirmed FD
  • Adults > 18 years of age
  • Evidence of cardiac involvement from FD involving either:
  • Any ECG abnormality associated with FD
  • Low T1 on CMR (below centre-specific normal range according to sex)
  • LVH on transthoracic echo (defined as MWT >12mm)

Exclusion Criteria:

  • Patient with an existing cardiac device (PPM, ICD or ILR).
  • Known dual pathology:
  • Known coronary artery disease (positive non-invasive imaging, confirmed myocardial infarction, percutaneous or surgical revascularisation). Patients >40 years old with symptoms that could be from coronary artery disease will have this excluded
  • Known cardiomyopathy disease causing mutation (e.g. SCN5, MYBPC3)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03305250


Contacts
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Contact: Ravi Vijapurapu, MD 01213716736 Ravi.Vijapurapu@uhb.nhs.uk
Contact: Shaun Bolton, BSc 01213716795 shaun.bolton@uhb.nhs.uk

Locations
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Australia
University of Sydney
Sydney, Australia
United Kingdom
University Hospitals Birmingham NHS Foundation Trust Not yet recruiting
Birmingham, West Midlands, United Kingdom, B15 2TH
Contact: Ravi Vijapurapu, MD    01213716736    Ravi.Vijapurapu@uhb.nhs.uk   
Contact: Shaun Bolton, BSc    01213716795    shaun.bolton@uhb.nhs.uk   
Principal Investigator: Richard Steeds, MD         
Principal Investigator: Tarekegn Hiwot, MD         
Cambridge University Hospitals NHS Foundation Trust Not yet recruiting
Cambridge, United Kingdom, CB2 0QQ
Contact: Rosemary Rusk       rosemary.rusk@nhs.net   
Principal Investigator: Rosemary Rusk, MD         
Royal Free NHS Foundation Trust Not yet recruiting
London, United Kingdom, NW3 2QG
Contact: Derralynn Hughes, MD       derralynnhughes@nhs.net   
Principal Investigator: Derralynn Hughes, MD         
Salford Royal NHS Foundation Trust Not yet recruiting
Manchester, United Kingdom, M6 8HD
Contact: Ana Jovanovic, MD       Ana.Jovanovic@srft.nhs.uk   
Principal Investigator: Ana Jovanovic, MD         
Sponsors and Collaborators
University Hospital Birmingham NHS Foundation Trust
Royal Free Hospital NHS Foundation Trust
Salford Royal NHS Foundation Trust
University of Sydney
Cambridge University Hospitals NHS Foundation Trust
Investigators
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Principal Investigator: Richard Steeds, MD University Hospitals Birmingham NHS Foundation Trust

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Responsible Party: Dr Richard Steeds, Consultant in Cardiology, University Hospital Birmingham NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT03305250     History of Changes
Other Study ID Numbers: FD-ILR-001
First Posted: October 9, 2017    Key Record Dates
Last Update Posted: April 17, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan 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.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
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Fabry Disease
Death
Death, Sudden, Cardiac
Sphingolipidoses
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Cerebral Small Vessel Diseases
Cerebrovascular Disorders
Vascular Diseases
Cardiovascular Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Metabolism, Inborn Errors
Lipidoses
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders
Pathologic Processes
Heart Arrest
Heart Diseases
Death, Sudden