Clinical trial NCT03305250: Arrhythmia Burden, Risk of Sudden Cardiac Death and Stroke in Patients With Fabry Disease
Official title: Arrhythmia Burden, Risk of Sudden Cardiac Death and Stroke in Patients With Fabry Disease: the Role of Implantable Loop Recorders
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Fabry Disease
Lead sponsor: University Hospital Birmingham NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: Royal Free Hospital NHS Foundation Trust
name: Northern Care Alliance NHS Foundation Trust
name: University of Sydney
name: Cambridge University Hospitals NHS Foundation Trust
name: Cardiff and Vale University Health Board
name: Sheffield Teaching Hospitals NHS Foundation Trust
First posted: 2017-10-09
Enrollment: 169
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

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.

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

Eligibility 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)

Primary outcomes:
measure: First occurrence of atrial fibrillation (AF) requiring anticoagulation
timeFrame: Total monitoring time period in study - 3 years
measure: First occurrence of bradyarrhythmia requiring cardiac pacing
timeFrame: Total monitoring time period in study - 3 years
measure: First occurrence of supraventricular arrhythmia requiring drug treatment or ablation.
timeFrame: Total monitoring time period in study - 3 years
measure: First occurrence of non-sustained ventricular tachyarrhythmia requiring drug treatment, ICD implantation or ablation
timeFrame: Total monitoring time period in study - 3 years
Secondary outcomes:
measure: Frequency of arrhythmia in patients with and without late gadolinium enhancement (LGE)
timeFrame: 3 years
measure: Frequency of arrhythmia according to location of myocardial fibrosis (inferolateral vs. non-inferolateral)
timeFrame: 3 years
measure: Frequency of arrhythmia in those patients with a QRS duration greater or less than 120ms
timeFrame: 3 years
measure: Frequency of arrhythmia in those with an atrial size above or below indexed normal range for age and sex
timeFrame: 3 years
Other outcomes:
Locations:
city: Sydney
country: Australia
facility: University of Sydney
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust
state: West Midlands
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
city: Cardiff
country: United Kingdom
facility: Cardiff and Vale University Health Board
city: London
country: United Kingdom
facility: Royal Free NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Salford Royal NHS Foundation Trust
city: Sheffield
country: United Kingdom
facility: Sheffield Teaching Hospitals NHS Foundation Trust
Study officials:
affiliation: University Hospital Birmingham NHS Foundation Trust
name: Richard Steeds, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Vijapurapu R, Kozor R, Hughes DA, Woolfson P, Jovanovic A, Deegan P, Rusk R, Figtree GA, Tchan M, Whalley D, Kotecha D, Leyva F, Moon J, Geberhiwot T, Steeds RP. A randomised controlled trial evaluating arrhythmia burden, risk of sudden cardiac death and stroke in patients with Fabry disease: the role of implantable loop recorders (RaILRoAD) compared with current standard practice. Trials. 2019 May 31;20(1):314. doi: 10.1186/s13063-019-3425-1.