Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04708301 |
| Other study ID # |
2014CD002 |
| Secondary ID |
REC Reference No |
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
March 12, 2014 |
| Est. completion date |
December 31, 2020 |
Study information
| Verified date |
October 2021 |
| Source |
Manchester University NHS Foundation Trust |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Fabry disease is a rare lysosomal storage disorder characterised by a genetic deficiency in
the α-galactosidase enzyme. This deficiency leads to a progressive accumulation of a fatty
substance, called glycosphingolipids within a specific part of our cells called the lysosome.
This lysosomal accumulation can have devastating effects on patients with Fabry disease,
affecting multiple organs. Heart involvement is particularly feared because it is the leading
cause of death in Fabry disease.
Cardiovascular magnetic resonance imaging (cardiac MRI) is a relatively new heart imaging
technique. A cardiac MRI technique called T1 mapping can measure the magnetic relaxation
properties of heart tissue. T1 mapping is important in Fabry disease because
glycosphingolipids have distinct magnetic relaxation properties. The abnormal build up of
glycosphingolipid within the heart may be detectable using T1 mapping. This accumulation of
glycosphingolipid could identify an earlier form of Fabry disease. Moreover, it is postulated
that T1 mapping may inform prognosis and response to therapy.
Whilst promising, further investigation and development of this innovative technique in Fabry
disease is required. This study aims to find out more about T1 mapping in Fabry disease.
Patients referred for clinical cardiac MRI scanning will also undergo T1 mapping. T1 mapping
results will be correlated with other markers of disease severity. This will allow heart
muscle T1 to be determined in a larger population of Fabry patients than currently exists in
the literature and T1 to be characterised across a wider range of Fabry disease severity than
currently exists in the literature.
Description:
Anderson-Fabry disease (Fabry disease) is a genetic lysosomal storage disorder. Lysosomes are
structures found within cells that contain enzymes which break down waste products and
foreign material. In Fabry disease there is an inborn deficiency of an enzyme called
α-galactosidase A. This leads to progressive accumulation of a fatty substance, called
glycosphingolipid, in the lysosomes.
Accumulation of glycosphingolipid in cells can affect the function of many organs, but in
particular it affects the heart, the brain and nerves and the kidneys. It manifests as severe
and chronic limb pain, progressive kidney dysfunction, transient ischaemic attacks and
strokes, coronary artery disease and heart failure. Heart involvement is particularly
important because it is responsible for the majority of deaths in patients with Fabry
disease.
Fabry disease affects between 1:17,000 to 1:117,000 people, although the prevalence is likely
to be underestimated due to difficulties in diagnosis. It is seen across all ethnic and
racial groups. It is a chronic disease with significantly reduced survival (median age of
death 50). The culprit gene is carried on the X chromosome, therefore males are generally
more severely affected than females, with symptoms beginning in childhood or adolescence.
Manifestations are more variable in females, from no apparent disease to full expression, but
up to 90% have symptoms.
There is no cure for Fabry disease, however enzyme replacement therapy (ERT), which consists
of providing affected patients with the deficient enzyme, is available. ERT has been
demonstrated to reverse or slow disease progression before irreversible end-organ damage has
occurred. However, there are no uniform guidelines as to which patients should receive ERT,
when to start it, how to monitor response and when to stop it. As such, patient care is far
from optimal, with patients who would benefit from ERT often getting it too late or
potentially not getting it at all. Furthermore, ERT is being started in patients in whom the
disease is irreversible, or continued in patients in whom it is no longer of benefit. As well
as the implications for patient care, this has significant implications for healthcare
provision, given that ERT costs in excess of £100,000 per patient per year.
The reason why there are no good guidelines for ERT is that there is no good test to
determine organ involvement or organ response to therapy. As explained above, heart
involvement is particularly important but the current technique to assess heart involvement
(ultrasound scanning of the heart (echocardiography)) is insensitive to accumulation of
glycosphingolipid. Echocardiography allows assessment for heart muscle thickening and
impairment of gross pumping function, but such changes occur late and are insensitive for
assessing response to ERT. Heart muscle biopsy can determine glycosphingolipid accumulation,
however this is very invasive, expensive and not an acceptable technique for this purpose.
A non-invasive technique to detect early heart involvement in Fabry disease, that would guide
initiation of ERT, monitor response to ERT and determine which patients will not benefit from
ERT, is urgently required, both in terms of improving and individualizing patient care and in
terms of optimizing healthcare provision.
Cardiovascular magnetic resonance imaging (cardiac MRI) is a relatively new clinical heart
imaging technique. It provides detailed and often unique information about heart structure
and function. Cardiac MRI images are acquired using magnetic fields. It is free from ionizing
radiation; indeed it is considered to be "one of the safest medical procedures currently
available" (www.nhs.uk), and thus is an ideal technique for disease surveillance and
treatment monitoring.
One of the unique attributes of cardiac MRI is its ability to non-invasively characterise the
make-up of heart muscle tissue. Just like all tissues have mass, all tissues have magnetic
properties. A cardiac MRI technique called T1 mapping can measure the magnetic relaxation
properties of tissues. T1 mapping techniques have been used to assess other organs for many
years, but have only relatively recently been applied to the heart.
Fat has different magnetic properties to heart muscle; specifically it has faster magnetic
relaxation than heart muscle. This difference can be measured using T1 mapping - fat has a
shorter (or lower value) T1 relaxation time than heart muscle.
As described above, in Fabry disease, there is accumulation of glycosphingolipid in the
heart. Also as described, glycosphingolipid is a fatty substance. Therefore, accumulation of
this fat in the heart could theoretically be detected using the T1 mapping technique.
Two small studies have demonstrated low T1 mapping values in Fabry disease patients in
comparison to healthy volunteers and in comparison to patients with other heart conditions
that cause heart muscle thickening (Sado et al Circ Cardiovasc Imaging. 2013;6:392-398 and
Thompson et al Circ Cardiovasc Imaging. 2013;6:637-645). Interestingly, low T1 mapping values
were seen in the absence of any other detectable changes in heart structure and function,
suggesting that this technique could allow early detection of heart involvement in Fabry
disease. T1 mapping and other allied cardiac MRI techniques (late gadolinium enhancement and
extracellular volume quantification) have also been used to demonstrate heart muscle scarring
in Fabry disease, which is irreversible and thus unlikely to be amenable to ERT.
Potentially therefore, cardiac MRI T1 mapping could allow early detection of heart
involvement in Fabry disease and thus better guide initiation of ERT, allow monitoring of
heart response to ERT and, together with the allied cardiac MRI techniques described,
determine when advanced disease is present and thus when ERT should be stopped or is not
appropriate to initiate.
Whilst promising, further investigation and development of this innovative technique in Fabry
disease is required. This study aims to find out more about T1 mapping in Fabry disease.
Patients referred for clinical cardiac MRI scanning will also undergo T1 mapping. T1 mapping
results will be correlated with other markers of disease severity. This will allow:
1. Heart muscle T1 to be determined in a larger population of Fabry patients than currently
exists in the literature
2. T1 to be characterised across a wider range of Fabry disease severity than currently
exists in the literature.
