Primary Objective(s):1. To study the presence and extend of exercise intolerance in male, female FD patients with classical FD and men with non-classical FD, in different stages of the disease.2. To determine the aetiology of exercise intolerance in…
ID
Source
Brief title
Condition
- Cardiac disorders, signs and symptoms NEC
- Congenital and hereditary disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. Differences in V*O2 kinetics between FD patients and healthy control
subjects as a readout of exercise capacity.
2. To assess the aetiology of exercise intolerance study parameters and
clinical follow-up data (Amsterdam UMC clinical Fabry database) will be used.
The following parameters will be taken into account and compared with the
healthy control group (NB cardiac imaging will not be performed the control
group):
- Pulmonary involvement/ bronchial obstruction:
Pulmonary function test: abnormal FEV1/VC (Tiffeneau-index) at rest. During
maximum CPX test: low V*O2 max, anaerobic threshold, low ventilation (VE)
reserve, high heart rate (HR) reserve, high CO2 ventilation equivalent (EqCO2)
and low O2 saturation O2 (pulse oximetry, SpO2).
- Cardiac dysfunction:
Cardiac imaging (part of routine clinical follow-up in FD patients): signs on
echocardiogram of Heart failure with preserved ejection fraction (HFpEF): low
early diastolic mitral annular velocity e* (septal < 7 cm/s and lateral < 10
cm/s), the ratio of transmitral Doppler early filling velocity to tissue
Doppler early diastolic mitral annular velocity (E/e*) >= 9 or tricuspid
regurgitation (TR) velocity > 2.8 m/s, global longitudinal strain (GLS) < 16%,
left atrial volume index (LAVI) >= 29 ml/m2, left ventricular mass index (LVMi)
of 115 g/m2 and 95 g/m2 for men and women, respectively, relative wall
thickness > 0.42, left ventricular wall thickness >= 12 mm), biochemical:
NT-proBNP >= 125 pg/ml (sinus rhythm) and NT-proBNP >= 365 pg/ml (atrial
fibrillation).
During maximum CPX: low V*O2 max, low HR reserve, low Cardiac output (CO) and
low anaerobic threshold. High EqCO2 and a O2 pulse plateau.
- Skeletal muscle alterations:
During maximum CPX: Low V*O2 max, low HR reserve, low maximum O2 pulse, low AT.
High VE reserve. Muscle biopsy with typical signs of sphingolipid accumulation
(electron microscopy) and mitochondrial dysfunction. Signs of muscle atrophy
and strength in comparison to the healthy control subjects.
Secondary outcome
To determine whether the proposed intermittent exercise test protocol can be
used to measure treatment outcome in future studies and to validate if the
intermittent exercise test can be useful for clinically meaningful outcomes,
one can correlate the V*O2 kinetics during intermittent exercise to:
1. V*O2 max on the incremental maximum CPX;
2. The activity score on the SQUASH Questionnaire.
Background summary
Fabry disease (FD) is an inherited, highly variable and slowly progressive X
linked disorder, which predominantly affects vascular endothelium, the heart,
kidneys and the brain. Exercise intolerance is a complaint expressed by the
majority of patients, at all stages of the disease. The exact cause, extent and
development over time of exercise intolerance in FD is insufficiently
understood. This limits preventive measures and adequate treatment.
Study objective
Primary Objective(s):
1. To study the presence and extend of exercise intolerance in male, female FD
patients with classical FD and men with non-classical FD, in different stages
of the disease.
2. To determine the aetiology of exercise intolerance in Fabry disease.
Secondary Objective(s):
1. To determine whether the exercise test protocol used in this study can be
used as a clinical outcome measure in future intervention studies.
2. To investigate difference in the time-relation between V*O2 and circulatory,
ventilatory and metabolic variables during intermittent exercise between FD
patient groups. These time-relations can provide an indication of the source of
possibly slowed V*O2 kinetics.
Study design
Monocenter cross-sectional prospective cohort study.
Study burden and risks
1. The number of site visits: two phone visits and one study visit (One extra
study visit in case of optional percutaneous muscle biopsy). Total hours for
physical visits: 5 hours. In case of an extra visit: 6 hours.
2. Questionnaires: two questionnaires SQUASH, and (Modified medical research
council (mMRC) dyspnea scale) questionnaire. The estimated time to fill in
these two questionnaires is 20 minutes.
3. Study procedures: muscle strength test, echo of the leg, rest spirometry,
maximum incremental and intermittent CPX test. The estimated time for all this
procedures is five to six hours.
4. Blood and other tests: intravenous blood will be taken at two points. The
total blood volume that will be drawn is 13.5 ml (3 ml extra in case of
optional percutaneous muscle biopsy) . The risk of drawing blood may include
some dizziness, discomfort around the bruise and a very low risk of infection.
5. Optional test will be a muscle needle biopsy of m. vastus lateralis,
associated with pain and muscle bleeding/ hematomas.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
For FD patients:
- Men and women with a definite known diagnosis of FD.
For Healthy controls:
- Healthy control subjects (men and women) with an age of 18 years or older.
Exclusion criteria
For FD patients:
- Pregnancy;
- Recent acute myocardial infarction (<6 months);
- Uncontrolled arrhythmia/severe conduction disorder (atrial fibrillation or
second/third-degree AV block) causing hemodynamic compromise;
- Implantable pacemaker or other cardiac device with complete ventricular
pacing;
- Uncontrolled heart failure with hemodynamic compromise;
- Uncontrolled hypertension (Systolic Blood Pressure >150 mmHg and Diastolic
Blood Pressure > 100 mmHg on repeated measurements);
- Using medication mimicking chronotropic incompetence (e.g.
beta-blockers) that cannot be ceaed 24h in advance of testing.
- Active infection, anaemia, severe renal dysfunction (estimated Glomerular
filtration rate <30 ml/min/1,73m2) likely to significantly impact on exercise
performance;
- In case of visit 2: use of direct or indirect anticoagulants therapy (DOAC or
vitamin K antagonists)
For healthy controls:
- All above mentioned exclusion criteria for FD patients;
- History of reduced lung capacity caused by smoking
- History of active drug use which can affect exercise intolerance;
- History of asthma, chronic obstructive pulmonary disease, heart failure,
heart surgery, heart rhythm disorders or congenital heart diseases;
- Use of chronic medication likely to affect exercise tolerance;
- Chronic illness (including orthopaedic, endocrinological, haematological,
malignant, gastrointestinal, neurological, muscle or inflammatory disorders)
likely to significantly impact on exercise performance;
- > 6 alcohol units per day or >14 alcohol units per week.
Design
Recruitment
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| ClinicalTrials.gov | NCT05413876 |
| CCMO | NL73534.018.21 |