Fabry Exercise Intolerance Study

Fabry Disease Clinical Trial

— FEISTY  

Official title:

Fabry Exercise Intolerance Study (FEISTY)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05413876
• Other study ID #: NL73534.018.21
• Status: Recruiting
• Start date: October 10, 2021
• Est. completion date: January 2, 2024

Study information

• Verified date: August 2023
• Source: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Contact: Bram Veldman, MD
• Phone: 0031205666791
• Email: b.c.f.veldman[@]amsterdamumc.nl
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Patients and healthy controls will undergo cardiopulmonary exercises and testing of the muscles strength to gain additional understanding of exercise intolerance as Fabry disease (FD) manifestation. An additional needle muscle biopsy may be performed. Tissue analysis from this biopsy will include evaluation of the lipidomics profile and mitochondrial function. Results of the tests and any potential exercise intolerance will be compared against healthy, age-, sex- and BMI-matched volunteers. The hypothesis is that patients with FD will have reduced exercise capacity due to changes in skeletal and cardiac muscle energy metabolism.

Description:

Background: 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 in insufficiently understood. This limits preventive measures and adequate treatment.

Hypothesis: 1) The development of energy metabolism in skeletal and cardiac muscle in FD is disturbed early on in disease development and this progresses as the disease worsens, resulting in reduced exercise capacity. 2) Intermittent CPX is an objective and sensitive tool to grade the level of exercise tolerance in FD patients and yields specific outcome parameters that can be used in future intervention studies.

Primary objectives: 1) To study the presence and extent 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 FD. Secondary objectives: 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 patients groups (potentially providing an indication of the source of possibly slowed V'O2 kinetics).

Methods: This study will consist of two screening visits, one testing procedure visit, and an optional second visit for all subjects enrolled in the study. During the first testing visit two cardiopulmonary exercise (CPX) test will be performed. During the CPX tests gas exchange, ventilation, blood pressure and cardiac output will be measured and exhaustion level monitored. Before and after the tests a blood sample will be taken. The upper leg muscle strength and the leg muscle size will be assessed. In order to detect alterations in skeletal muscle energy metabolism, a needle biopsy of the upper leg muscle will be taken during the second optional study visit. In the biopsy specimen, lipidomics profile, electronic microscopic characteristics of muscle tissue and mitochondrial function will be assessed.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: January 2, 2024
• Est. primary completion date: January 2, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• FD patients: Men and women with a definite known diagnosis of FD.

• Healthy controls: Healthy control subjects (men and women) with an age of 18 years of older.

Exclusion Criteria:

FD patients:

• Pregnancy

• Recent acute myocardial infarct (<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)

• Active infection, anaemia, severe renal dysfunction (estimated Glomerular filtration rate <30 ml/min/1,73m2) likely to significantly impact on exercise performance

• In some cases: use of anticoagulants or anti platelet therapy (see study procedure)

Healthy controls:

• All abovementioned exclusion criteria for FD patients

• History of 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

Related Conditions & MeSH terms

• Fabry Disease
• Fabry Disease, Cardiac Variant

Intervention

Other:
• Intermittent cardiopulmonary exercise test
Exercise test with step-change from rest to a relatively low constant workload.
• Incremental cardiopulmonary exercise test
Exercise test with incremental workload until maximal workload.

Locations

Country	Name	City	State
Netherlands	Amsterdam UMC, location AMC	Amsterdam

Sponsors (1)

Lead Sponsor	Collaborator
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Body height (cm)		Baseline
Other	Body weight (kg)		Baseline
Other	NT-proBNP (ng/L)		Baseline
Other	Troponin (µg/L)		Baseline
Other	Lactate (mmol/L)		Baseline and after maximum exercise
Other	Haemoglobin (mmol/L)		Baseline
Primary	Differences in V'O2 max kinetics (ml/kg/min)		At rest (baseline) and after maximum CPX test (30 min)
Primary	Tiffeneau-index (FEV1/IVC ratio)	Pulmonary involvement	At rest (baseline)
Primary	Anaerobic threshold (ml/kg/min)	Pulmonary involvement/Cardiac dysfunction/Skeletal muscle alterations	During maximum exercise (max 30 min).
Primary	Ventilation reserve (L)	Pulmonary involvement/Skeletal muscle alterations	During maximum exercise (max 30 min).
Primary	CO2 ventilation equivalent (L/L)	Pulmonary involvement/Cardiac dysfunction	During maximum exercise (max 30 min).
Primary	O2 saturation (%)	Pulmonary involvement/Cardiac dysfunction	During maximum exercise (max 30 min).
Primary	Cardiac Output (L/min)	Cardiac dysfunction	During maximum exercise (max 30 min).
Primary	Heart rate reserve (per minute)	Cardiac dysfunction:	During maximum exercise (max 30 min).
Primary	Muscle size on echography (cm)	Skeletal muscle alterations	Baseline
Primary	Muscle strength via resistance test (kg)	Skeletal muscle alterations	Biopsy at baseline
Primary	Lipidomics profile of muscle tissue	Skeletal muscle alterations	Biopsy at baseline
Primary	Electronic microscopic characteristics of muscle tissue	Skeletal muscle alterations	Biopsy at baseline
Primary	Mitochondrial function of muscle tissue	Skeletal muscle alterations	Biopsy at baseline
Secondary	Correlation between V'O2 kinetics during intermittent exercise and V'O2 max on the incremental maximum CPX (Pearson correlation coefficient).		Day 1
Secondary	Correlation between V'O2 kinetics during intermittent exercise and activity score on the SQUASH Questionnaire (Pearson correlation coefficient).		Day 1
Secondary	Correlation between V'O2 kinetics during intermittent exercise and functional and morphological cardiac parameters on cardiac imaging (Magnetic resonance or echocardiography) (Pearson correlation coefficient).		Day 1