Clinical trial NCT06758648: Characterizing the Retinal Microvasculature in Patients with Fabry Disease: a Prospective Observational Study
Official title: Characterizing the Retinal Microvasculature in Patients with Fabry Disease: a Prospective Observational Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Fabry Disease
Endothelial Dysfunction
Microvasculature
Keywords: Chronic inflammation
retinal microvasculature
retinal vessel analysis
vasculopathy
Lead sponsor: Technical University of Munich
Sponsor class: OTHER
Collaborators: name: Takeda
First posted: 2025-01-06
Enrollment: 63
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients included in this study are recruited through our in-house metabolic outpatient clinic (Stoffwechselambulanz), which specializes in the diagnosis, treatment, and long-term management of rare metabolic disorders, including Fabry disease. The clinic serves as a comprehensive care center, offering multidisciplinary services such as genetic counseling, laboratory diagnostics, and individualized treatment planning. Patients are identified and approached during routine follow-ups or initial consultations after confirmation of a Fabry disease diagnosis through genetic testing or measurement of globotriaosylceramide (Gb3) activity in leukocytes. This structured recruitment process ensures the inclusion of well-characterized patients who meet the study's eligibility criteria.

Brief summary: This study aims to gain a deeper understanding of endothelial dysfunction in patients with Fabry disease through a prospective study of the retinal microvasculature and to identify an objective, non-invasive marker to assess disease severity and cardiovascular risk in patients.

The main questions addressed are: Do dynamic and static retinal vessel analysis parameters differ from those in healthy individuals? Can these parameters predict cardiovascular and/or Fabry-related events during follow-up? Do these parameters change during follow-up in patients with a non-stable disease?

Detailed description: Fabry disease is a rare genetic disorder characterized by the pathological accumulation of glycosphingolipids, specifically globotriaosylceramide (Gb3), within lysosomes in various cells of the body. This accumulation leads to damage in the cardiovascular, cerebrovascular, and renal systems and is characterized by dysfunction of endothelial cells. This dysfunction results in disturbances in the microcirculation and damage to the supplied systems, leading to a significantly increased cardiovascular risk in patients with Fabry disease. Studies have shown that these patients have a higher risk of premature death due to these risk factors compared to the general population.

Early diagnosis and adequate monitoring of enzyme replacement therapy (ERT) are crucial in reducing the risk of cardiovascular events associated with Fabry disease. Currently, LysoGb3 (lysosphingolipid globotriaosylceramide) is considered a biomarker for the diagnosis and monitoring of Fabry disease. Elevated levels of LysoGb3 have been observed in the blood of patients with Fabry disease, and its measurement has been proposed as a diagnostic tool. Additionally, measuring LysoGb3 levels before and after treatment with ERT can be used as a tool to monitor the effectiveness of the therapy in reducing the accumulation of glycosphingolipids in cells and improving symptoms and outcomes in patients with Fabry disease.

However, the performance of LysoGb3 as a predictor of cardiovascular events in patients with Fabry disease is not well understood, and more research is needed to confirm its utility in this regard.

Therefore, there is a need for additional reliable measurements of the microcirculation that can be performed non-invasively and represent a low burden for participants. The use of non-invasive markers of microcirculation can aid in the early diagnosis and monitoring of Fabry disease, which is crucial for the effective use of ERT.

In summary, this study aims to validate new microcirculation markers that can be measured non-invasively in a prospective cohort of patients with Fabry disease and to correlate these markers with established clinical and laboratory parameters. By validating these markers, the study seeks to improve the management of Fabry disease, reduce the burden on participants, and ultimately reduce the incidence of cardiovascular events associated with the disease.

Eligibility criteria: Inclusion Criteria:

* Age \> 18 years
* Diagnosis of Fabry disease by genetic testing or GB3 activity in leukocytes.
* Signed informed consent form

Exclusion Criteria:

* Active infection or cancer
* Surgery less than 2 weeks prior to inclusion in the study
* Known glaucoma
* Lack of capacity to give consent; lack of informed consent.
* Known epilepsy

Primary outcomes:
measure: Change in Retinal Arteriolar Diameter (CRAE)
timeFrame: From enrollment (T0) to the occurrence of death or the end of the study, whichever comes first, assessed over an estimated period of up to 4 years. Measurements will be conducted annually, starting at T0, then at 1 year (T1), 2 year (T2), T3 and T4.
measure: Change in Retinal Arteriolar Diameter (CRVE)
timeFrame: From enrollment (T0) to the occurrence of death or the end of the study, whichever comes first, assessed over an estimated period of up to 4 years. Measurements will be conducted annually, starting at T0, then at 1 year (T1), 2 year (T2), T3 and T4.
measure: Change in arteriolar-venular ration (AVR)
timeFrame: From enrollment (T0) to the occurrence of death or the end of the study, whichever comes first, assessed over an estimated period of up to 4 years. Measurements will be conducted annually, starting at T0, then at 1 year (T1), 2 year (T2), T3 and T4.
measure: Change in Flicker-Induced Venular Dilation (vFID)
timeFrame: From enrollment (T0) to the occurrence of death or the end of the study, whichever comes first, assessed over an estimated period of up to 4 years. Measurements will be conducted annually, starting at T0, then at 1 year (T1), 2 year (T2), T3 and T4
measure: Change in Flicker-Induced Venular Dilation (aFID)
timeFrame: From enrollment (T0) to the occurrence of death or the end of the study, whichever comes first, assessed over an estimated period of up to 4 years. Measurements will be conducted annually, starting at T0, then at 1 year (T1), 2 year (T2), T3 and T4
measure: Predictive Value of SVA and DVA Parameters in Fabry Disease Outcomes
timeFrame: From enrollment (T0) to the occurrence of death /FACE or the end of the study, whichever comes first, assessed over an estimated period of up to 4 years. Measurements will be conducted annually, starting at T0, then at 1 year (T1), 2 year (T2), T3 and T4
Secondary outcomes:
measure: Correlation Between Retinal Vessel Parameters and Symptom Severity (DS3)
timeFrame: Measurement at enrollment (T0)
measure: Patients with Fabry disease and impaired retinal microcirculation Elevated Markers of Endothelial Dysfunction and Chronic Inflammation in Patients With Impaired Retinal Microcirculation
timeFrame: Measurement at enrollment (T0)
measure: Correlation Between Retinal Microcirculation Markers and Cardiac Damage
timeFrame: Measurement at enrollment (T0)
measure: Correlation Between Genetic Phenotypes and Retinal Vessel Parameters
timeFrame: Measurement at enrollment (T0)
measure: Polymorphisms in the Human Endothelial Nitric Oxide Synthase Gene (eNOS)
timeFrame: Measurement at enrollment (T0)
measure: Comparison of Vessel Density in OCT-A Between Fabry Patients and Healthy Cohort
timeFrame: Measurement at enrollment (T0)
Other outcomes:
Locations:
city: München
country: Germany
facility: Department of nephrology, Klinikum rechts der Isar
state: Bavaria
Study officials:
affiliation: Abteilung für Nephrologie
name: Roman Günthner, PD Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Abteilung für Nephrologie
name: Timon Kuchler
role: PRINCIPAL_INVESTIGATOR
affiliation: Abteilung für Nephrologie
name: Matthias Braunisch, Pd Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Abteilung für Nephrologie
name: Claudia Regenbogen
role: STUDY_CHAIR
affiliation: Abteilung für Nephrologie
name: Christoph Schmaderer
role: STUDY_DIRECTOR
References:
citation: Giannini EH, Mehta AB, Hilz MJ, Beck M, Bichet DG, Brady RO, West M, Germain DP, Wanner C, Waldek S, Clarke JT, Mengel E, Strotmann JM, Warnock DG, Linhart A. A validated disease severity scoring system for Fabry disease. Mol Genet Metab. 2010 Mar;99(3):283-90. doi: 10.1016/j.ymgme.2009.10.178. Epub 2009 Oct 30.
citation: Hughes DA, Bichet DG, Giugliani R, Hopkin RJ, Krusinska E, Nicholls K, Olivotto I, Feldt-Rasmussen U, Sakai N, Skuban N, Sunder-Plassmann G, Torra R, Wilcox WR. Long-term multisystemic efficacy of migalastat on Fabry-associated clinical events, including renal, cardiac and cerebrovascular outcomes. J Med Genet. 2023 Jul;60(7):722-731. doi: 10.1136/jmg-2022-108669. Epub 2022 Dec 21.