Characterizing the Retinal Microvasculature in Patients with Fabry Disease: a Prospective Observational Study (VASCinFABRY)

December 30, 2024 updated by: PD Dr. Christoph Schmaderer, Technical University of Munich

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?

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Observational

Enrollment (Estimated)

63

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Germany
    • Bavaria
      • München, Bavaria, Germany, 81675
        • Recruiting
        • Department of nephrology, Klinikum rechts der Isar
        • Contact:
        • Contact:
        • Contact:
          • Christoph Schmaderer, Prof.Dr.
        • Contact:
          • Matthias Braunisch, PD. Dr.
        • Contact:
          • Roman Günthner, Dr.
        • Contact:
          • Timon Kuchler, Dr

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

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.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Retinal Arteriolar Diameter (CRAE)
Time Frame: 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.

What will be measured: Central Retinal Arteriolar Equivalent (CRAE) in micrometers (µm).

Unit of Measure: Micrometers (µm). How it will be reported: Mean CRAE values at baseline for Fabry disease patients compared with age- and sex-matched healthy controls.
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.
Change in Retinal Arteriolar Diameter (CRVE)
Time Frame: 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.

What will be measured: Central Retinal Arteriolar Equivalent (CRVE) in micrometers (µm).

Unit of Measure: Micrometers (µm). How it will be reported: Mean CRAE values at baseline for Fabry disease patients compared with age- and sex-matched healthy controls.
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.
Change in arteriolar-venular ration (AVR)
Time Frame: 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.
What will be measured: AVR as a quotient out of CRAE/CRVE Unit of Measure: no unit How it will be reported: Mean or Median AVR values at baseline for Fabry disease patients compared with age- and sex-matched healthy controls.
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.
Change in Flicker-Induced Venular Dilation (vFID)
Time Frame: 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

What will be measured: Maximum percentage change in retinal venular diameter during flicker stimulation.

Unit of Measure: Percentage (%). How it will be reported: Mean vFID percentage change at baseline for Fabry disease patients compared with age- and sex-matched healthy controls.
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
Change in Flicker-Induced Venular Dilation (aFID)
Time Frame: 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

What will be measured: Maximum percentage change in retinal arteriolar diameter during flicker stimulation.

Unit of Measure: Percentage (%). How it will be reported: Mean vFID percentage change at baseline for Fabry disease patients compared with age- and sex-matched healthy controls.
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
Predictive Value of SVA and DVA Parameters in Fabry Disease Outcomes
Time Frame: 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

What will be measured: The predictive value of Static Retinal Vessel Analysis (SVA) parameters (CRAE, CRVE, AVR) and Dynamic Retinal Vessel Analysis (DVA) parameters (vFID, aFID) in forecasting Fabry disease-associated events (FACE) FACE are measured as preciously described (https://pmc.ncbi.nlm.nih.gov/articles/PMC10359570/) Unit of Measure: Micrometers (µm) for CRAE, CRVE; unitless ratio for AVR; percentage (%) for vFID and aFID.

Measurement Tools: Retinal vessel analyzers (Static Retinal Vessel Analyzer and Dynamic Retinal Vessel Analyzer, IMEDOS Systems, Jena, Germany), echocardiography, clinical laboratory markers (e.g., LysoGb3), and DS3 scoring system. FACE.

How it will be reported Hazard Ratios (HR): Derived from Cox proportional hazard models Odds Ratios (OR): For binary outcomes Multivariable Regression Models

Receiver Operating Characteristic (ROC) Analysis:

Correlation Coefficients: (e.g., Pearson or Spearman)
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Correlation Between Retinal Vessel Parameters and Symptom Severity (DS3)
Time Frame: Measurement at enrollment (T0)

What will be measured: Correlation of static retinal vessel analysis parameters (CRAE, CRVE, AVR) and dynamic parameters (vFID, aFID) with the Fabry disease severity score (DS3, Giannini et al. 2009).

Unit of Measure: Micrometers (µm) for CRAE, CRVE, AVR; percentage (%) for vFID and aFID; unitless for DS3 score (range 0-32).

Measurement Tools: Dynamic Retinal Vessel Analyzer (IMEDOS Systems, Jena, Germany), Static Retinal Vessel Analyzer (IMEDOS Systems, Jena, Germany), and the DS3 scoring system.

How it will be reported: Statistical correlation coefficients (e.g., Spearman or Pearson).
Measurement at enrollment (T0)
Patients with Fabry disease and impaired retinal microcirculation Elevated Markers of Endothelial Dysfunction and Chronic Inflammation in Patients With Impaired Retinal Microcirculation
Time Frame: Measurement at enrollment (T0)

What will be measured: Concentration of markers of endothelial dysfunction (sICAM, sVCAM, Thrombomodulin, P-Selectin, E-Selectin, ADMA, SADMA, Endothelin-1) and chronic inflammation (IFN-β, IFN-λ1, TNF-α).

Unit of Measure: Nanograms per milliliter (ng/mL) for most markers; other units (e.g., µmol/L for ADMA) as specified.

Measurement Tools: ELISA, flow cytometry (e.g., FACS analysis for PBMCs). How it will be reported: Mean concentrations or median with interquartile range (IQR).
Measurement at enrollment (T0)
Correlation Between Retinal Microcirculation Markers and Cardiac Damage
Time Frame: Measurement at enrollment (T0)

What will be measured: Static retinal vessel analysis parameters (CRAE, CRVE, AVR) and dynamic parameters (vFID, aFID) correlated with cardiac measurements ( thickness of interventricular septum, posterior wall thickness, left ventricular end diastolic diameter) and incidence of cardiovascular events (e.g., heart failure, arrhythmia).

Unit of Measure: Micrometers (µm) for retinal vessel parameters; millimeters (mm) for cardiac measurements.

Measurement Tools: Retinal vessel analyzers (IMEDOS Systems, Jena, Germany) and echocardiography.

How it will be reported: Statistical correlation coefficients (e.g., Spearman or Pearson).
Measurement at enrollment (T0)
Correlation Between Genetic Phenotypes and Retinal Vessel Parameters
Time Frame: Measurement at enrollment (T0)

What will be measured: Static retinal vessel analysis parameters (CRAE, CRVE, AVR) and dynamic parameters (vFID, aFID) correlated with genetic classifications (classical, non-classical Fabry disease) and pathogenicity of GLA gene variants.

Unit of Measure: Micrometers (µm) for retinal vessel parameters; categorical classifications for genetic phenotypes (classical, non-classical).

Measurement Tools: Retinal vessel analyzers (IMEDOS Systems, Jena, Germany) and genetic analysis using ACMG guidelines.

How it will be reported: Mean retinal parameters for each genetic phenotype group; statistical correlations.
Measurement at enrollment (T0)
Polymorphisms in the Human Endothelial Nitric Oxide Synthase Gene (eNOS)
Time Frame: Measurement at enrollment (T0)

What will be measured: Frequency and type of gene polymorphisms in the human endothelial nitric oxide synthase (eNOS) gene.

Unit of Measure: Proportion of participants (%) with specific polymorphisms. Measurement Tools: Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis.

How it will be reported: Percentage of participants with each polymorphism type.
Measurement at enrollment (T0)
Comparison of Vessel Density in OCT-A Between Fabry Patients and Healthy Cohort
Time Frame: Measurement at enrollment (T0)

What will be measured: Vessel density in the retina using optical coherence tomography angiography (OCT-A).

Unit of Measure: Percentage (%) of vessel density. Measurement Tools: Optical coherence tomography angiography (OCT-A). How it will be reported: Mean vessel density values for Fabry patients versus healthy controls.
Measurement at enrollment (T0)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Technical University of Munich

Collaborators

Takeda

Investigators

  • Principal Investigator: Roman Günthner, PD Dr., Abteilung für Nephrologie
  • Principal Investigator: Timon Kuchler, Abteilung für Nephrologie
  • Principal Investigator: Matthias Braunisch, Pd Dr., Abteilung für Nephrologie
  • Study Chair: Claudia Regenbogen, Abteilung für Nephrologie
  • Study Director: Christoph Schmaderer, Abteilung für Nephrologie

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 25, 2020

Primary Completion (Actual)

September 1, 2021

Study Completion (Estimated)

November 1, 2025

Study Registration Dates

First Submitted

April 17, 2023

First Submitted That Met QC Criteria

December 30, 2024

First Posted (Actual)

March 25, 2025

Study Record Updates

Last Update Posted (Actual)

March 25, 2025

Last Update Submitted That Met QC Criteria

December 30, 2024

Last Verified

December 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • FD062020

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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