Effect of Migalastat on Cardiac Involvement in Fabry Disease (MAIORA)

March 17, 2021 updated by: Antonia Camporeale, Ospedale San Donato

Anderson-Fabry Disease (AFD) is one of the rare lysosomal storage disorders for which a cause - specific therapy is available. Recently, a new specific drug has been marketed, namely Migalastat, a small-molecule pharmacological chaperone. The effect of Migalastat on cardiac involvement has been assessed so far by 2D echocardiography, demonstrating a significant reduction in left ventricular (LV) mass after 18 months of therapy. Calculation of LV mass by 2D echocardiography is limited by geometrical assumptions and quality of echocardiographic window, with a strong impact on accuracy. Cardiac Magnetic Resonance (CMR) overcomes these limitations, thus representing the gold standard technique for ventricular mass, volumes and function estimation. Moreover, CMR offers the unique possibility to perform a non-invasive tissue characterization, including the detection of both myocardial fibrosis by Late Gadolinium Enhancement and sphingolipid storage by T1 mapping. Beyond an accurate morphological description and a detailed tissue characterization, a complete cardiological assessment should also integrate functional data and bio-humoral profile.

This study is designed to provide a comprehensive evaluation of the therapeutic effect of Migalastat (123 mg every other day) on cardiac involvement after 18 months of therapy, integrating a morphological, functional and bio-humoral assessment.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Anderson-Fabry disease is a rare X-linked lysosomal disorder, mainly affecting cardiovascular, renal and nervous systems. Cardiac injury is the leading cause of death in these patients. Heart involvement is characterized by left ventricular hypertrophy (LVH), myocardial scarring and/or inflammation, Bradyarrhythmias or tachyarrhythmias, heart failure and represents the main cause of death in these patients. Since 2001, specific therapies (enzyme replacement therapy (ERT) first and pharmacological chaperone migalastat more recently) are available to treat these patients.

Migalastat is a small-molecule pharmacological chaperone stabilizing specific mutant forms of the enzyme (α-Gal ) and promoting its catabolic function. These mutant forms of α-Gal are defined as amenable to Migalastat. In patients with amenable mutations, orally administered Migalastat is a potential alternative treatment to intravenous ERT. Because of its chemical nature (small molecule) and route of administration (orally), Migalastat would avoid ERT-associated immunogenicity and infusion-associated reactions. Additionally, the higher volume of distribution of migalastat relative to ERT suggests enhanced penetration of organs and tissues. Theoretically, the chaperoning of α-Gal by Migalastat to lysosomes may better mimic natural enzyme trafficking and result in more constant α-Gal activity than biweekly ERT infusions.

Two main clinical studies have been published so far about safety and efficacy of Migalastat in AFD, demonstrating good safety, tolerability and comparable efficacy to ERT. These studies reported a significant decrease in LV mass index assessed by 2D echocardiography (-6,6 g/m2 in 33 patients after 18 months of therapy), mostly in patients with overt cardiac involvement and greater than the changes observed with ERT (-2 g/m2 in 16 patients after 18 months of therapy).

Calculation of LV mass by 2D echocardiography is based on the "Devereux formula", assuming that the LV is a prolate ellipsoid with a 2:1 long/short axis ratio and symmetric distribution of hypertrophy. This is not always the case in AFD Cardiomyopathy, showing a wide variety of hypertrophy patterns. Moreover, since linear measurements of LV wall thickness and diameters are cubed in this formula, even small measurement errors in dimensions or thickness have a strong impact on accuracy.

Cardiac magnetic resonance (CMR) represents the gold standard technique for ventricular mass, volumes and function estimation because of the possibility to directly measure these parameters without geometrical assumption. Therefore, CMR has an excellent inter-study reproducibility both in normal and in pathologic hearts, overcoming 2D echocardiography. Beyond its high reproducibility in LV mass measurement, CMR offers the unique possibility of non-invasive tissue characterization. This concept includes both detection and quantification of myocardial fibrosis by Late Gadolinium Enhancement images and application of new techniques, namely T1 mapping, detecting myocardial sphingolipid storage even before LVH occurs. Also, CMR allows a detailed characterization of myocardial deformation by feature tracking. Feature tracking CMR (FT-CMR) approximately applies the same principles of speckle tracking echocardiography (even though with differences methods of image acquisition and reconstruction) in order to measure global and segmental myocardial deformation. The strength of FT-CMR consists of its relatively unrestricted access to large fields of view, its high spatial resolution and its relatively high signal to noise and contrast to noise ratios.

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the post-transcriptional level. MiRNAs have emerged as key regulators of several physiological and pathophysiological processes. Besides their intracellular function, recent studies demonstrated that miRNAs can be exported or released by cells and circulate in blood in a remarkably stable form. The discovery of circulating miRNAs opens the possibilities to use circulating miRNA patterns as biomarkers for several pathologies also for cardiovascular diseases. In a recent study, a common microRNA signature in AFD patients regardless of gender and age has been identified.15 miRNAs differentially expressed between 10 AFD subjects and 10 normal controls (NC) have been found. The levels of these 15 miRNAs in plasma sample of 10 subjects with LVH and no mutation in the Galactosidase Alpha (GLA) gene have also been studied. Among these 15 miRNAs, 3 discriminated AFD patients from subjects with LVH. In particular, 2 microRNAs (mir-199a-5p and mir126a-3p) were up-regulated and 1 miRNA (mir-423-5p) was down-expressed in AFD patients. Interestingly, in a recent study increased plasmatic levels of miR-126 and miR-199a were significantly associated with a lower major adverse Cardiovascular (CV) event rate in patients with coronary artery disease. Instead, elevated plasmatic levels of mir-423-5p is strongly related to the clinical diagnosis of Heart Failure. Several evidences indicate that the aberrantly expressed plasmatic miRNAs in AFD are linked to microvascular or macrovascular damage involved in the typical AFD vasculopathy and could be attractive as diagnostic markers as well as for the monitoring of the pharmacological treatment.

Integration of all these aspects allows a complete morpho-functional evaluation of cardiac involvement in AFD and a detailed monitoring of the effects of specific drugs.

This study is designed to provide a comprehensive evaluation of the therapeutic effect of Migalastat on cardiac involvement, integrating a morphological, functional and bio-humoral assessment of heart involvement. 15 patients with amenable mutation, clinical indication to Migalastat and signs of early or overt cardiac involvement with will undergo a complete cardiological evaluation before and 18 months after therapy with Migalastat. The cardiological assessment will include ECG, 2D echocardiography, CMR, cardio-pulmonary test, dosage of peripheral biomarkers (TnT High Sensitive; NT-proBNP, mir-199a-5p and mir126a-3p, mir-423-5p).

Study Type

Observational

Enrollment (Actual)

18

Contacts and Locations

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

Study Locations

  • Italy
    • Milano
      • San Donato Milanese, Milano, Italy, 20097
        • IRCCS Policlinico San Donato

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

16 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Between patients with genetic diagnosis of AFD referred for CMR at Policlinico San Donato, 15 patients with amenable mutation, clinical indication to Migalastat and signs of early or overt cardiac involvement (low myocardial native T1 value ± left ventricular hypertrophy) will be enrolled.

Description

Inclusion Criteria:

  • Genetic diagnosis of Fabry Disease and amenable mutation
  • Clinical indication to Migalastat
  • Signs of clinical or preclinical cardiac involvement (low T1 values with or without left ventricular hypertrophy)
  • Age >16
  • Ability to give a complete informed consent (for minor patients informed consent will be given by parents)

Exclusion Criteria:

  • Contraindication to Migalastat (pregnancy, age <16, Glomerular Filtration Rate <30 ml/min, hypersensitivity to the active ingredient)
  • Contraindication to CMR study (metallic fragment or foreign body, known claustrophobia, PaceMaker/Implantable Cardioverter Defibrillator not CMR conditional, electronic implant or device, eg, insulin pump or other infusion pump)

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

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Fabry Disease patients
Patients with genetic diagnosis of Fabry Disease, clinical indication to Migalastat and signs of cardiac involvement (early or advanced) will undergo cardiological evaluation before and 18 months after therapy with Migalastat (123 mg every other day)
Diagnostic test: Cardiological evaluation

Baseline evaluation

  • FAbry STabilization indEX (FASTEX)
  • 12 leads ECG
  • Blood samples for microRNA, TnT HS and NT-proBNP dosages
  • 2D echocardiogram
  • Cardio-pulmonary test

  • Contrast-enhanced CMR including:

    • Cine images
    • T2 mapping sequences
    • T1 mapping sequences before and 15' after contrast medium administration
    • Late Gadolinium Enhancement (LGE) imaging
    • Phase contrast images (LVOT, aortic flow)

Follow up evaluation

•After 18 months, the same procedures will be repeated

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Delta left ventricular mass
Time Frame: 18 months
Changes in left ventricular mass measured by cardiac magnetic resonance
18 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Delta native myocardial T1 values
Time Frame: 18 months
Changes in native myocardial T1 values measured by cardiac magnetic resonance
18 months
Delta left ventricular global longitudinal strain
Time Frame: 18 months
Changes in left ventricular global longitudinal strain measured by cardiac magnetic resonance
18 months
Delta 3 plasmatic microRNAs levels
Time Frame: 18 months
Changes in mir-199a-5p, mir126a-3p, mir-423-5p levels measured by Real-Time quantitative Polymerase Cycle Reaction (RT-qPCR)
18 months

Collaborators and Investigators

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

Sponsor

Ospedale San Donato

Collaborators

Amicus Therapeutics
Institute of Biomedicine and Molecular Immunology - CNR

Investigators

  • Principal Investigator: Antonia Camporeale, MD, PhD, IRCCS Policlinico San Donato

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)

January 10, 2018

Primary Completion (Actual)

January 22, 2021

Study Completion (Actual)

January 22, 2021

Study Registration Dates

First Submitted

February 10, 2019

First Submitted That Met QC Criteria

February 10, 2019

First Posted (Actual)

February 12, 2019

Study Record Updates

Last Update Posted (Actual)

March 18, 2021

Last Update Submitted That Met QC Criteria

March 17, 2021

Last Verified

March 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 148/int/2017

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

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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