Effect of Migalastat on Cardiac Involvement in Fabry Disease

NCT03838237 | Completed DMC

• 1 other identifier: 148/int/2017
• Study Type: observational
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Fabry Disease; Heart Diseases

Keywords

Fabry Disease; Migalastat; Cardiomyopathy; Cardiac Magnetic Resonance; T1 mapping

Outcome Measures

Primary Outcomes (1)

• Delta left ventricular mass

  Changes in left ventricular mass measured by cardiac magnetic resonance

  18 months

Secondary Outcomes (3)

• Delta native myocardial T1 values

  18 months

• Delta left ventricular global longitudinal strain

  18 months

• Delta 3 plasmatic microRNAs levels

  18 months

Study Arms (1)

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

Interventions

Cardiological evaluation DIAGNOSTIC_TEST

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

Fabry Disease patients

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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)

You may not qualify if:

• 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)

Sponsors & Collaborators

• Ospedale San Donato: lead
• Amicus Therapeutics: collaborator
• Institute of Biomedicine and Molecular Immunology - CNR: collaborator

Study Sites (1)

IRCCS Policlinico San Donato

San Donato Milanese, Milano, 20097, Italy

Location

Related Publications (38)

• Hughes DA, Nicholls K, Shankar SP, Sunder-Plassmann G, Koeller D, Nedd K, Vockley G, Hamazaki T, Lachmann R, Ohashi T, Olivotto I, Sakai N, Deegan P, Dimmock D, Eyskens F, Germain DP, Goker-Alpan O, Hachulla E, Jovanovic A, Lourenco CM, Narita I, Thomas M, Wilcox WR, Bichet DG, Schiffmann R, Ludington E, Viereck C, Kirk J, Yu J, Johnson F, Boudes P, Benjamin ER, Lockhart DJ, Barlow C, Skuban N, Castelli JP, Barth J, Feldt-Rasmussen U. Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study. J Med Genet. 2017 Apr;54(4):288-296. doi: 10.1136/jmedgenet-2016-104178. Epub 2016 Nov 10.

  PMID: 27834756 BACKGROUND

• Sado DM, White SK, Piechnik SK, Banypersad SM, Treibel T, Captur G, Fontana M, Maestrini V, Flett AS, Robson MD, Lachmann RH, Murphy E, Mehta A, Hughes D, Neubauer S, Elliott PM, Moon JC. Identification and assessment of Anderson-Fabry disease by cardiovascular magnetic resonance noncontrast myocardial T1 mapping. Circ Cardiovasc Imaging. 2013 May 1;6(3):392-8. doi: 10.1161/CIRCIMAGING.112.000070. Epub 2013 Apr 5.

  PMID: 23564562 BACKGROUND

• Patel V, O'Mahony C, Hughes D, Rahman MS, Coats C, Murphy E, Lachmann R, Mehta A, Elliott PM. Clinical and genetic predictors of major cardiac events in patients with Anderson-Fabry Disease. Heart. 2015 Jun;101(12):961-6. doi: 10.1136/heartjnl-2014-306782. Epub 2015 Feb 5.

  PMID: 25655062 BACKGROUND

• Linhart A, Elliott PM. The heart in Anderson-Fabry disease and other lysosomal storage disorders. Heart. 2007 Apr;93(4):528-35. doi: 10.1136/hrt.2005.063818. No abstract available.

  PMID: 17401074 BACKGROUND

• Moon JC, Sheppard M, Reed E, Lee P, Elliott PM, Pennell DJ. The histological basis of late gadolinium enhancement cardiovascular magnetic resonance in a patient with Anderson-Fabry disease. J Cardiovasc Magn Reson. 2006;8(3):479-82. doi: 10.1080/10976640600605002.

  PMID: 16755835 BACKGROUND

• Eng CM, Guffon N, Wilcox WR, Germain DP, Lee P, Waldek S, Caplan L, Linthorst GE, Desnick RJ; International Collaborative Fabry Disease Study Group. Safety and efficacy of recombinant human alpha-galactosidase A replacement therapy in Fabry's disease. N Engl J Med. 2001 Jul 5;345(1):9-16. doi: 10.1056/NEJM200107053450102.

  PMID: 11439963 BACKGROUND

• Schiffmann R, Kopp JB, Austin HA 3rd, Sabnis S, Moore DF, Weibel T, Balow JE, Brady RO. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA. 2001 Jun 6;285(21):2743-9. doi: 10.1001/jama.285.21.2743.

  PMID: 11386930 BACKGROUND

• Weidemann F, Breunig F, Beer M, Sandstede J, Turschner O, Voelker W, Ertl G, Knoll A, Wanner C, Strotmann JM. Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: a prospective strain rate imaging study. Circulation. 2003 Sep 16;108(11):1299-301. doi: 10.1161/01.CIR.0000091253.71282.04. Epub 2003 Sep 2.

  PMID: 12952834 BACKGROUND

• Imbriaco M, Pisani A, Spinelli L, Cuocolo A, Messalli G, Capuano E, Marmo M, Liuzzi R, Visciano B, Cianciaruso B, Salvatore M. Effects of enzyme-replacement therapy in patients with Anderson-Fabry disease: a prospective long-term cardiac magnetic resonance imaging study. Heart. 2009 Jul;95(13):1103-7. doi: 10.1136/hrt.2008.162800. Epub 2009 Apr 15.

  PMID: 19372091 BACKGROUND

• Germain DP, Weidemann F, Abiose A, Patel MR, Cizmarik M, Cole JA, Beitner-Johnson D, Benistan K, Cabrera G, Charrow J, Kantola I, Linhart A, Nicholls K, Niemann M, Scott CR, Sims K, Waldek S, Warnock DG, Strotmann J; Fabry Registry. Analysis of left ventricular mass in untreated men and in men treated with agalsidase-beta: data from the Fabry Registry. Genet Med. 2013 Dec;15(12):958-65. doi: 10.1038/gim.2013.53. Epub 2013 May 23.

  PMID: 23703683 BACKGROUND

• Beer M, Weidemann F, Breunig F, Knoll A, Koeppe S, Machann W, Hahn D, Wanner C, Strotmann J, Sandstede J. Impact of enzyme replacement therapy on cardiac morphology and function and late enhancement in Fabry's cardiomyopathy. Am J Cardiol. 2006 May 15;97(10):1515-8. doi: 10.1016/j.amjcard.2005.11.087. Epub 2006 Mar 29.

  PMID: 16679096 BACKGROUND

• Germain DP, Charrow J, Desnick RJ, Guffon N, Kempf J, Lachmann RH, Lemay R, Linthorst GE, Packman S, Scott CR, Waldek S, Warnock DG, Weinreb NJ, Wilcox WR. Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease. J Med Genet. 2015 May;52(5):353-8. doi: 10.1136/jmedgenet-2014-102797. Epub 2015 Mar 20.

  PMID: 25795794 BACKGROUND

• Germain DP, Fan JQ. Pharmacological chaperone therapy by active-site-specific chaperones in Fabry disease: in vitro and preclinical studies. Int J Clin Pharmacol Ther. 2009;47 Suppl 1:S111-7.

  PMID: 20040321 BACKGROUND

• Johnson FK, Mudd PN Jr, Bragat A, Adera M, Boudes P. Pharmacokinetics and Safety of Migalastat HCl and Effects on Agalsidase Activity in Healthy Volunteers. Clin Pharmacol Drug Dev. 2013 Apr;2(2):120-32. doi: 10.1002/cpdd.1. Epub 2013 Feb 21.

  PMID: 27121667 BACKGROUND

• Khanna R, Soska R, Lun Y, Feng J, Frascella M, Young B, Brignol N, Pellegrino L, Sitaraman SA, Desnick RJ, Benjamin ER, Lockhart DJ, Valenzano KJ. The pharmacological chaperone 1-deoxygalactonojirimycin reduces tissue globotriaosylceramide levels in a mouse model of Fabry disease. Mol Ther. 2010 Jan;18(1):23-33. doi: 10.1038/mt.2009.220. Epub 2009 Sep 22.

  PMID: 19773742 BACKGROUND

• Germain DP, Hughes DA, Nicholls K, Bichet DG, Giugliani R, Wilcox WR, Feliciani C, Shankar SP, Ezgu F, Amartino H, Bratkovic D, Feldt-Rasmussen U, Nedd K, Sharaf El Din U, Lourenco CM, Banikazemi M, Charrow J, Dasouki M, Finegold D, Giraldo P, Goker-Alpan O, Longo N, Scott CR, Torra R, Tuffaha A, Jovanovic A, Waldek S, Packman S, Ludington E, Viereck C, Kirk J, Yu J, Benjamin ER, Johnson F, Lockhart DJ, Skuban N, Castelli J, Barth J, Barlow C, Schiffmann R. Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat. N Engl J Med. 2016 Aug 11;375(6):545-55. doi: 10.1056/NEJMoa1510198.

  PMID: 27509102 BACKGROUND

• Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Rietzschel ER, Rudski L, Spencer KT, Tsang W, Voigt JU. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015 Jan;28(1):1-39.e14. doi: 10.1016/j.echo.2014.10.003.

  PMID: 25559473 BACKGROUND

• Deva DP, Hanneman K, Li Q, Ng MY, Wasim S, Morel C, Iwanochko RM, Thavendiranathan P, Crean AM. Cardiovascular magnetic resonance demonstration of the spectrum of morphological phenotypes and patterns of myocardial scarring in Anderson-Fabry disease. J Cardiovasc Magn Reson. 2016 Mar 31;18:14. doi: 10.1186/s12968-016-0233-6.

  PMID: 27036375 BACKGROUND

• Grothues F, Smith GC, Moon JC, Bellenger NG, Collins P, Klein HU, Pennell DJ. Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy. Am J Cardiol. 2002 Jul 1;90(1):29-34. doi: 10.1016/s0002-9149(02)02381-0.

  PMID: 12088775 BACKGROUND

• Moon JC, Sachdev B, Elkington AG, McKenna WJ, Mehta A, Pennell DJ, Leed PJ, Elliott PM. Gadolinium enhanced cardiovascular magnetic resonance in Anderson-Fabry disease. Evidence for a disease specific abnormality of the myocardial interstitium. Eur Heart J. 2003 Dec;24(23):2151-5. doi: 10.1016/j.ehj.2003.09.017.

  PMID: 14643276 BACKGROUND

• Koeppe S, Neubauer H, Breunig F, Weidemann F, Wanner C, Sandstede J, Machann W, Hahn D, Kostler H, Beer M. MR-based analysis of regional cardiac function in relation to cellular integrity in Fabry disease. Int J Cardiol. 2012 Sep 20;160(1):53-8. doi: 10.1016/j.ijcard.2011.03.023. Epub 2011 Apr 3.

  PMID: 21463907 BACKGROUND

• Kramer J, Niemann M, Stork S, Frantz S, Beer M, Ertl G, Wanner C, Weidemann F. Relation of burden of myocardial fibrosis to malignant ventricular arrhythmias and outcomes in Fabry disease. Am J Cardiol. 2014 Sep 15;114(6):895-900. doi: 10.1016/j.amjcard.2014.06.019. Epub 2014 Jul 2.

  PMID: 25073565 BACKGROUND

• Kramer J, Niemann M, Liu D, Hu K, Machann W, Beer M, Wanner C, Ertl G, Weidemann F. Two-dimensional speckle tracking as a non-invasive tool for identification of myocardial fibrosis in Fabry disease. Eur Heart J. 2013 Jun;34(21):1587-96. doi: 10.1093/eurheartj/eht098. Epub 2013 Mar 21.

  PMID: 23520186 BACKGROUND

• Bottomley PA, Foster TH, Argersinger RE, Pfeifer LM. A review of normal tissue hydrogen NMR relaxation times and relaxation mechanisms from 1-100 MHz: dependence on tissue type, NMR frequency, temperature, species, excision, and age. Med Phys. 1984 Jul-Aug;11(4):425-48. doi: 10.1118/1.595535.

  PMID: 6482839 BACKGROUND

• Pica S, Sado DM, Maestrini V, Fontana M, White SK, Treibel T, Captur G, Anderson S, Piechnik SK, Robson MD, Lachmann RH, Murphy E, Mehta A, Hughes D, Kellman P, Elliott PM, Herrey AS, Moon JC. Reproducibility of native myocardial T1 mapping in the assessment of Fabry disease and its role in early detection of cardiac involvement by cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2014 Dec 5;16(1):99. doi: 10.1186/s12968-014-0099-4.

  PMID: 25475749 BACKGROUND

• Thompson RB, Chow K, Khan A, Chan A, Shanks M, Paterson I, Oudit GY. T(1) mapping with cardiovascular MRI is highly sensitive for Fabry disease independent of hypertrophy and sex. Circ Cardiovasc Imaging. 2013 Sep;6(5):637-45. doi: 10.1161/CIRCIMAGING.113.000482. Epub 2013 Aug 6.

  PMID: 23922004 BACKGROUND

• Pedrizzetti G, Claus P, Kilner PJ, Nagel E. Principles of cardiovascular magnetic resonance feature tracking and echocardiographic speckle tracking for informed clinical use. J Cardiovasc Magn Reson. 2016 Aug 26;18(1):51. doi: 10.1186/s12968-016-0269-7.

  PMID: 27561421 BACKGROUND

• Tijsen AJ, Creemers EE, Moerland PD, de Windt LJ, van der Wal AC, Kok WE, Pinto YM. MiR423-5p as a circulating biomarker for heart failure. Circ Res. 2010 Apr 2;106(6):1035-9. doi: 10.1161/CIRCRESAHA.110.218297. Epub 2010 Feb 25.

  PMID: 20185794 BACKGROUND

• Fichtlscherer S, De Rosa S, Fox H, Schwietz T, Fischer A, Liebetrau C, Weber M, Hamm CW, Roxe T, Muller-Ardogan M, Bonauer A, Zeiher AM, Dimmeler S. Circulating microRNAs in patients with coronary artery disease. Circ Res. 2010 Sep 3;107(5):677-84. doi: 10.1161/CIRCRESAHA.109.215566. Epub 2010 Jul 1.

  PMID: 20595655 BACKGROUND

• Zampetaki A, Kiechl S, Drozdov I, Willeit P, Mayr U, Prokopi M, Mayr A, Weger S, Oberhollenzer F, Bonora E, Shah A, Willeit J, Mayr M. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res. 2010 Sep 17;107(6):810-7. doi: 10.1161/CIRCRESAHA.110.226357. Epub 2010 Jul 22.

  PMID: 20651284 BACKGROUND

• Jansen F, Yang X, Proebsting S, Hoelscher M, Przybilla D, Baumann K, Schmitz T, Dolf A, Endl E, Franklin BS, Sinning JM, Vasa-Nicotera M, Nickenig G, Werner N. MicroRNA expression in circulating microvesicles predicts cardiovascular events in patients with coronary artery disease. J Am Heart Assoc. 2014 Oct 27;3(6):e001249. doi: 10.1161/JAHA.114.001249.

  PMID: 25349183 BACKGROUND

• Goren Y, Kushnir M, Zafrir B, Tabak S, Lewis BS, Amir O. Serum levels of microRNAs in patients with heart failure. Eur J Heart Fail. 2012 Feb;14(2):147-54. doi: 10.1093/eurjhf/hfr155. Epub 2011 Nov 25.

  PMID: 22120965 BACKGROUND

• Mignani R, Pieruzzi F, Berri F, Burlina A, Chinea B, Gallieni M, Pieroni M, Salviati A, Spada M. FAbry STabilization indEX (FASTEX): an innovative tool for the assessment of clinical stabilization in Fabry disease. Clin Kidney J. 2016 Oct;9(5):739-47. doi: 10.1093/ckj/sfw082. Epub 2016 Sep 9.

  PMID: 27679722 BACKGROUND

• Cammarata G, Scalia S, Colomba P, Zizzo C, Pisani A, Riccio E, Montalbano M, Alessandro R, Giordano A, Duro G. A pilot study of circulating microRNAs as potential biomarkers of Fabry disease. Oncotarget. 2018 Jun 8;9(44):27333-27345. doi: 10.18632/oncotarget.25542. eCollection 2018 Jun 8.

  PMID: 29937989 BACKGROUND

• Baig S, Edward NC, Kotecha D, Liu B, Nordin S, Kozor R, Moon JC, Geberhiwot T, Steeds RP. Ventricular arrhythmia and sudden cardiac death in Fabry disease: a systematic review of risk factors in clinical practice. Europace. 2018 Sep 1;20(FI2):f153-f161. doi: 10.1093/europace/eux261.

  PMID: 29045633 BACKGROUND

• Nordin S, Kozor R, Baig S, Abdel-Gadir A, Medina-Menacho K, Rosmini S, Captur G, Tchan M, Geberhiwot T, Murphy E, Lachmann R, Ramaswami U, Edwards NC, Hughes D, Steeds RP, Moon JC. Cardiac Phenotype of Prehypertrophic Fabry Disease. Circ Cardiovasc Imaging. 2018 Jun;11(6):e007168. doi: 10.1161/CIRCIMAGING.117.007168.

  PMID: 29853467 BACKGROUND

• Nordin S, Kozor R, Medina-Menacho K, Abdel-Gadir A, Baig S, Sado DM, Lobascio I, Murphy E, Lachmann RH, Mehta A, Edwards NC, Ramaswami U, Steeds RP, Hughes D, Moon JC. Proposed Stages of Myocardial Phenotype Development in Fabry Disease. JACC Cardiovasc Imaging. 2019 Aug;12(8 Pt 2):1673-1683. doi: 10.1016/j.jcmg.2018.03.020. Epub 2018 May 16.

  PMID: 29778854 BACKGROUND

• Camporeale A, Bandera F, Pieroni M, Pieruzzi F, Spada M, Bersano A, Econimo L, Lanzillo C, Rubino M, Mignani R, Motta I, Olivotto I, Tanini I, Valaperta R, Chow K, Baroni I, Boveri S, Graziani F, Pica S, Tondi L, Guazzi M, Lombardi M. Effect of Migalastat on cArdiac InvOlvement in FabRry DiseAse: MAIORA study. J Med Genet. 2023 Sep;60(9):850-858. doi: 10.1136/jmg-2022-108768. Epub 2023 Jan 20.

  PMID: 36669872 DERIVED

Biospecimen

Retention: SAMPLES WITHOUT DNA

Blood samples for Troponin T, NT-proBNP and microRNA assay

MeSH Terms

Conditions

Fabry Disease; Heart Diseases; Cardiomyopathies

Condition Hierarchy (Ancestors)

Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Vascular Diseases; Cardiovascular Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolism, Inborn Errors; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Study Officials

• Antonia Camporeale, MD, PhD

  IRCCS Policlinico S. Donato

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: February 10, 2019
• First Posted: February 12, 2019
• Study Start: January 10, 2018
• Primary Completion: January 22, 2021
• Study Completion: January 22, 2021
• Last Updated: March 18, 2021

Record last verified: 2021-03

Locations

IT (1)