Effect of Migalastat on Cardiac Involvement in Fabry Disease

Heart Diseases Clinical Trial

— MAIORA  

Official title:

Effect of Migalastat on Cardiac Involvement in Fabry Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03838237
• Other study ID #: 148/int/2017
• Status: Completed
• Start date: January 10, 2018
• Est. completion date: January 22, 2021

Study information

• Verified date: March 2021
• Source: Ospedale San Donato
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 18
• Est. completion date: January 22, 2021
• Est. primary completion date: January 22, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Fabry Disease
• Heart Diseases

Intervention

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

Locations

Country	Name	City	State
Italy	IRCCS Policlinico San Donato	San Donato Milanese	Milano

Sponsors (3)

Lead Sponsor	Collaborator
Ospedale San Donato	Amicus Therapeutics, Institute of Biomedicine and Molecular Immunology - CNR

Country where clinical trial is conducted

Italy, 

References & Publications (37)

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. — View Citation

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. Epub 2006 Mar 29. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Fichtlscherer S, De Rosa S, Fox H, Schwietz T, Fischer A, Liebetrau C, Weber M, Hamm CW, Röxe T, Müller-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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

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-ß: data from the Fabry Registry. Genet Med. 2013 Dec;15(12):958-65. doi: 10.1038/gim.2013.53. Epub 2013 May 23. — View Citation

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. — View Citation

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. — View Citation

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. Erratum in: J Med Genet. 2018 Apr 16;:. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Koeppe S, Neubauer H, Breunig F, Weidemann F, Wanner C, Sandstede J, Machann W, Hahn D, Köstler 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. — View Citation

Krämer 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. — View Citation

Krämer J, Niemann M, Störk 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. — View Citation

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. — View Citation

Linhart A, Elliott PM. The heart in Anderson-Fabry disease and other lysosomal storage disorders. Heart. 2007 Apr;93(4):528-35. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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;16:99. doi: 10.1186/s12968-014-0099-4. — View Citation

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. — View Citation

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. — View Citation

Thompson RB, Chow K, Khan A, Chan A, Shanks M, Paterson I, Oudit GY. T1 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. — View Citation

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. — View Citation

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. Epub 2003 Sep 2. — View Citation

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. — View Citation

* Note: There are 37 references in all — Click here to view all references

Outcome

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