Establishment of Biomarkers for Fabry Disease

Fabry Disease Clinical Trial

Official title:

Establishment of Biomarkers for Fabry Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01165697
• Other study ID #: 2009H0137
• Status: Completed
• Phase: N/A
• First received: July 16, 2010
• Last updated: January 11, 2017
• Start date: July 2010
• Est. completion date: December 2014

Study information

• Verified date: January 2017
• Source: Ohio State University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Observational

Clinical Trial Summary

Fabry disease, an x-linked recessive lysosomal storage disease (LSD) is commonly recognized as a cause of renal failure in involved men and more recently recognized in women too. Women are involved in significant numbers and with complications, as are men, of vascular disease. This manifests as unexpected strokes in young adults. We have morphologic evidence that storage-endotheliopathy induced microvascular disease is the cause of cardiopathy and of cryptogenic strokes, and that storage endotheliopathy starts in early life, probably before birth. Based on our earlier work with other endotheliopathies such as diabetes mellitus, Susac syndrome, and hypertension, we will find and study patients using unique methods, neuro-retinal fluorescein angiography (NRFA), that we have developed for this purpose. These methods include NRFA to demonstrate capillary perfusion in the optic nerve head and retinal quadrants. We anticipate, based on our earlier experience with other endotheliopathies, that we will show more vascular pathology earlier than previously reported. Using epidemiologic and genetic tools we will find more patients than previously known or expected. It will offer opportunity for earlier diagnosis, prognosis, and response to enzyme replacement therapy.

We hypothesize that Fabry disease is a poorly recognized and poorly characterized cause of microvascular disease and cryptogenic strokes in young women and men. Neuroretinal capillary perfusion abnormalities in Fabry disease will be predictive of equivalent vascular disease in kidney, heart, brain and other organs, and further that it will be responsive to change induced by enzyme replacement therapy treatment.

Description:

Specific Aims

Specific Aim 1. To demonstrate the specificity and sensitivity of the diagnostic capabilities of a neuroretinal examination which includes slit lamp and fundoscopy, and NRFA for the diagnosis of Fabry disease on a subject population of identified FD patients.

Specific Aim 2. To show capillary perfusion abnormalities in optic nerve and retina using neuroretinal fluorescein angiography in patients with Fabry disease and compare these to renal (measured by GFR).

Specific Aim 3. To show that the change in capillary perfusion studies when compared to baseline in response to enzyme replacement therapy treatment over time, as a manifestation of tissue burden and prognosis is a more sensitive biomarker of the extent of patient disease than corneal keratopathy.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 4
• Est. completion date: December 2014
• Est. primary completion date: July 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Fabry patient

• evidence of angiopathy (renal, cardiac, or ocular)

• Patients above the age of 18

Exclusion Criteria:

• Patients unable or unwilling to provide written informed consent will not be recruited

• Patients who are below the age of 18

• Patients who have not or will not be undergoing Fluorescein angiography

• Allergy to fluorescein

• Pregnant women and fetuses are exclude from the study due to risks related to fluorescein and no direct benefit to the pregnant woman and fetus

Study Design

Observational Model: Case-Only, Time Perspective: Prospective

Related Conditions & MeSH terms

• Fabry Disease

Intervention

Other:
• Fluorescein angiography
Fluorescein angiography once every 6 months for 3 years

Locations

Country	Name	City	State
United States	Eye and Ear Institute	Columbus	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
Ohio State University	Genzyme, a Sanofi Company

Country where clinical trial is conducted

United States, 

References & Publications (18)

Caggana M, Ashley GA, Desnick RJ, Eng CM. Fabry disease: molecular carrier detection and prenatal diagnosis by analysis of closely linked polymorphisms at Xq22.1. Am J Med Genet. 1997 Aug 22;71(3):329-35. — View Citation

Cook SC, Ferketich AK, Raman SV. Myocardial ischemia in asymptomatic adults with repaired aortic coarctation. Int J Cardiol. 2009 Mar 20;133(1):95-101. doi: 10.1016/j.ijcard.2007.12.015. — View Citation

Eng CM, Fletcher J, Wilcox WR, Waldek S, Scott CR, Sillence DO, Breunig F, Charrow J, Germain DP, Nicholls K, Banikazemi M. Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis. 2007 Apr;30(2):184-92. — View Citation

Eng CM, Germain DP, Banikazemi M, Warnock DG, Wanner C, Hopkin RJ, Bultas J, Lee P, Sims K, Brodie SE, Pastores GM, Strotmann JM, Wilcox WR. Fabry disease: guidelines for the evaluation and management of multi-organ system involvement. Genet Med. 2006 Sep;8(9):539-48. Review. — View Citation

Gilbert-Barness E. Review: Metabolic cardiomyopathy and conduction system defects in children. Ann Clin Lab Sci. 2004 Winter;34(1):15-34. Review. — View Citation

Glass RB, Astrin KH, Norton KI, Parsons R, Eng CM, Banikazemi M, Desnick RJ. Fabry disease: renal sonographic and magnetic resonance imaging findings in affected males and carrier females with the classic and cardiac variant phenotypes. J Comput Assist Tomogr. 2004 Mar-Apr;28(2):158-68. — View Citation

Kampmann C, Wiethoff CM, Perrot A, Beck M, Dietz R, Osterziel KJ. The heart in Anderson Fabry disease. Z Kardiol. 2002 Oct;91(10):786-95. Review. — View Citation

Knowles SR, Weber EA, Berbrayer CS. Allergic reaction to fluorescein dye: successful one-day desensitization. Can J Ophthalmol. 2007 Apr;42(2):329-30. — View Citation

Mehta A, Ginsberg L; FOS Investigators.. Natural history of the cerebrovascular complications of Fabry disease. Acta Paediatr Suppl. 2005 Mar;94(447):24-7; discussion 9-10. — View Citation

Michels H, Mengel E. Lysosomal storage diseases as differential diagnoses to rheumatic disorders. Curr Opin Rheumatol. 2008 Jan;20(1):76-81. doi: 10.1097/BOR.0b013e3282f169fe. Review. — View Citation

Mitsias P, Levine SR. Cerebrovascular complications of Fabry's disease. Ann Neurol. 1996 Jul;40(1):8-17. — View Citation

Strujic BJ, Jeren T. Fabry disease--a diagnostic and therapeutic problem. Ren Fail. 2005;27(6):783-6. — View Citation

Svarstad E, Bostad L, Kaarbøe O, Houge G, Tøndel C, Lyngdal PT, Iversen BM. Focal and segmental glomerular sclerosis (FSGS) in a man and a woman with Fabry's disease. Clin Nephrol. 2005 May;63(5):394-401. — View Citation

Tøndel C, Bostad L, Hirth A, Svarstad E. Renal biopsy findings in children and adolescents with Fabry disease and minimal albuminuria. Am J Kidney Dis. 2008 May;51(5):767-76. doi: 10.1053/j.ajkd.2007.12.032. Erratum in: Am J Kidney Dis. 2009 Mar;53(3):567. — View Citation

Tøndel C, Bostad L, Laegreid LM, Houge G, Svarstad E. Prominence of glomerular and vascular changes in renal biopsies in children and adolescents with Fabry disease and microalbuminuria. Clin Ther. 2008;30 Suppl B:S42. — View Citation

Tøndel C, Laegreid LM, Hirth A, Houge G, Månsson JE, Søvik O. [Intravenous enzyme substitution therapy in children with Fabry's disease]. Tidsskr Nor Laegeforen. 2003 Dec 4;123(23):3388-90. Norwegian. — View Citation

Whybra C, Kampmann C, Willers I, Davies J, Winchester B, Kriegsmann J, Brühl K, Gal A, Bunge S, Beck M. Anderson-Fabry disease: clinical manifestations of disease in female heterozygotes. J Inherit Metab Dis. 2001 Dec;24(7):715-24. — View Citation

Wilcox WR, Oliveira JP, Hopkin RJ, Ortiz A, Banikazemi M, Feldt-Rasmussen U, Sims K, Waldek S, Pastores GM, Lee P, Eng CM, Marodi L, Stanford KE, Breunig F, Wanner C, Warnock DG, Lemay RM, Germain DP; Fabry Registry.. Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry. Mol Genet Metab. 2008 Feb;93(2):112-28. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Presence of specific findings commonly associated with Fabry's disease using neuroretinal examination		every 6 months, for up to 3 years	No
Secondary	Capillary perfusion abnormalities in optic nerve and retina		every 6 months, for up to 3 years	No