Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Enzyme Replacement Therapy in Fabry Disease

This study has been terminated.
(Difficulties in the patient's enrolment)
Sponsor:
Information provided by (Responsible Party):
Mario Negri Institute for Pharmacological Research
ClinicalTrials.gov Identifier:
NCT00149318
First received: September 6, 2005
Last updated: November 7, 2014
Last verified: November 2014

September 6, 2005
November 7, 2014
December 2002
October 2008   (final data collection date for primary outcome measure)
Not Provided
Not Provided
Complete list of historical versions of study NCT00149318 on ClinicalTrials.gov Archive Site
Not Provided
Not Provided
Not Provided
Not Provided
 
Enzyme Replacement Therapy in Fabry Disease
Evaluation of the Long Term Efficacy of Enzyme Replacement Therapy in Fabry Disease

Fabry disease is an X-linked rare metabolic disease, caused by a deficient activity of the hydrolase α-Galactosidase A, and characterized by a progressive and systematic deposition of glycosphingolipids in many organs.

The disease is most severe in affected males. In the classic form (where the enzyme activity is absent) the clinical findings are represented by pain and paresthesias in the extremities, vessel ectasia (called angiokeratoma) in skin and mucous membranes, and hypohidrosis (a reduced sweating) during childhood or adolescence. Corneal and lenticular opacities may be present. Proteinuria, renal impairment,cardiac and neurological lesions develop with time, together with hypertension. When end stage renal disease occurs, dialysis or renal transplantation may be necessary. In heterozygous females a residual enzymatic activity may be demonstrated and they usually have asymptomatic or later onset disease manifestations, although rarely they could develop a disease as severe as in males.

A cardiac and a renal variant, where the heart and kidney are the only organs involved by the disease have been described too.

The recombinant human α-galactosidase A is now available for patients. Infusions of the enzyme replacement treatment have been demonstrated to be safe and effective. This study wants to evaluate the long term efficacy of enzyme replacement therapy in patients with Fabry disease and renal involvement.

Clinical period evaluations together with a genetic counselling will be offered to each patient.

INTRODUCTION Fabry disease is an X-linked error of glycosphingolipid catabolism caused by the deficient activity of the lysosomal hydrolase α-galactosidase A (α-gal A) in tissues and fluids of affected hemizygous males; most heterozygous females have an intermediate level of enzymatic activity. The enzymatic defect leads to a systemic deposition of glycosphingolipids, predominantly globotriaosylceramide (Gb3), in body fluids and in the lysosomes of endothelial, perithelial, and smooth-muscle cells of blood vessels. Deposition also occurs in ganglion cells.

Clinical manifestations in classically affected hemizygotes (with absent α-gal A activity), include pain and paresthesias in the extremities, vessel ectasia (angiokeratoma) in skin and mucous membranes, and hypohidrosis during childhood or adolescence. Corneal and lenticular opacities are early findings. With increasing age, proteinuria and renal impairment lead to hypertension and uremia. Renal failure typically occurs in the third-fifth decades of life, and these patients need chronic hemodialysis and/or renal transplantation.

Atypical hemizygotes with residual α-gal A activity may be asymptomatic or have late-onset, mild disease manifestations primarily limited to the heart (the "cardiac variant"). Recently a renal variant has been identified too. Heterozygous females may have an attenuated form of the disease.The most frequent clinical finding in females is the characteristic whorl-like corneal epithelial dystrophy. They usually are asymptomatic, although rarely can be severely affected as hemizygous males.

In the kidney accumulation of glycosphingolipids appear in the sequence in endothelial and epithelial cells of the glomerulus and of Bowman's space, epithelium of the loops of Henle and in distal tubules till proximal tubules, interstitial histiocytes and fibrocytes. Lipid-laden distal tubular epithelial cells desquamate and may be detected in the urinary sediment.

Renal blood vessels may be involved progressively and extensively. An early finding is arterial fibrinoid deposits. Other histologic renal findings are severe arteriolar sclerosis, glomerular atrophy and fibrosis, pseudotubular proliferation of residual glomerular epithelium, tubular atrophy and diffuse interstitial fibrosis. Preliminary studies of enzyme replacement therapy demonstrate that periodic infusions of recombinant human α-galactosidase A are safe and effective in patients with Fabry disease.

The purpose of this study is to evaluate the long term efficacy of enzyme replacement therapy in patients with Fabry disease and renal involvement.

AIM Primary

  • To evaluate the effect of enzyme replacement therapy on the rate of decline in the glomerular filtration rate (GFR, measured by inulin clearance) in Fabry patients with renal involvement
  • To evaluate the biological activity of recombinant human galactosidase in terms of clearance of plasma Gb3 (that is directly correlated with renal endothelial glycosphingolipid clearance) Secondary

To evaluate the effect of enzyme replacement therapy on:

  • 24-hour urinary protein excretion
  • renal plasma flow (PAH renal clearance)
  • glomerular perm-selectivity (fractional dextran clearances)
  • end stage renal failure, kidney transplantation or death
  • systolic and diastolic blood pressure
  • cardiac anomalies (left ventricular hypertrophy, arrhythmias, conduction anomalies)
  • cutaneous anomalies
  • ocular anomalies DESIGN Twenty patients (males and females) with Fabry disease, and renal involvement, referred to the SMIMAF - Studio Multicentrico Italiano sulla Malattia di Anderson-Fabry - will be enrolled in the study.
Observational
Observational Model: Case-Only
Time Perspective: Prospective
Not Provided
Retention:   Samples With DNA
Description:

Whole blood on EDTA. Serum. Urine samples.

Non-Probability Sample

Patients with Fabry disease.

Fabry Disease
Other: Biochemical analyses.
Biochemical analyses.
Patients with Fabry disease
Intervention: Other: Biochemical analyses.
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
2
November 2014
October 2008   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • age ≥ 16 years and ≤ 65 years
  • clinical diagnosis of Fabry disease, confirmed by α-galactosidase A assay and detection of mutation in α-GalA gene
  • serum creatinine ≥ 1.4 mg/dl (females) and ≥ 1.6 mg/dl (males) and/or proteinuria ≥ 0.4 g/24h
  • written informed consent

Exclusion Criteria:

  • any clinically relevant condition that may affect study participation and/or study results
  • inability to fully understand the purpose and the risks of the study
Both
16 Years to 65 Years
No
Contact information is only displayed when the study is recruiting subjects
Italy
 
NCT00149318
FABRY DISEASE
No
Mario Negri Institute for Pharmacological Research
Mario Negri Institute for Pharmacological Research
Not Provided
Principal Investigator: Erica Daina, MD Mario Negri Institute
Mario Negri Institute for Pharmacological Research
November 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP