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Low-dose agalsidase beta treatment in male pediatric patients with Fabry disease: A 5-year randomized controlled trial
U. Ramaswami, DG. Bichet, LA. Clarke, G. Dostalova, A. Fainboim, A. Fellgiebel, CM. Forcelini, K. An Haack, RJ. Hopkin, M. Mauer, B. Najafian, CR. Scott, SP. Shankar, BL. Thurberg, C. Tøndel, A. Tylki-Szymanska, B. Bénichou, FA. Wijburg,
Jazyk angličtina Země Spojené státy americké
Typ dokumentu klinické zkoušky, fáze III, časopisecké články, multicentrická studie, randomizované kontrolované studie, Research Support, N.I.H., Extramural, práce podpořená grantem
- MeSH
- alfa-galaktosidasa terapeutické užití MeSH
- dítě MeSH
- enzymová substituční terapie statistika a číselné údaje MeSH
- Fabryho nemoc farmakoterapie MeSH
- izoenzymy terapeutické užití MeSH
- kůže chemie patologie MeSH
- lidé MeSH
- mladiství MeSH
- předškolní dítě MeSH
- trihexosylceramidy analýza MeSH
- výsledek terapie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Research Support, N.I.H., Extramural MeSH
BACKGROUND: Fabry disease is a rare, X-linked, lifelong progressive lysosomal storage disorder. Severely deficient α-galactosidase A activity in males is associated with the classic phenotype with early-onset, multisystem manifestations evolving to vital organ complications during adulthood. We assessed the ability of 2 low-dose agalsidase beta regimens to lower skin, plasma, and urine globotriaosylceramide (GL-3) levels, and influence clinical manifestations in male pediatric Fabry patients. METHODS: In this multicenter, open-label, parallel-group, phase 3b study, male patients aged 5-18 years were randomized to receive agalsidase beta at 0.5 mg/kg 2-weekly (n = 16) or 1.0 mg/kg 4-weekly (n = 15) for 5 years. All had plasma/urine GL-3 accumulation but no clinically evident organ involvement. The primary outcome was GL-3 accumulation in superficial skin capillary endothelium (SSCE). RESULTS: The mean age was 11.6 (range: 5-18) years and all but one of the 31 patients had classic GLA mutations. In the overall cohort, shifts from non-0 to 0-scores for SSCE GL-3 were significant at years 1, 3, and 5, but results were variable. Plasma GL-3 normalized and urine GL-3 reduced substantially. Higher anti-agalsidase beta antibody titers were associated with less robust SSCE GL-3 clearance and higher urine GL-3 levels. Renal function remained stable and normal. Most Fabry signs and symptoms tended to stabilize; abdominal pain was significantly reduced (-26.3%; P = .0215). No new clinical major organ complications were observed. GL-3 accumulation and cellular and vascular injury were present in baseline kidney biopsies (n = 7). Treatment effects on podocyte GL-3 content and foot process width were highly variable. Fabry arteriopathy overall increased in severity. Two patients withdrew and 2 had their agalsidase beta dose increased. CONCLUSIONS: Our findings increase the limited amount of available data on long-term effects of enzyme replacement therapy in pediatric, classic Fabry patients. The low-dose regimens studied here over a period of 5 years did not demonstrate a consistent benefit among the patients in terms of controlling symptomatology, urine GL-3 levels, and pathological histology. The current available evidence supports treatment of pediatric, classic male Fabry patients at the approved agalsidase beta dose of 1.0 mg/kg 2-weekly if these patients are considered for enzyme replacement therapy with agalsidase beta.
Child and Family Research Institute University of British Columbia Vancouver BC Canada
Department of Pathology University of Washington Seattle WA USA
Department of Psychiatry and Psychotherapy University Medical Center Mainz Mainz Germany
Departments of Human Genetics and Ophthalmology Emory University School of Medicine Decatur GA USA
Departments of Pediatrics and Clinical Medicine Haukeland University Hospital Bergen Norway
Departments of Pediatrics and Medicine University of Minnesota Minneapolis MN USA
Formerly Sanofi Genzyme Saint Germain en Laye Cedex France
Citace poskytuje Crossref.org
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