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Immune Response in Subjects With Fabry Disease Who Are Switching From Agalsidase Alfa to Agalsidase Beta

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01745185
Recruitment Status : Completed
First Posted : December 10, 2012
Last Update Posted : April 4, 2017
Information provided by (Responsible Party):
O & O Alpan LLC

Tracking Information
First Submitted Date December 5, 2012
First Posted Date December 10, 2012
Last Update Posted Date April 4, 2017
Actual Study Start Date June 2012
Actual Primary Completion Date April 7, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: December 7, 2012)
Monitoring antibody formation against agalsidase alfa and beta [ Time Frame: 12 months ]
Blood samples will be collected prior to infusion (screening & month 12). At baseline, antibodies against agalsidase alfa and beta measured, and at 12 months, antibodies against agalsidase beta will be measured by ELISA technique and will be isotyped immunoglobulins (IgG, IgA, IgM, or IgE). Positive samples will subsequently tested for enzyme neutralizing activity using an in vitro assay. Antibody measurements will be done by Shire Human Genetics Therapies, INC.
Original Primary Outcome Measures Same as current
Change History
Current Secondary Outcome Measures
 (submitted: December 7, 2012)
Measurement of plasma/urine Gb3 and plasma lyso-Gb3 [ Time Frame: 12 months ]
Plasma samples collected after at least 8 hours of fasting prior to the blood draw. Plasma and urine samples (Gb3 only) analyzed using mass spectrometry. Gb3 measurements will be performed by Shire HGT.
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title Immune Response in Subjects With Fabry Disease Who Are Switching From Agalsidase Alfa to Agalsidase Beta
Official Title Immune Response in Subjects With Fabry Disease Who Are Switching From Agalsidase Alfa to Agalsidase Beta
Brief Summary This study is a prospective active comparator study to assess the immune response elicited by human recombinant agalsidase therapy in subjects who are switching from agalsidase alfa to agalsidase beta with Fabry disease. Fabry disease is an X-linked lysosomal storage disorder, due to deficient alpha-galactosidase A activity. The progressive accumulation of globotriaosylceramide (GL-3) in the lysosomes of the vascular endothelial cells of multiple organ systems like the kidneys, heart, skin, and brain, leads to a microvascular disease. In Fabry disease, nephropathy dominates and renal function impairment occurs as a result of accumulation of GL-3 in renal cells
Detailed Description

Clinically, the development of an immune response is anticipated in a number of patients treated with any recombinant human proteins and suggested to be more common especially when the native protein is deficient or absent as many male patients with Fabry disease.

The immune response that results in the development of antibodies against the infused proteins may affect the clinical outcome of enzyme replacement therapy by the development of hypersensitivity, anaphylactoid, or febrile reactions, or may lead to the development of cytokine release and a generalized inflammatory response or immune complex formation. Furthermore, the mounted immune response may lead to inactivation or degradation of the recombinant enzyme or may change the pharmacokinetic and pharmacodynamic properties of the therapeutic protein.

The different rates of antibody formation with agalsidase alfa and agalsidases beta are often attributed to differences in techniques used to measure antibody formation. However, other factors such as host, structural similarity of the infused protein and tertiary structural difference such as glycosylation may lead to differences in the immune response. Among the factors that may affect host response are also the dose and the infusion frequency. Although agalsidase alfa and beta are derived from the same complementary DNA sequence there are minor differences in glycosylation patterns, and different dosing is used, 0.2 mg per kg every other week for agalsidase alfa, 1.0 mg per kg for agalsidase beta.

The investigator hypothesize that although the observation that the antibodies exhibit in vitro neutralizing capacity may suggest the presence of a single immunogenic epitope for both human recombinant alpha-galactosidases, the immunogenicity may not be similar for both agalsidase alfa and beta, and thus the differences in immune response will be determined by the host factors and the escalating dose of infused protein.

Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Blood, Urine
Sampling Method Non-Probability Sample
Study Population 30 subjects of (7 and above) who meet eligibility criteria.
Condition Fabry Disease
Intervention Not Provided
Study Groups/Cohorts
  • Fabry disease switch group
    Subjects will include individuals with Fabry disease who are switching from agalsidase alfa to agalsidase beta
  • Control Group
    Controls will include individuals with Fabry disease who have only received agalsidase beta as treatment in their lifetime.
Publications * Bénichou B, Goyal S, Sung C, Norfleet AM, O'Brien F. A retrospective analysis of the potential impact of IgG antibodies to agalsidase beta on efficacy during enzyme replacement therapy for Fabry disease. Mol Genet Metab. 2009 Jan;96(1):4-12. doi: 10.1016/j.ymgme.2008.10.004. Epub 2008 Nov 20.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status Completed
Estimated Enrollment
 (submitted: December 7, 2012)
Original Estimated Enrollment Same as current
Actual Study Completion Date August 7, 2016
Actual Primary Completion Date April 7, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • Confirmed diagnosis of Fabry disease
  • Have been treated with ERT using recombinant human agalsidase A.

Exclusion Criteria:

  • If the diagnosis of Fabry disease is not confirmed
  • If the subject or guardian is not able to provide consent
  • Any chronic immunosuppressive state or therapy such as patients on dialysis or post-transplantation immunosuppressive therapy.
Sexes Eligible for Study: All
Ages 7 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries United States
Removed Location Countries  
Administrative Information
NCT Number NCT01745185
Other Study ID Numbers 12-CFCT-03
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party O & O Alpan LLC
Study Sponsor O & O Alpan LLC
Collaborators Not Provided
Principal Investigator: Ozlem Goker-Alpan, MD O & O Alpan LLC
PRS Account O & O Alpan LLC
Verification Date April 2017