Alternative Dosing and Regimen of Replagal to Treat Fabry Disease

NCT ID: NCT00075244

Last Updated: 2008-03-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 25 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2004-01-31
• Study Completion Date: 2005-11-30

Brief Summary

The main goal of this study is to assess the pharmacodynamic effects of different or more frequent doses of Replagal compared to the standard dosing regimen. Replagal is a genetically engineered form of alpha-Galactosidase A, an enzyme that normally breaks down a fatty substance called globotriaosylceramide (Gb(3)). In patients with Fabry disease, GB(3) does not function properly and therefore builds up causing problems with the kidneys, heart, nerves, and blood vessels.

Male patients 18 years of age or older with Fabry disease who are not on dialysis and have not received a kidney transplant may be eligible for this study.

Participants are randomly assigned to receive one of the following five regimens of Replagal infusions, given through a vein over 20 to 80 minutes:

0.1 mg/kg body weight every week

0.2 mg/kg body weight every week

0.2 mg/kg body weight every other week

0.4 mg/kg body weight every week

0.4 mg/kg body wieght every other week

In the US, the infusions are given at the NIH Clinical Center. Vital signs are measured before, immediately after, and 1 hour after each infusion.

Baseline evaluations are done on an inpatient or outpatient basis. Baseline tests include a check of vital signs (temperature, respiratory rate, pulse rate, and blood pressure); physical examination; laboratory tests; and review of treatment side effects. Evaluations are also done at every infusion visit, and 1 week and 1 month after the last infusion.

Safety evaluations are done periodically and include vital sign measurements, physical examination, blood and urine tests, review of drug side effects, electrocardiogram (ECG), Holder monitor (2 hour ECG), and QSART (NIH only). The QSART (quantitative sudomotor axon reflex test) measures the amount of sweat in a particular area of skin, mostly the forearm. For this test, a cup partly filled with a liquid is strapped on the arm. A weak electric current is turned on, stimulating the sweat glands, and the amount of sweat produced is measured. There is a tingling sensation when the current is turned on.

Patients who complete the study will be offered the opportunity of receiving Replagal for 6 months in an extension study.

Detailed Description

OBJECTIVES: The goal of this study is to assess the pharmacodynamic effects of alternative weekly and every two week dosing regimens of Replagal (agalsidase alfa) in comparison to the current standard Replagal treatment regimen of 0.2 mg/kg given intravenously every two weeks.

STUDY POPULATION: Hemizygous males with Fabry disease who are 18 years of age or older.

DESIGN: This is a randomized, open-label study that will assess the pharmacodynamics and pharmacokinetics of five different dosing regimens of enzyme replacement therapy with Replagal. The effects of dose as well as dosing frequency will be evaluated and compared to the standard Replagal regimen.

OUTCOME MEASURES: The pharmacodynamic parameter to be assessed is plasma globotriaosylceramide (Gb3). The hypothesis to be tested is the role that frequency (weekly) and/or dose (0.1 to 0.4 mg/kg) of Replagal will play in pharmacodynamics as measured by reductions in plasma Gb3 compared to the current dose and frequency of 0.2 mg/kg given every two weeks. Clinical parameters including sweating, heart rate variability, proteinuria, severity of neuropathic pain, pain and anti-diarrheal medication usage, frequency and severity of abdominal pain, and frequency of diarrhea also will be assessed.

Conditions

Fabry Disease

Study Design

• Primary Study Purpose: TREATMENT

Interventions

Replagal

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

Subject is a male hemizygote, age 18 years or older, with confirmed diagnosis of Fabry Disease. Diagnosis of Fabry disease may be confirmed by proof of a mutation of the alpha-Galactosidase A gene compatible with Fabry Disease and/or a deficiency of alpha-Galactosidase A (less than 4.0 nmol/mL/hour in plasma or serum or less than 8% of average mean normal in leukocytes).

Subject must have one or more clinical manifestations of Fabry disease including neuropathic pain, angiokeratoma, corneal verticillata, cardiomyopathy, hypo- or anhydrosis, abdominal pain and/or diarrhea, serum creatinine greater than 1.0 mg/dl or proteinuria greater than 300 mg/24 hours.

Subject must have voluntarily signed an Institutional Review Board (IRB) approved informed consent form after all relevant aspects of the study have been explained and discussed with the subject.

Exclusion Criteria

Subject has been previously treated with Replagal or any other enzyme replacement therapy for Fabry Disease. If the patient has previously been treated with Replagal or another enzyme replacement therapy then they must have been off the therapy for at least 30 days and must have a Day-14 antibody blood sample drawn and that test must be negative for anti-agalsidase alfa IgG and IgE antibodies and not experienced a prior severe infusion reactions with prior enzyme replacement therapy.

Subject has been enrolled in another clinical investigative study in the past 30 days.

Subject is unable to give informed consent or is deemed unable to comply with all aspects of the clinical trial.

Subject has plasma Gb(3) drawn on Day -14 less than 4.0 nmol/mL.

Subject is undergoing dialysis or who has received a renal transplant.

Subjects who cannot tolerate the study procedures or who are unable or unwilling to travel to the study center as required by this protocol.

Subjects with an inter-current medical condition that would render them unsuitable for the study (e.g. HIV, diabetes) by confounding an assessment of the effects of the experimental therapy and its adverse events.

Subjects who in the opinion of the investigator (for whatever reason) are thought to be unsuitable for the study.

• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Neurological Disorders and Stroke (NINDS)

NIH

Sponsor Role: lead

Locations

National Institute of Neurological Disorders and Stroke (NINDS)

Bethesda, Maryland, United States

Countries

United States

References

Brady RO, Gal AE, Bradley RM, Martensson E, Warshaw AL, Laster L. Enzymatic defect in Fabry's disease. Ceramidetrihexosidase deficiency. N Engl J Med. 1967 May 25;276(21):1163-7. doi: 10.1056/NEJM196705252762101. No abstract available.

Reference Type: BACKGROUND

PMID: 6023233 (View on PubMed)

Brady RO, Schiffmann R. Clinical features of and recent advances in therapy for Fabry disease. JAMA. 2000 Dec 6;284(21):2771-5. doi: 10.1001/jama.284.21.2771.

Reference Type: BACKGROUND

PMID: 11105184 (View on PubMed)

Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999 Jan 20;281(3):249-54. doi: 10.1001/jama.281.3.249.

Reference Type: BACKGROUND

PMID: 9918480 (View on PubMed)

Other Identifiers

04-N-0073

Identifier Type: -

Identifier Source: secondary_id

040073

Identifier Type: -

Identifier Source: org_study_id