Safety and Efficacy Study of Several Replagal Dosing Regimens on Cardiac Function in Adults With Fabry Disease

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Overview

The purpose of this study is to compare the safety and effectiveness of various doses of Replagal in patients with cardiomyopathy due to Fabry disease.

Fabry disease is an inherited, metabolic disease caused by mutations in the GALA gene. Patients with Fabry disease accumulate a complex glycosphingolipid named globotriaosylceramide (Gb3) in various tissues and organs. All organs are affected in Fabry disease but the majority of the morbidity and mortality are caused by cardiac, renal and neurological dysfunction. Accumulation of Gb3 in the heart causes hypertrophic cardiomyopathy, valvular abnormalities, arrhythmias and infarctions. Replagal has been shown to reduce Gb3 from key tissues and organs, and stabilize renal function in patients with Fabry disease. Evidence suggests that Replagal reduces left ventricular mass (LVM) and improves midwall fractional shortening (MFS) of the heart. Left ventricular hypertrophy is a major cause of morbidity and mortality in patients with Fabry disease. This is a study of the safety and effectiveness of 3 dosing regimens of Replagal in adult patients with left ventricular hypertrophy due to Fabry disease. The primary objective of the study is to compare the effects of 2 dosing regimens of Replagal (0.2 mg/kg IV every other week and 0.2 mg/kg IV weekly) on the reduction of left ventricular mass as measured by echocardiography. The secondary objectives of this study are to compare the effects of 2 dosing regimens of Replagal (0.2 mg/kg IV every other week and 0.2 mg/kg IV weekly) on each of the following: exercise tolerance; improvement in disease-specific quality of life in heart failure patients; improvement of heart failure symptoms; magnitude of reduction in Gb3; rate of decline in renal function and improvement in the severity of proteinuria/albuminuria; and safety. An alternative treatment regimen of 0.4 mg/kg Replagal IV weekly will also be explored but without formal comparison to the 0.2 mg/kg regimens. The investigation of the safety and efficacy of the 0.4 mg/kg IV weekly regimen is a secondary objective of this study.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Fabry Disease

Interventions

ReplagalBIOLOGICAL

Intravenous (IV) infusion for 12 months

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * \>18 years-old; * Male:Fabry disease confirmed by deficiency of alfa galactosidase A activity OR Female:Fabry disease confirmed by a mutation of the alfa galactosidase A gene; * ERT-naïve; * LVM/h \> 50g/m2.7 for males and \>47 g/m2.7 for females; * Negative pregnancy test at enrollment and contraception use required throughout study for female patients; * Signed informed consent; Exclusion Criteria: * Class IV heart failure; * Clinically significant hypertension; * Hemodynamically significant valvular stenosis or regurgitation; * Morbid obesity; * Known autosomal dominant sarcoplasmic contractile protein gene mutation; * Treatment with any investigational drug or device within the 30 days; * Unable to comply with the protocol as determined by the Investigator; * Positive for hepatitis B, hepatitis C or HIV

Locations (12)

AKDHC Tucson Access Center

Tucson, Arizona, United States

University of Iowa Hospitals and Clinics

Iowa City, Iowa, United States

New York Unversity School of Medicine

New York, New York, United States

Outcomes

Primary Outcomes

Change From Baseline to Month 12 in Left Ventricular Mass Indexed to Height (LVMI)

Left ventricular mass (LVM) was measured through echocardiography.

Time frame: Baseline, Month 12 (Week 53)

Secondary Outcomes

Change From Baseline to Month 12 in Maximal Oxygen Consumption (VO2 Max) at Peak Exercise

Exercise tolerance as measured by VO2 max at peak exercise using the standard exponential exercise protocol (STEEP).

Time frame: Baseline, Month 12 (Week 53)

Change From Baseline to Month 12 in Distance Walked in 6-Minute Walk Test (6MWT)

Exercise tolerance using the 6MWT was measured as the total distance walked in 6 minutes.

Time frame: Baseline, Month 12 (Week 53)

Change From Baseline to Month 12 in the Minnesota Living With Heart Failure Questionnaire (MLHF-Q) Summary Score

Quality of life (QoL) was evaluated using the MLHF-Q, version 2. The questionnaire is designed to assess the degree to which heart failure symptoms affect a patient's daily life. The summary score ranges from 0 to 105, with a score of 105 representing the highest adverse impact on a patient's QoL.

Time frame: Baseline, Month 12 (Week 53)

Change From Baseline to Month 12 in New York Heart Association (NYHA) Functional Class

The NYHA functional classification system relates symptoms to everyday activities and the patient's quality of life. NYHA Classification - The Stages of Heart Failure: Class I (Mild): No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea (shortness of breath). Class II (Mild): Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea. Class III (Moderate): Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV (Severe): Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency at rest. If any physical activity is undertaken, discomfort is increased.

Data from ClinicalTrials.gov

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