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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Multi-Center, Open-Label, Randomized Study Evaluating the Safety and Efficacy of Three Dosing Regimens of Replagal Enzyme Replacement Therapy in Adult Patients With Fabry Disease

Conditions
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Fabry Disease

Intervention / Treatment
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* Biological: Replagal


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Replagal 0.2 mg/kg, IV, every other week<br>Patients randomized to receive Replagal 0.2 mg/kg via intravenous infusion every other week for 52 weeks. | Biological: Replagal<br>* Intravenous (IV) infusion for 12 months<br>* Other names: algasidase alfa;|
| Active Comparator: Replagal 0.2 mg/kg, IV, weekly<br>Patients randomized to receive Replagal 0.2 mg/kg via intravenous infusion every week for 52 weeks. | Biological: Replagal<br>* Intravenous (IV) infusion for 12 months<br>* Other names: algasidase alfa;|
| Active Comparator: Replagal 0.4 mg/kg, IV, weekly<br>Patients randomized to receive Replagal 0.4 mg/kg via intravenous infusion every week for 52 weeks. | Biological: Replagal<br>* Intravenous (IV) infusion for 12 months<br>* Other names: algasidase alfa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Month 12 in Left Ventricular Mass Indexed to Height (LVMI) | Left ventricular mass (LVM) was measured through echocardiography. | Baseline, Month 12 (Week 53) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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. | 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. | 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. | Baseline, Month 12 (Week 53) | 
| Change From Baseline to Month 12 in Plasma Globotriaosylceramide (GB3) |  | Baseline, Month 12 (Week 53) | 
| Change From Baseline to Month 12 in Estimated Glomerular Filtration Rate (eGFR) | Renal function was assessed by an evaluation of change from baseline to Month 12 in eGFR as calculated using the Modification of Diet for Renal Disease (MDRD) equation. | Baseline, Month 12 (Week 53) | 
| Change From Baseline to Month 12 in Urinary Albumin/Creatinine (A/Cr) Ratio |  | Baseline, Month 12 (Week 53) | 
| Safety Evaluation | Adverse events were collected throughout the study, from the time of informed consent to approximately 30 days post-final infusion. | 56 Weeks |