Clinical trial NCT00864851: Safety and Efficacy Study of Several Replagal Dosing Regimens on Cardiac Function in Adults With Fabry Disease
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Fabry Disease
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2009-03-19
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change From Baseline to Month 12 in Left Ventricular Mass Indexed to Height (LVMI)
timeFrame: Baseline, Month 12 (Week 53)
Secondary outcomes:
measure: Change From Baseline to Month 12 in Maximal Oxygen Consumption (VO2 Max) at Peak Exercise
timeFrame: Baseline, Month 12 (Week 53)
measure: Change From Baseline to Month 12 in Distance Walked in 6-Minute Walk Test (6MWT)
timeFrame: Baseline, Month 12 (Week 53)
measure: Change From Baseline to Month 12 in the Minnesota Living With Heart Failure Questionnaire (MLHF-Q) Summary Score
timeFrame: Baseline, Month 12 (Week 53)
measure: Change From Baseline to Month 12 in New York Heart Association (NYHA) Functional Class
timeFrame: Baseline, Month 12 (Week 53)
measure: Change From Baseline to Month 12 in Plasma Globotriaosylceramide (GB3)
timeFrame: Baseline, Month 12 (Week 53)
measure: Change From Baseline to Month 12 in Estimated Glomerular Filtration Rate (eGFR)
timeFrame: Baseline, Month 12 (Week 53)
measure: Change From Baseline to Month 12 in Urinary Albumin/Creatinine (A/Cr) Ratio
timeFrame: Baseline, Month 12 (Week 53)
measure: Safety Evaluation
timeFrame: 56 Weeks
Other outcomes:
Locations:
city: Tucson
country: United States
facility: AKDHC Tucson Access Center
state: Arizona
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: New York
country: United States
facility: New York Unversity School of Medicine
state: New York
city: Springfield
country: United States
facility: O & O Alpan, LLC
state: Virginia
city: Parkville
country: Australia
facility: The Royal Melbourne Hospital
state: Victoria
city: Prague
country: Czechia
facility: The Charles University Hospital
city: Turku
country: Finland
facility: Turku University Central Hospital
city: Asuncion
country: Paraguay
facility: Gobemador Irala y Coronel Lopez - Barrio Sojania
city: Krakow
country: Poland
facility: Szpital Uniwersytecki w Krakowie
city: Warsaw
country: Poland
facility: Instytut Kardiologii
city: Slovenj Gradec
country: Slovenia
facility: General Hospital Slovenj Gradec
city: Salford
country: United Kingdom
facility: Salford Royal NHS Foundation Trust
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Malek LA, Chojnowska L, Spiewak M, Klopotowski M, Misko J, Petryka J, Milosz B, Ruzyllo W. Cardiac magnetic resonance imaging in patients with Fabry's disease. Kardiol Pol. 2010 Aug;68(8):929-34.