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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Shire Human Genetic Therapies, Inc.
ClinicalTrials.gov Identifier:
NCT00864851
First received: March 18, 2009
Last updated: May 19, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention Phase
Fabry Disease
Biological: Replagal
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Shire Human Genetic Therapies, Inc.:

Primary Outcome Measures:
  • Change From Baseline to Month 12 in Left Ventricular Mass Indexed to Height (LVMI) [ Time Frame: Baseline, Month 12 (Week 53) ] [ Designated as safety issue: No ]
    Left ventricular mass (LVM) was measured through echocardiography.


Secondary Outcome Measures:
  • Change From Baseline to Month 12 in Maximal Oxygen Consumption (VO2 Max) at Peak Exercise [ Time Frame: Baseline, Month 12 (Week 53) ] [ Designated as safety issue: No ]
    Exercise tolerance as measured by VO2 max at peak exercise using the standard exponential exercise protocol (STEEP).

  • Change From Baseline to Month 12 in Distance Walked in 6-Minute Walk Test (6MWT) [ Time Frame: Baseline, Month 12 (Week 53) ] [ Designated as safety issue: No ]
    Exercise tolerance using the 6MWT was measured as the total distance walked in 6 minutes.

  • Change From Baseline to Month 12 in the Minnesota Living With Heart Failure Questionnaire (MLHF-Q) Summary Score [ Time Frame: Baseline, Month 12 (Week 53) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline to Month 12 in New York Heart Association (NYHA) Functional Class [ Time Frame: Baseline, Month 12 (Week 53) ] [ Designated as safety issue: No ]

    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.


  • Change From Baseline to Month 12 in Plasma Globotriaosylceramide (GB3) [ Time Frame: Baseline, Month 12 (Week 53) ] [ Designated as safety issue: No ]
  • Change From Baseline to Month 12 in Estimated Glomerular Filtration Rate (eGFR) [ Time Frame: Baseline, Month 12 (Week 53) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline to Month 12 in Urinary Albumin/Creatinine (A/Cr) Ratio [ Time Frame: Baseline, Month 12 (Week 53) ] [ Designated as safety issue: No ]
  • Safety Evaluation [ Time Frame: 56 Weeks ] [ Designated as safety issue: Yes ]
    Adverse events were collected throughout the study, from the time of informed consent to approximately 30 days post-final infusion.


Enrollment: 44
Study Start Date: December 2008
Study Completion Date: July 2012
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Replagal 0.2 mg/kg, IV, every other week
Patients randomized to receive Replagal 0.2 mg/kg via intravenous infusion every other week for 52 weeks.
Biological: Replagal
Intravenous (IV) infusion for 12 months
Other Name: algasidase alfa
Active Comparator: Replagal 0.2 mg/kg, IV, weekly
Patients randomized to receive Replagal 0.2 mg/kg via intravenous infusion every week for 52 weeks.
Biological: Replagal
Intravenous (IV) infusion for 12 months
Other Name: algasidase alfa
Active Comparator: Replagal 0.4 mg/kg, IV, weekly
Patients randomized to receive Replagal 0.4 mg/kg via intravenous infusion every week for 52 weeks.
Biological: Replagal
Intravenous (IV) infusion for 12 months
Other Name: algasidase alfa

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00864851

Locations
United States, Arizona
AKDHC Tucson Access Center
Tucson, Arizona, United States, 85719
United States, Iowa
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States, 52242
United States, New York
New York Unversity School of Medicine
New York, New York, United States, 10016
United States, Virginia
O & O Alpan, LLC
Springfield, Virginia, United States, 22152
Australia, Victoria
The Royal Melbourne Hospital
Parkville, Victoria, Australia, 3052
Czech Republic
The Charles University Hospital
Prague, Czech Republic, 128 OO
Finland
Turku University Central Hospital
Turku, Finland, FI-20520
Paraguay
Gobemador Irala y Coronel Lopez - Barrio Sojania
Asuncion, Paraguay
Poland
Szpital Uniwersytecki w Krakowie
Krakow, Poland, 31-066
Instytut Kardiologii
Warsaw, Poland, 04-628
Slovenia
General Hospital Slovenj Gradec
Slovenj Gradec, Slovenia, SI 2380
United Kingdom
Salford Royal NHS Foundation Trust
Salford, United Kingdom, M6 8HD
Sponsors and Collaborators
Shire Human Genetic Therapies, Inc.
Investigators
Principal Investigator: Gregory M. Pastores, MD New York University School of Medicine
Principal Investigator: Ademola K. Abiose, MD University of Iowa
Principal Investigator: Bojan Vujkovac, MD General Hospital Slovenj Gradec
Principal Investigator: Myrl D. Holida, PA-C University of Iowa
Principal Investigator: Kathleen Nicholls, MB.BS, MD Melbourne Health
Principal Investigator: Jacek Musial, MD, PhD Szpital Uniwersytecki w Krakowie
Principal Investigator: Lubor Golan, MD The Charles University Hospital
Principal Investigator: Derlis Emilio Gonzalez Rodriguez, MD Gobernador Irala Y Coronel Lopez - Barrio Sajonia
Principal Investigator: Lidia Chojnowska, MD, PhD Instytut Kardiologii
Principal Investigator: Stephen Waldek, MB BCh, FRCP Salford Royal NHS Foundation Trust
Principal Investigator: Ilkka Kantola, MD, PhD University of Turku
Principal Investigator: Y. Howard Lien, MD, PhD AKDHC Tucson Access Center
Principal Investigator: Ozlem Goker-Alpan, MD O & O Alpan LLC
Principal Investigator: Reena Sharma, MD Salford Royal NHS Foundation Trust
  More Information

No publications provided

Responsible Party: Shire Human Genetic Therapies, Inc.
ClinicalTrials.gov Identifier: NCT00864851     History of Changes
Other Study ID Numbers: TKT028
Study First Received: March 18, 2009
Results First Received: January 30, 2014
Last Updated: May 19, 2014
Health Authority: Poland: Ministry of Health
Czech Republic: State Institute for Drug Control
Australia: Department of Health and Ageing Therapeutic Goods Administration
Paraguay: Ministerio de Salud Pública y Bienestar Social
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Finland: Finnish Medicines Agency
United States: Food and Drug Administration
Slovenia: Agency for Medicinal Products - Ministry of Health

Additional relevant MeSH terms:
Fabry Disease
Sphingolipidoses
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Cerebral Small Vessel Diseases
Cerebrovascular Disorders
Vascular Diseases
Cardiovascular Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Metabolism, Inborn Errors
Lipidoses
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders

ClinicalTrials.gov processed this record on October 19, 2014