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A Multicenter Open-Label Treatment Protocol to Observe the Safety of Replagal (Agalsidase Alfa) Enzyme Replacement Therapy in Canadian Patients With Fabry Disease

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ClinicalTrials.gov Identifier: NCT01298141
Recruitment Status : Completed
First Posted : February 17, 2011
Results First Posted : February 15, 2019
Last Update Posted : February 15, 2019
Sponsor:
Information provided by (Responsible Party):
Shire

Brief Summary:
The purpose of this study is to observe the safety of agalsidase alfa in Canadian patients with Fabry disease.

Condition or disease Intervention/treatment Phase
Fabry Disease Biological: agalsidase alfa Phase 3

Detailed Description:

This study will evaluate the safety of agalsidase alfa in patients with Fabry disease.

Patients diagnosed with Fabry disease who meet current Canadian guidelines for enzyme replacement therapy will be eligible to enroll in the study and will receive agalsidase alfa at a dose of 0.2 mg/kg body weight administered by an IV infusion over 40 minutes every week or every other week, based on previous treatment.

Shire has implemented a change to the drug substance manufacturing process. Safety data will be collected in patients receiving product manufactured with this process. There are no changes to the drug product formulation, manufacturing site, manufacturing process, and container closure.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 171 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter Open-Label Treatment Protocol to Observe the Safety of Replagal® (Agalsidase Alfa) Enzyme Replacement Therapy in Canadian Patients With Fabry Disease
Actual Study Start Date : August 10, 2011
Actual Primary Completion Date : September 25, 2017
Actual Study Completion Date : September 25, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Replagal®
All eligible patients may receive Replagal produced by the bioreactor process (AF Replagal) on this treatment plan until AF Replagal is commercially available for the patient, the patient's participation is discontinued, or the study is discontinued, whichever comes first.
Biological: agalsidase alfa

Cohort 1: 0.2 mg/kg body weight administered as an intravenous (IV) infusion over 40 minutes every other week (EOW)

Cohort 2: 0.2 mg/kg body weight administered as an intravenous (IV) infusion over 40 minutes weekly

Other Name: Replagal




Primary Outcome Measures :
  1. Number of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: From the start of study treatment up to 30 days after the last dose of study drug administration (up to 320 weeks) ]
    An adverse event (AE) was any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered investigational product-related.Treatment-emergent adverse events (TEAEs) were defined as those events which occurred or worsened in severity after first treatment with Replagal AF until 30 days after the last dose. A serious AE (SAE) was any AE occurred at any dose that resulted in death, life-threatening, hospitalization, prolongation of existing hospitalization, persistent or significant disability or incapacity and congenital anomaly or birth defect.

  2. Number of Participants With Infusion-Related Reactions (IRR) [ Time Frame: From the start of study treatment up to 30 days after the last dose of study drug administration (up to 320 weeks) ]
    An IRR (also referred to as infusion-related adverse event [IRAE]) was defined as an AE that began either during the infusion or within 12 hours after the start of the infusion and was judged as possibly or probably related to study drug. The IRRs were classified based on the severity as Mild=No limitation of usual activities, Moderate=Some limitation of usual activities, Severe=Inability to carry out usual activities and Life-threatening=Immediate risk of death. The number of participants with infusion-related reactions was reported.

  3. Number of Participants Who Reported Positive to Immunoglobulin A (IgA) [ Time Frame: Baseline (within 6 months prior to first dose) up to Week 129 ]
    The IgA status was measured using enzyme-linked immunosorbent assay (ELISA). Number of participants who reported positive to IgA was reported.

  4. Number of Participants Who Reported Positive to Immunoglobulin E (IgE) [ Time Frame: Baseline (within 6 months prior to first dose) up to Week 129 ]
    The IgE status was measured using ELISA. Number of participants who reported positive to IgE was reported.

  5. Number of Participants Who Reported Positive to Immunoglobulin M (IgM) [ Time Frame: Baseline (within 6 months prior to first dose) up to Week 129 ]
    The IgM status was measured using ELISA. Number of participants who reported positive to IgM was reported.

  6. Number of Participants Who Reported Positive to Anti-drug Antibody (ADA) [ Time Frame: Baseline (within 6 months prior to first dose) up to Week 285 ]
    The ADA status was measured using ELISA and electrochemiluminescent (ECL) immunoassay. Number of participants who reported positive to ADA was reported.

  7. Number of Participants Who Reported Positive to Neutralizing Antibody (NAb) [ Time Frame: Baseline (within 6 months prior to first dose) up to Week 285 ]
    The NAb status was measured using enzyme activity inhibition assay. Number of participants who reported positive to NAb was reported.



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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Cohort 1:

  1. The patient has a documented diagnosis of Fabry disease.
  2. The patient is sufficiently compliant with study activities to participate in this treatment plan, as judged by the Investigator.
  3. The patient must meet current Canadian guidelines for enzyme replacement therapy for Fabry disease by meeting one of the following criteria:

    1. Age-adjusted glomerular filtration rate (GFR) <80 ml/min or a decline in GFR of >10% which is sustained for 3 months and for which other causes of declining renal function have been excluded by a nephrologist or any 2 of the following:

      • Isolated proteinuria ≥500 mg/day/1.73 m2 without other cause
      • Nephrogenic diabetes insipidus
      • Fanconi syndrome
      • Hypertension
    2. Evidence of cardiac involvement related to Fabry disease including any 2 of the following:

      • Left ventricular (LV) wall thickness >12 mm
      • Left ventricular hypertrophy (LVH) by electrocardiogram (ECG); Estes ECG score must be >5
      • Left ventricular mass index (LVMI) by 2D echocardiogram 20% above normal for age
      • Diastolic filling abnormalities by 2D echocardiogram or by other accepted measures of diastolic filling. E/A ration >2.0 and deceleration time <140 msec
      • Increase of LV mass of at least 5 g/m2/year, with three measurements over a minimum of 12 months
      • Increase of left atrium (LA) size on 2D echo at least 10% above normal for age. In parasternal long axis view (PLAX) >33 mm; in four chamber view >42 mm
      • Cardiac conduction and rhythm abnormalities: atrioventricular (AV) block, short PR interval, left branch bundle block (LBBB), ventricular or atrial tachyarrhythmias, sinus bradycardia (in the absence of drugs with negative chronotropic activity)
      • Delayed posterolateral left ventricular wall late enhancement on MRI as evidence of advanced cardiac disease with fibrosis
    3. Evidence of neurological involvement related to Fabry disease including 1 of the following:

      • Stroke or transient ischemic attack (TIA) prior to the age of 55 documented by a neurologist
      • Acute onset unilateral hearing loss
      • Acut monocular visual loss without other cause
    4. Chronic, intractable diarrhea and/or abdominal pain/cramps, refractory to standard management for at least 6 months.
    5. Chronic, intractable neuropathic pain, refractory to analgesics and standard pain management for at least 6 months.

    Cohort 2:

  4. Patient must have participated in Study REP001a.

Exclusion Criteria:

  1. The patient has experienced an anaphylactic or anaphylactoid reaction or other infusion-related reaction which, in the opinion of the Investigator, precludes further treatment with agalsidase alfa or may interfere with the interpretation of the study.
  2. The patient is otherwise unsuitable for the study, in the opinion of the Investigator.
  3. The patient is enrolled in another clinical study, other than the Canadian Fabry Disease Initiative (CFDI).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01298141


Locations
Canada, Alberta
Alberta Children's Hospital
Calgary, Alberta, Canada, T3B 6A8
University of Alberta Hospital
Edmonton, Alberta, Canada, T6G 2H7
Canada, British Columbia
Vancouver General Hospital
Vancouver, British Columbia, Canada, V5Z 1M9
Canada, Manitoba
University of Manitoba
Winnipeg, Manitoba, Canada, R3A 1S1
Canada, Nova Scotia
Queen Elizabeth II Health Sciences Centre
Halifax, Nova Scotia, Canada, B3H 1V8
Izaak Walton Killam (IWK) Health Centre
Halifax, Nova Scotia, Canada, B3K 6R8
Canada, Ontario
Kingston General Hospital
Kingston, Ontario, Canada, K7L 3J6
London Health Sciences Centre - Victoria Hospital
London, Ontario, Canada, N6C 2V5
The Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8
The Fred A. Litwin Family Centre in Genetic Medicine
Toronto, Ontario, Canada, M5T 3L9
Canada, Quebec
Hopital du Sacre-Coeur de Montreal
Montreal, Quebec, Canada, H4J 1C5
Centre Hospitalier Universitaire de Sherbrooke (CHUS)
Sherbrooke, Quebec, Canada, J1H 5N4
Sponsors and Collaborators
Shire
Investigators
Study Director: Shire Physician Shire
  Study Documents (Full-Text)

Documents provided by Shire:
Study Protocol: Original Protocol  [PDF] September 30, 2010
Study Protocol: Amendment 1  [PDF] November 23, 2010
Study Protocol: Amendment 2  [PDF] December 6, 2010
Study Protocol: Amendment 3  [PDF] September 15, 2011
Study Protocol: Amendment 4  [PDF] March 28, 2013
Study Protocol: Amendment 5  [PDF] March 27, 2015
Statistical Analysis Plan  [PDF] December 6, 2017


Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT01298141     History of Changes
Other Study ID Numbers: HGT-REP-081
First Posted: February 17, 2011    Key Record Dates
Results First Posted: February 15, 2019
Last Update Posted: February 15, 2019
Last Verified: May 2018

Keywords provided by Shire:
Replagal
Enzyme Replacement Therapy
agalsidase alfa

Additional relevant MeSH terms:
Fabry Disease
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
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders
Sphingolipidoses
Metabolism, Inborn Errors
Lipidoses
Lipid Metabolism, Inborn Errors