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A 12-Week Safety and Pharmacodynamic Study of AT1001 (Migalastat Hydrochloride) in Female Participants With Fabry Disease

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ClinicalTrials.gov Identifier: NCT00304512
Recruitment Status : Completed
First Posted : March 20, 2006
Results First Posted : September 7, 2018
Last Update Posted : October 3, 2018
Sponsor:
Information provided by (Responsible Party):
Amicus Therapeutics

Brief Summary:
Study to evaluate the safety, tolerability, and pharmacodynamics of migalastat hydrochloride (HCl) (migalastat) in participants with Fabry disease.

Condition or disease Intervention/treatment Phase
Fabry Disease Drug: migalastat HCl Phase 2

Detailed Description:
This was a Phase 2, open-label study in female participants with Fabry disease. The study consisted of a 4-week screening period, during which participants' galactosidase (GLA) genotype was assessed for α-galactosidase A (α-Gal A) activity in response to migalastat. Participants were required to have α-Gal A activity responsive to migalastat. The study consisted of a 12-week treatment period, followed by an optional 36-week extension period. Participants received migalastat once every other day (QOD) for 12 weeks during the treatment period and the optional 36-week extension period for a total treatment duration of up to 48 weeks. Participants were stratified by α-Gal A enzyme activity (high >40%, and low ≤40%) then randomly assigned to receive migalastat at 1 of 3 specified dose levels (50, 150, or 250 milligrams [mg]).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2, Open-Label, Multiple Dose Level, 12-Week Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of AT1001 in Female Patients With Fabry Disease
Actual Study Start Date : September 7, 2006
Actual Primary Completion Date : May 9, 2008
Actual Study Completion Date : May 9, 2008

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Migalastat Low Dose 50 mg
Migalastat 50 mg was administered orally QOD during the 12-week treatment period and then during the optional 36-week treatment extension period.
Drug: migalastat HCl
Other Names:
  • AT1001
  • Galafold
  • migalastat

Experimental: Migalastat Middle Dose 150 mg
Migalastat 150 mg was administered orally QOD during the 12-week treatment period and then during the optional 36-week treatment extension period.
Drug: migalastat HCl
Other Names:
  • AT1001
  • Galafold
  • migalastat

Experimental: Migalastat High Dose 250 mg
Migalastat 250 mg was administered orally QOD during the 12-week treatment period and then during the optional 36-week treatment extension period.
Drug: migalastat HCl
Other Names:
  • AT1001
  • Galafold
  • migalastat




Primary Outcome Measures :
  1. Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Day 1 (after dosing) through Week 48 ]
    TEAEs were defined as any adverse event with start date on or after administration of study drug or pre-existing conditions that worsened on or after the start of the first study drug administration (on Day 1). A severe adverse event was defined as an adverse event that was incapacitating and required medical intervention. The number of participants who experienced one or more severe TEAEs after dosing on Day 1 through Week 48 is presented. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.


Secondary Outcome Measures :
  1. PK: Area Under The Concentration Versus Time Curve (AUC) After Administration Of Migalastat [ Time Frame: 0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, and 10 hours (postdose) ]
    The AUC to the last measurable concentration (AUC0-t) was evaluated in plasma following a single oral dose of migalastat on Day 1 and following multiple oral doses on Day 14 (2 weeks) and Day 84 (12 weeks). All samples were collected on each dosing day.

  2. α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 [ Time Frame: Baseline, Week 12 (end of treatment period), Week 48 (end of extension period) ]
    Leukocytes were isolated from whole blood and lysed, and α-Gal A activity was measured using a validated fluorometric assay, with catalysis to fluorescent 4-methylumbelliferone (4-MU) as the activity measure. The activity values obtained were normalized to protein (measured using a colorimetric assay) and reported as enzyme activity (nanomole [nmol] 4-MU/hr) per mg of protein. On Day 1 of the first visit and at every visit thereafter, the samples were collected prior to dosing with migalastat. α-Gal A activity in leukocytes are presented by individual participants.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Females between 18 and 65 years of age (inclusive)
  • Heterozygous for Fabry disease
  • Had a confirmed diagnosis of Fabry disease with a documented missense gene mutation (individual or familial)
  • Had enhanceable enzyme activity based on in vitro tests
  • Were naïve to enzyme replacement therapy (ERT) and other therapies, except for palliative therapies for the signs and symptoms of Fabry disease, or stopped ERT for at least 18 weeks
  • Had end organ dysfunction, even minimal, demonstrated by abnormal electrocardiogram (ECG) or evidence of left ventricular hypertrophy documented by echocardiogram or by cardiac biopsy; or renal insufficiency documented by common clinical assessments such as creatinine and glomerular filtration rate or by renal biopsy; or brain tissue dysfunction as documented by evidence of stroke (clinically or imaging); or peripheral nervous tissue dysfunction documented by complaints of intolerance to heat or cold, decreased vibratory sense and proprioception, decreased ability to perspire, or acroparesthesia.
  • Were willing to undergo 2 renal and 3 skin biopsies
  • Agreed to be sexually abstinent or practice an effective method of contraception when engaging in sexual activity during the course of the study and for a period of 30 days following their completion of the study for women of childbearing potential.
  • Were willing and able to provide written informed consent

Exclusion Criteria:

  • Pregnant or lactating
  • History of organ transplant
  • History of significant disease other than Fabry disease (for example, end-stage renal disease; Class III or IV heart disease [per the New York Heart Association classification]; current diagnosis of cancer, except for basal cell carcinoma of the skin; diabetes [unless hemoglobin A1c ≤8]; or neurological disease that would have impaired the participant's ability to participate in the study)
  • Serum creatinine >176 micromoles/liter on Day -2
  • Screening 12-lead ECG demonstrating corrected QT interval >450 milliseconds
  • Pacemaker or other contraindication for magnetic resonance imaging scanning
  • Taking a medication prohibited by the protocol: Fabrazyme® (agalsidase beta), Replagal™ (agalsidase alfa), Glyset® (miglitol), Zavesca® (miglustat), or any experimental therapy for any indication
  • Participated in a previous clinical trial in the last 30 days
  • Any other condition which, in the opinion of the investigator would jeopardize the safety of the participant or impact the validity of the study results.

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): NCT00304512


Locations
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United States, Georgia
Decatur, Georgia, United States, 30033
Australia, Victoria
Parkville, Victoria, Australia, 3050
Brazil
Porto Alegre, Brazil, RS, 90035-903
Canada
Montréal, Canada, H4J 1C5
France
Paris, France, 75015
United Kingdom
Salford, United Kingdom, M6 8HD
Sponsors and Collaborators
Amicus Therapeutics
Investigators
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Study Director: Medical Monitor, Clinical Research Amicus Therapeutics

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Amicus Therapeutics
ClinicalTrials.gov Identifier: NCT00304512     History of Changes
Other Study ID Numbers: FAB-CL-204
First Posted: March 20, 2006    Key Record Dates
Results First Posted: September 7, 2018
Last Update Posted: October 3, 2018
Last Verified: October 2018

Keywords provided by Amicus Therapeutics:
Amicus Therapeutics
AT1001
Galafold
Migalastat
Substrate

Additional relevant MeSH terms:
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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
1-Deoxynojirimycin
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action