Clinical trial NCT00304512: A 12-Week Safety and Pharmacodynamic Study of AT1001 (Migalastat Hydrochloride) in Female Participants With Fabry Disease
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Fabry Disease
Keywords: Amicus Therapeutics
AT1001
Galafold
Migalastat
Substrate
Lead sponsor: Amicus Therapeutics
Sponsor class: INDUSTRY
First posted: 2006-03-20
Enrollment: 9
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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 \[mg\]).

Eligibility 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.

Primary outcomes:
measure: Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs)
timeFrame: Day 1 (after dosing) through Week 48
Secondary outcomes:
measure: PK: Area Under The Concentration Versus Time Curve (AUC) After Administration Of Migalastat
timeFrame: 0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, and 10 hours (postdose)
measure: α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48
timeFrame: Baseline, Week 12 (end of treatment period), Week 48 (end of extension period)
Other outcomes:
Locations:
city: Decatur
country: United States
state: Georgia
city: Parkville
country: Australia
state: Victoria
city: Porto Alegre
country: Brazil
city: Montréal
country: Canada
city: Paris
country: France
city: Salford
country: United Kingdom
Study officials:
affiliation: Amicus Therapeutics
name: Medical Monitor, Clinical Research
role: STUDY_DIRECTOR
References:
citation: Benjamin ER, Della Valle MC, Wu X, Katz E, Pruthi F, Bond S, Bronfin B, Williams H, Yu J, Bichet DG, Germain DP, Giugliani R, Hughes D, Schiffmann R, Wilcox WR, Desnick RJ, Kirk J, Barth J, Barlow C, Valenzano KJ, Castelli J, Lockhart DJ. The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat. Genet Med. 2017 Apr;19(4):430-438. doi: 10.1038/gim.2016.122. Epub 2016 Sep 22.
citation: Giugliani R, Waldek S, Germain DP, Nicholls K, Bichet DG, Simosky JK, Bragat AC, Castelli JP, Benjamin ER, Boudes PF. A Phase 2 study of migalastat hydrochloride in females with Fabry disease: selection of population, safety and pharmacodynamic effects. Mol Genet Metab. 2013 May;109(1):86-92. doi: 10.1016/j.ymgme.2013.01.009. Epub 2013 Jan 26.