Clinical trial NCT00925301: Study of the Effects of Oral AT1001 (Migalastat Hydrochloride) in Patients With Fabry Disease
Official title: A Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy, Safety and Pharmacodynamics of AT1001 in Patients With Fabry Disease and AT1001-Responsive GLA Mutations
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Fabry Disease
Keywords: Amicus Therapeutics
AT1001
Migalastat
Pharmacokinetics
Substrate
Galafold
Lead sponsor: Amicus Therapeutics
Sponsor class: INDUSTRY
First posted: 2009-06-22
Enrollment: 67
Sex: ALL
Minimum age (years): 16
Maximum age (years): 74
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of this study was to compare the effect of migalastat (123 milligrams \[mg\] of migalastat \[equivalent to 150 mg of migalastat hydrochloride\]) (migalastat) versus placebo on kidney globotriaosylceramide (GL-3).

Detailed description: This double-blind, randomized, placebo-controlled study was conducted in 67 participants at 46 sites worldwide. The study consisted of 2 stages and an optional open-label treatment extension phase:

Stage 1 included a screening period of up to 2 months followed by a 6-month treatment period which involved 4 visits to the clinic. Participants were randomized in equal proportions to receive either migalastat or placebo.

After completing the 6-month double-blind phase, all participants entered Stage 2 of the study and received migalastat in an open-label manner. Stage 2 treatment lasted for 6 months and involved up to 4 visits to the clinic.

Participants who completed both Stage 1 and Stage 2 of the study as scheduled were offered the opportunity to participate in an open-label treatment extension phase with migalastat. The open-label treatment extension phase lasted 12 months and involved 2 visits to the clinic. A follow-up visit was undertaken 1 month following completion or discontinuation from the open-label treatment extension. Participants completing the 12-month open-label treatment extension and providing consent to enter a separate long-term extension were not required to complete this follow-up visit.

Study assessments included clinical laboratory tests, 12-lead electrocardiogram, kidney biopsy, kidney function testing, echocardiography, and patient-reported outcomes.

Eligibility criteria: Inclusion Criteria:

* Male or female between the ages of 16 and 74 diagnosed with Fabry disease.
* Confirmed mutant form of α-galactosidase A shown to be responsive to migalastat in vitro.
* Participant has never been treated with enzyme replacement therapy (ERT) or has not received ERT for 6 consecutive months or longer before the screening visit for the study.
* Urine GL-3 ≥4 times the upper limit of normal at screening.
* Participants taking angiotensin converting enzyme inhibitors or angiotensin receptor blockers must be on a stable dose for a minimum of 4 weeks before the baseline visit.
* Females who can become pregnant and all males agree to be sexually abstinent or use medically accepted methods of birth control during the study and for 30 days after study completion.
* Participant is willing and able to provide written informed consent and assent, if applicable.

Exclusion Criteria:

* Participant has undergone or is scheduled to undergo kidney transplantation, or is currently on dialysis.
* Estimated glomerular filtration rate \<30 milliliters per minute per 1.73 meters squared (chronic kidney disease Stage 4 or 5) based on the Modification of Diet in Renal Disease equation at screening.
* Pregnant or breast-feeding.
* History of allergy or sensitivity to study medication (including excipients) or other iminosugars (for example, miglustat, miglitol).
* Participant is treated or has been treated with any investigational drug within 30 days of study start.
* Participant is currently treated or has ever been treated with migalastat.

Primary outcomes:
measure: Percentage Of Participants With At Least A 50% Reduction From Baseline To Month 6 In The Average Number Of Kidney Interstitial Capillary (IC) Globotriaosylceramide (GL-3) Inclusions
timeFrame: Baseline, Month 6
Secondary outcomes:
measure: Percent Change In Kidney IC GL-3 Inclusions From Baseline To Month 6
timeFrame: Baseline, Month 6
measure: Change From Baseline Through Month 24 In Urine GL-3 Levels
timeFrame: Baseline, Months 6, 12, and 24
Other outcomes:
measure: Change From Month 6 To Month 12 In Average Number Of Kidney IC GL-3 Inclusions
timeFrame: Month 6, Month 12
Locations:
city: Los Angeles
country: United States
state: California
city: San Francisco
country: United States
state: California
city: Decatur
country: United States
state: Georgia
city: Chicago
country: United States
state: Illinois
city: Kansas City
country: United States
state: Kansas
city: Boston
country: United States
state: Massachusetts
city: Grand Rapids
country: United States
state: Michigan
city: New York
country: United States
state: New York
city: Pittsburgh
country: United States
state: Pennsylvania
city: Dallas
country: United States
state: Texas
city: Salt Lake City
country: United States
state: Utah
city: Springfield
country: United States
state: Virginia
city: Seattle
country: United States
state: Washington
city: Buenos Aires
country: Argentina
city: Adelaide
country: Australia
city: Parkville
country: Australia
city: Porto Alegre
country: Brazil
city: Sao Paulo
country: Brazil
city: Montreal
country: Canada
state: Quebec
city: Kobenhavn
country: Denmark
city: Cairo
country: Egypt
city: Garches
country: France
city: Roma
country: Italy
city: Warszawa
country: Poland
city: Barcelona
country: Spain
city: Zaragoza
country: Spain
city: Ankara
country: Turkey
city: Salford
country: United Kingdom
Study officials:
affiliation: Amicus Therapeutics
name: Medical Monitor, Clinical Research
role: STUDY_DIRECTOR
References:
citation: Bichet DG, Aerts JM, Auray-Blais C, Maruyama H, Mehta AB, Skuban N, Krusinska E, Schiffmann R. Assessment of plasma lyso-Gb3 for clinical monitoring of treatment response in migalastat-treated patients with Fabry disease. Genet Med. 2021 Jan;23(1):192-201. doi: 10.1038/s41436-020-00968-z. Epub 2020 Sep 30.
citation: Germain DP, Nicholls K, Giugliani R, Bichet DG, Hughes DA, Barisoni LM, Colvin RB, Jennette JC, Skuban N, Castelli JP, Benjamin E, Barth JA, Viereck C. Efficacy of the pharmacologic chaperone migalastat in a subset of male patients with the classic phenotype of Fabry disease and migalastat-amenable variants: data from the phase 3 randomized, multicenter, double-blind clinical trial and extension study. Genet Med. 2019 Sep;21(9):1987-1997. doi: 10.1038/s41436-019-0451-z. Epub 2019 Feb 6.
citation: Schiffmann R, Bichet DG, Jovanovic A, Hughes DA, Giugliani R, Feldt-Rasmussen U, Shankar SP, Barisoni L, Colvin RB, Jennette JC, Holdbrook F, Mulberg A, Castelli JP, Skuban N, Barth JA, Nicholls K. Migalastat improves diarrhea in patients with Fabry disease: clinical-biomarker correlations from the phase 3 FACETS trial. Orphanet J Rare Dis. 2018 Apr 27;13(1):68. doi: 10.1186/s13023-018-0813-7.
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: Germain DP, Hughes DA, Nicholls K, Bichet DG, Giugliani R, Wilcox WR, Feliciani C, Shankar SP, Ezgu F, Amartino H, Bratkovic D, Feldt-Rasmussen U, Nedd K, Sharaf El Din U, Lourenco CM, Banikazemi M, Charrow J, Dasouki M, Finegold D, Giraldo P, Goker-Alpan O, Longo N, Scott CR, Torra R, Tuffaha A, Jovanovic A, Waldek S, Packman S, Ludington E, Viereck C, Kirk J, Yu J, Benjamin ER, Johnson F, Lockhart DJ, Skuban N, Castelli J, Barth J, Barlow C, Schiffmann R. Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat. N Engl J Med. 2016 Aug 11;375(6):545-55. doi: 10.1056/NEJMoa1510198.