DRUG
migalastat hydrochloride
Oral capsule QOD
Study of the Effects of Oral AT1001 (Migalastat Hydrochloride) in Patients With Fabry Disease
Status
Completed
Phase
Phase 3
Enrollment
67
Locations
28
Results
Posted
Publications
5
Study summary
What the protocol is testing.
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).
Full 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.
Interventions
Treatment arms and agents.
DRUG
Placebo
Oral capsule QOD
Timeline
From registration to results.
First posted
Jun 22, 2009
Study start
Oct 23, 2009
Primary completion
Jun 12, 2012
Study completion
Jan 29, 2014
Results posted
Oct 30, 2018
Registry updated
Oct 30, 2018
Outcomes
What the study measures.
Primary outcomes
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
Time frame · Baseline, Month 6
Renal biopsies were taken at Baseline and Month 6 (Stage 1). The specimens were evaluated using virtual microscopy. The annotation, scoring, and adjudication of the kidney histology assessments were performed by the Clinical Pathology Endpoints Committee. The number of kidney IC GL-3 inclusions was assessed by 3 renal pathologists who were blinded to treatment assignments, participants' data, and biopsy sequence. One pathologist served as annotator and identified the 300 capillaries on up to 8 slides per specimen to be scored. Two pathologists served as scorers; these pathologists completed the blinded paired assessments. Each pathologist served as annotator/adjudicator for 1/3 of the cases. Paired assessments were undertaken at Baseline and Month 6. Assessments were made using digital images. A responder was defined as a participant with a ≥50% reduction from Baseline to Month 6 in the average number of kidney IC GL-3 inclusions.
Secondary outcomes
Percent Change In Kidney IC GL-3 Inclusions From Baseline To Month 6
Time frame · Baseline, Month 6
Renal biopsies were taken at Baseline and Month 6. The specimens were evaluated using virtual microscopy. The annotation, scoring, and adjudication of the kidney histology assessments were performed by the Clinical Pathology Endpoints Committee. The number of kidney IC GL-3 inclusions was assessed by 3 renal pathologists who were blinded to treatment assignments, participants' data, and biopsy sequence. One pathologist served as annotator and identified the 300 capillaries on up to 8 slides per specimen to be scored. Two pathologists served as scorers; these pathologists completed the blinded paired assessments. Each pathologist served as annotator/adjudicator for 1/3 of the cases. Paired assessments were undertaken at Baseline and Month 6. Assessments were made using digital images.
Change From Baseline Through Month 24 In Urine GL-3 Levels
Time frame · Baseline, Months 6, 12, and 24
The effect of migalastat versus placebo on urine GL-3 levels was measured by liquid chromatography-mass spectrometry/mass spectrometry. The 24-hour urine samples were collected at Baseline, Month 6 (Stage 1), Month 12 (Stage 2), and Month 24 (OLE). Results are presented as changes in nanograms (ng)/mg creatinine from Baseline to the end of the 3 stages.
Eligibility
Who can take part.
- Minimum age
- 16 Years
- Maximum age
- 74 Years
- Sex
- ALL
- Healthy volunteers
- No
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.
Study locations
28 registered sites.
Argentina · Australia · Brazil · Canada · Denmark · Egypt · France · Italy · Poland · Spain · Turkey (Türkiye) · United Kingdom · United States. Showing up to 24 locations stored in the fast local snapshot.
Facility not named
Los Angeles, California, United States
Facility not named
San Francisco, California, United States
Facility not named
Decatur, Georgia, United States
Facility not named
Chicago, Illinois, United States
Facility not named
Kansas City, Kansas, United States
Facility not named
Boston, Massachusetts, United States
Facility not named
Grand Rapids, Michigan, United States
Facility not named
New York, New York, United States
Facility not named
Pittsburgh, Pennsylvania, United States
Facility not named
Dallas, Texas, United States
Facility not named
Salt Lake City, Utah, United States
Facility not named
Springfield, Virginia, United States
Facility not named
Seattle, Washington, United States
Facility not named
Buenos Aires, Argentina
Facility not named
Adelaide, Australia
Facility not named
Parkville, Australia
Facility not named
Porto Alegre, Brazil
Facility not named
São Paulo, Brazil
Facility not named
Montreal, Quebec, Canada
Facility not named
Copenhagen, Denmark
Facility not named
Cairo, Egypt
Facility not named
Garches, France
Facility not named
Roma, Italy
Facility not named
Warsaw, Poland
Publications
Results and literature.
PMID 32994552 ↗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.PMID 30723321 ↗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.PMID 29703262 ↗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.PMID 27657681 ↗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.PMID 27509102 ↗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.
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