Study of the Effects of Oral AT1001 (Migalastat Hydrochloride) in Patients With Fabry Disease

• ClinicalTrials.gov Identifier: NCT00925301
• Recruitment Status: Completed
• First Posted: June 22, 2009
• Results First Posted: October 30, 2018
• Last Update Posted: October 30, 2018
• Sponsor: Amicus Therapeutics
• Information provided by (Responsible Party): Amicus Therapeutics

Tracking Information

• First Submitted Date: June 19, 2009
• First Posted Date: June 22, 2009
• Results First Submitted Date: August 10, 2018
• Results First Posted Date: October 30, 2018
• Last Update Posted Date: October 30, 2018
• Actual Study Start Date: October 23, 2009
• Actual Primary Completion Date: June 12, 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 1, 2018)

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.

• Original Primary Outcome Measures (submitted: June 19, 2009): kidney GL-3 (assessed histologically in kidney biopsy samples) [ Time Frame: 6 months ]

Current Secondary Outcome Measures (submitted: October 1, 2018)

• 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.

Original Secondary Outcome Measures (submitted: June 19, 2009)

• urine GL-3 levels [ Time Frame: 6 months ]
• renal function (assessed by iohexol GFR, eGFR, and 24-hour urine protein) [ Time Frame: 6 months ]
• safety and tolerability [ Time Frame: 12 months ]

Current Other Pre-specified Outcome Measures (submitted: October 1, 2018)

Change From Month 6 To Month 12 In Average Number Of Kidney IC GL-3 Inclusions [ Time Frame: Month 6, Month 12 ]

Renal biopsies were taken at Month 6 and Month 12. 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 Month 6 and Month 12. Assessments were made using digital images.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description:

Sponsor and Assessor were also blinded

Primary Purpose: Treatment

• Condition: Fabry Disease

Intervention

• Drug: migalastat hydrochloride
  Oral capsule QOD
  Other Names:

  • AT1001
  • Galafold
  • Migalastat
• Drug: Placebo
  Oral capsule QOD

Study Arms

• Experimental: Migalastat
  Migalastat 150-mg capsule taken orally every other day (QOD) for 6 months and an open-label 6-month treatment extension, followed by an optional, 12-month, open-label treatment extension.
  Intervention: Drug: migalastat hydrochloride
• Placebo Comparator: Placebo
  Placebo capsule taken orally QOD for 6 months.
  Intervention: Drug: Placebo

Publications *

• 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. Erratum In: Genet Med. 2020 Nov 20;:
• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 20, 2014): 67
• Original Estimated Enrollment (submitted: June 19, 2009): 60
• Actual Study Completion Date: January 29, 2014
• Actual Primary Completion Date: June 12, 2012 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 16 Years to 74 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Brazil, Canada, Denmark, Egypt, France, Italy, Poland, Spain, Turkey, United Kingdom, United States
• Removed Location Countries: Belgium, Chile, Germany, Israel, Netherlands, South Africa

Administrative Information

• NCT Number: NCT00925301
• Other Study ID Numbers: AT1001-011; FACETS ( Other Identifier: Amicus Therapeutics ); 2009-013459-31 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Amicus Therapeutics
• Original Responsible Party: Medical Monitor, Clinical Research, Amicus Therapeutics
• Current Study Sponsor: Amicus Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Monitor, Clinical Research; Amicus Therapeutics

• PRS Account: Amicus Therapeutics
• Verification Date: October 2018