Drug-Drug Interaction Study Between AT1001 (Migalastat Hydrochloride) and Agalsidase in Participants With Fabry Disease

NCT01196871 | Completed Phase 2 Results DMC

• 1 other identifier: AT1001-013
• Study Type: interventional
• Target: 20
• Locations: 5 countries
• Sites: 10

Brief Summary

The objective was to determine the effects of a single dose of migalastat hydrochloride (HCl) (migalastat) 150 and 450 milligrams (mg) on the safety and plasma pharmacokinetics (PK) of agalsidase and the effects of agalsidase on the safety and PK of migalastat 150 mg.

Conditions

Fabry Disease

Keywords

Amicus Therapeutics; AT1001; Galafold; Migalastat; Pharmacokinetics

Outcome Measures

Primary Outcomes (10)

• Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat

  This measure characterized the effects of migalastat on the plasma PK of agalsidase by measurement of the active α-Gal A enzyme level in plasma using a qualified assay that measured the rate of enzyme activity using an artificial, fluorescent substrate. The agalsidase plasma PK parameter values for AUC extrapolated from time 0 to infinity (AUCinfinity) and AUC to the last time point at which concentration is quantified (AUC0-t) are reported in hr\*\[nanomoles/hr/milliliter\] (hr\*\[nmol/hr/mL\]). In Period 1 of Stages 1 and 2, blood samples were collected: immediately before the agalsidase infusion and over a 24-hr period after infusion; on Days 2, 7, and 14. In Period 2 of Stages 1 and 2, blood samples were collected: prior to dosing with migalastat (2 hr prior to the agalsidase infusion) and 1 hr after migalastat dosing; immediately before initiation of the agalsidase infusion and over a 24-hr period after initiation of the agalsidase infusion; on Days 2, 7, and 14.

  0 hr, 2 hr, 2 days, 7 days, 14 days post dose

• Change In Maximum Observed Plasma Concentration (Cmax) For Active α-Gal A Levels After Administration Of Migalastat

  This measure characterized the effects of migalastat on the plasma PK of agalsidase by measurement of the active α-Gal A enzyme level in plasma using a qualified assay that measured the rate of enzyme activity using an artificial, fluorescent substrate. The agalsidase plasma PK parameter value for Cmax is reported in nmol/hr/mL. In Period 1 of Stages 1 and 2, blood samples were collected: immediately before the agalsidase infusion and over a 24-hr period after infusion; on Days 2, 7, and 14. In Period 2 of Stages 1 and 2, blood samples were collected: prior to dosing with migalastat (2 hr prior to the agalsidase infusion) and 1 hr after migalastat dosing; immediately before initiation of the agalsidase infusion and over a 24-hr period after initiation of the agalsidase infusion; on Days 2, 7, and 14.

  0 hr, 2 hr, 2 days, 7 days, 14 days post dose

• Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat

  This measure characterized the effects of migalastat on the plasma PK of agalsidase by measurement of the active α-Gal A enzyme level in plasma using a qualified assay that measured the rate of enzyme activity using an artificial, fluorescent substrate. The agalsidase plasma PK parameter values for tmax and t1/2 are reported in hr. In Period 1 of Stages 1 and 2, blood samples were collected: immediately before the agalsidase infusion and over a 24-hr period after infusion; on Days 2, 7, and 14. In Period 2 of Stages 1 and 2, blood samples were collected: prior to dosing with migalastat (2 hr prior to the agalsidase infusion) and 1 hr after migalastat dosing; immediately before initiation of the agalsidase infusion and over a 24-hr period after initiation of the agalsidase infusion; on Days 2, 7, and 14.

  0 hr, 2 hr, 2 days, 7 days, 14 days post dose

• Change In AUC For Total α-Gal A Protein Levels After Administration Of Migalastat

  This measure characterized the effects of migalastat on the plasma PK of agalsidase by measurement of the α-Gal A protein level in plasma by Western blot using anti-human Gal A antibody. The agalsidase plasma PK parameter value for AUC0-t is reported in hr\*\[nanogram (ng)/hr/mL\]. In Period 1 of Stages 1 and 2, blood samples were collected: immediately before the agalsidase infusion and over a 24-hr period after infusion; on Days 2, 7, and 14. In Period 2 of Stages 1 and 2, blood samples were collected: prior to dosing with migalastat (2 hr prior to the agalsidase infusion) and 1 hr after migalastat dosing; immediately before initiation of the agalsidase infusion and over a 24-hr period after initiation of the agalsidase infusion; on Days 2, 7, and 14.

  0 hr, 2 hr, 2 days, 7 days, 14 days post dose

• Change In Percentage Of AUCinfinity Extrapolated From The Last Time Point At Which Concentration Is Quantified To Infinity (AUCextrapolated %) For Total α-Gal A Protein Levels After Administration Of Migalastat

  This measure characterized the effects of migalastat on the plasma PK of agalsidase by measurement of the α-Gal A protein level by Western blot using anti-human Gal A antibody. The agalsidase plasma PK parameter values for AUCextrapolated % are reported. AUCextrapolated % is reported instead of AUCinfinity because small but quantifiable concentrations of α-Gal A protein past 24 hr post-dose extrapolated to infinity comprised \>50% of total AUC in most participants and were unevaluable. In Period 1 of Stages 1 and 2, blood samples were collected: immediately before the agalsidase infusion and over a 24-hr period after infusion; on Days 2, 7, and 14. In Period 2 of Stages 1 and 2, blood samples were collected: prior to dosing with migalastat (2 hr prior to the agalsidase infusion) and 1 hour after migalastat dosing; immediately before initiation of the agalsidase infusion and over a 24-hr period after initiation of the agalsidase infusion; on Days 2, 7, and 14.

  0 hr, 2 hr, 2 days, 7 days, 14 days post dose

• Change In Cmax For Total α-Gal A Protein Levels After Administration Of Migalastat

  This measure characterized the effects of migalastat on the plasma PK of agalsidase by measurement of the α-Gal A protein level in plasma by Western blot using anti-human Gal A antibody. The agalsidase plasma PK parameter values for Cmax is reported in nmol/hr/mL. In Period 1 of Stages 1 and 2, blood samples were collected: immediately before the agalsidase infusion and over a 24-hr period after infusion; on Days 2, 7, and 14. In Period 2 of Stages 1 and 2, blood samples were collected: prior to dosing with migalastat (2 hr prior to the agalsidase infusion) and 1 hr after migalastat dosing; immediately before initiation of the agalsidase infusion and over a 24-hr period after initiation of the agalsidase infusion; on Days 2, 7, and 14.

  0 hr, 2 hr, 2 days, 7 days, 14 days post dose

• Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat

  This measure characterized the effects of migalastat on the plasma PK of agalsidase by measurement of the total α-Gal A protein level in plasma by Western blot using anti-human Gal A antibody. The agalsidase plasma PK parameter values for tmax and t1/2 are reported in hr. In Period 1 of Stages 1 and 2, blood samples were collected: immediately before the agalsidase infusion and over a 24-hr period after infusion; on Days 2, 7, and 14. In Period 2 of Stages 1 and 2, blood samples were collected: prior to dosing with migalastat (2 hr prior to the agalsidase infusion) and 1 hr after migalastat dosing; immediately before initiation of the agalsidase infusion and over a 24-hr period after initiation of the agalsidase infusion; on Days 2, 7, and 14.

  0 hr, 2 hr, 2 days, 7 days, 14 days post dose

• Change In AUC For Migalastat After Administration Of Agalsidase

  This measure characterized the effects of agalsidase on the plasma PK of migalastat using a validated liquid chromatography-tandem mass spectrometry (LC-MS) assay. The migalastat plasma PK parameter values for AUCinfinity and AUC0-t are reported in hr\*\[ng/hr/mL\]. In Period 2 of Stages 1 and 2, blood samples were collected: just before dosing with migalastat (2 hr prior to the agalsidase infusion) and at 1 hr after migalastat dosing; immediately before the agalsidase infusion and over a 24-hr period after infusion. In Period 3 (Stage 1 only), blood samples were collected before dosing and over the 24-hr period after administration of migalastat.

  0 hr, 1 day post dose

• Change In Cmax For Migalastat After Administration Of Agalsidase

  This measure characterized the effects of agalsidase on the plasma PK of migalastat using a validated liquid LC-MS assay. The migalastat plasma PK parameter values for Cmax are reported in nmol/hr/mL. In Period 2 of Stages 1 and 2, blood samples were collected: just before dosing with migalastat (2 hr prior to the agalsidase infusion) and at 1 hr after migalastat dosing; immediately before the agalsidase infusion and over a 24-hr period after infusion. In Period 3 (Stage 1 only), blood samples were collected before dosing and over the 24-hr period after administration of migalastat.

  0 hr, 1 day post dose

• Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase

  This measure characterized the effects of agalsidase on the plasma PK of migalastat using a validated LC-MS assay. The migalastat plasma PK parameter values for tmax and t1/2 are reported in hr. In Period 2 of Stages 1 and 2, blood samples were collected: just before dosing with migalastat (2 hr prior to the agalsidase infusion) and at 1 hr after migalastat dosing; immediately before the agalsidase infusion and over a 24-hr period after infusion. In Period 3 (Stage 1 only), blood samples were collected before dosing and over the 24-hr period after administration of migalastat.

  0 hr, 1 day post dose

Secondary Outcomes (1)

• Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat

  Baseline, Day 7

Study Arms (6)

Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg)

EXPERIMENTAL

Drug: Migalastat HCl; Biological: Agalsidase Beta

Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg)

EXPERIMENTAL

Drug: Migalastat HCl; Biological: Agalsidase Beta

Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg)

EXPERIMENTAL

Drug: Migalastat HCl; Biological: Agalsidase Alfa

Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg)

EXPERIMENTAL

Drug: Migalastat HCl; Biological: Agalsidase Beta

Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg)

EXPERIMENTAL

Drug: Migalastat HCl; Biological: Agalsidase Beta

Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg)

EXPERIMENTAL

Drug: Migalastat HCl; Biological: Agalsidase Alfa

Interventions

Migalastat HCl DRUG

Oral capsules, single dose

Also known as: AT1001, Galafold, migalastat

Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg); Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg); Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg); Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg); Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg); Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg)

Agalsidase Beta BIOLOGICAL

IV infusion, single dose

Also known as: Fabrazyme

Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg); Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg); Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg); Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg)

Agalsidase Alfa BIOLOGICAL

IV infusion, single dose

Also known as: Replagal

Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg); Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male diagnosed with Fabry disease and between 18 and 65 years of age, inclusive
• Body mass index between 18-35 kg per meter squared
• Had initiated treatment with agalsidase at least 1 month prior to screening, and had received at least 2 infusions before screening
• Had stable dose level, dosing regimen, and form of agalsidase for at least 1 month before screening
• Had an estimated creatinine clearance greater than or equal to 50 milliliters (mL)/minute at screening
• Agreed to use medically accepted methods of contraception during the study and for 30 days after study completion
• Were willing and able to provide written informed consent

You may not qualify if:

• Had a documented transient ischemic attack, ischemic stroke, unstable angina, or myocardial infarction within the 3 months before screening
• Had clinically significant unstable cardiac disease (for example, cardiac disease requiring active management, such as symptomatic arrhythmia, unstable angina, or New York Heart Association class III or IV congestive heart failure)
• History of allergy or sensitivity to study drug (including excipients) or other iminosugars (such as miglustat, miglitol)
• Required a concomitant medication prohibited by the protocol: Glyset® (miglitol), or Zavesca® (miglustat)
• Any investigational/experimental drug or device within 30 days of screening, except for use of investigational enzyme replacement therapy for Fabry disease
• Had any intercurrent illness or condition that might have precluded the participant from fulfilling the protocol requirements or suggested to the investigator that the potential participant might have had an unacceptable risk by participating in this study

Sponsors & Collaborators

• Amicus Therapeutics: lead

Study Sites (10)

Unknown Facility

Birmingham, Alabama, 35294, United States

Location

Unknown Facility

Decatur, Georgia, 30033, United States

Location

Unknown Facility

Iowa City, Iowa, 52242, United States

Location

Unknown Facility

Kansas City, Kansas, 66160, United States

Location

Unknown Facility

Springfield, Virginia, 22152, United States

Location

Unknown Facility

Nedlands, Australia

Location

Unknown Facility

Parkville, Australia

Location

Unknown Facility

Edegem, Belgium

Location

Unknown Facility

Montreal, Canada

Location

Unknown Facility

Amsterdam, Netherlands

Location

Related Publications (1)

• Warnock DG, Bichet DG, Holida M, Goker-Alpan O, Nicholls K, Thomas M, Eyskens F, Shankar S, Adera M, Sitaraman S, Khanna R, Flanagan JJ, Wustman BA, Barth J, Barlow C, Valenzano KJ, Lockhart DJ, Boudes P, Johnson FK. Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active alpha-Galactosidase A in Fabry Patients when Co-Administered with Infused Agalsidase. PLoS One. 2015 Aug 7;10(8):e0134341. doi: 10.1371/journal.pone.0134341. eCollection 2015.

  PMID: 26252393 RESULT

MeSH Terms

Conditions

Fabry Disease

Interventions

migalastat; larazotide acetate; agalsidase beta; agalsidase alfa

Condition Hierarchy (Ancestors)

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; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolism, Inborn Errors; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Results Point of Contact

• Title: Amicus Therapeutics
• Organization: Medical Affairs

MedInfoUSA@amicusrx.com

+1-877-426-4287 (877-4-AMICUS)

Study Officials

• Medical Monitor Clinical Research

  Amicus Therapeutics

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: A 2-stage design was used to study the effects of 2 dose levels of migalastat, while a 2- or 3-period design within each stage enabled study of the effects of one drug on the PK, pharmacodynamics, and safety of the other drug.

Study Record Dates

• First Submitted: September 7, 2010
• First Posted: September 9, 2010
• Study Start: February 2, 2011
• Primary Completion: October 9, 2012
• Study Completion: October 9, 2012
• Last Updated: December 19, 2018
• Results First Posted: November 1, 2018

Record last verified: 2018-11

Locations

AU (2); US (5); NL (1); BE (1); CA (1)