A Study to Evaluate Migalastat in Fabry Subjects With Amenable GLA Variants and Severe Renal Impairment
Study Details
Study Description
Brief Summary
This is an Open-label Study to Evaluate the Safety and Pharmacokinetics of Migalastat HCl in Fabry Subjects With Amenable GLA Variants and Severe Renal Impairment
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
This is an open-label, non-comparative study for subjects with Fabry disease who have an estimated glomerular filtration rate (eGFR) based on the Modification of Diet in Renal Disease (eGFRMDRD) value of < 30 mL/min/1.73 m2. Subjects may have previously participated in or be withdrawing from another migalastat study. Subjects withdrawing from a current (ongoing) study are to enter this study immediately, in order to maintain the continuity of treatment.
Subjects entering into this study who are not currently on migalastat treatment, or who were previously on migalastat but discontinued treatment over 30 days before enrolling into this study, will undergo screening (Visit 1) to confirm enrollment eligibility. Subjects who meet eligibility criteria will have a Baseline Visit (Visit 2) within 30 days of screening.
Subjects will be enrolled in approximately even numbers into 1 of 2 treatment regimens (150 mg migalastat HCl once every 4 days [Q4D] or once every 7 days [Q7D], based on eGFR at Visit
- After approximately 4 to 8 weeks of dosing with either regimen, subjects will undergo blood and urine sampling for plasma migalastat determinations at steady state. An end of treatment visit (Visit 4) will be scheduled at Week 12. For subjects who do not enroll in another migalastat study, a follow-up visit (Visit 5) will be scheduled approximately 14 days after the last dose of migalastat.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: migalastat HCl 150 mg All subjects will receive migalastat 123 mg, equivalent to 150 mg migalastat HCl (hereafter, migalastat) at a dose regimen based on their eGFRMDRD result at Visit 1. Subjects will take 1 migalastat capsule orally with water either every 4 or 7 days. |
Drug: migalastat HCl 150 mg
migalastat HCl 150 mg capsule
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Maximum observed concentration (Cmax) [Baseline through Week 12]
To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations for dose selection in Fabry subjects with severe renal impairment.
- Concentration at the end of a dosing interval at steady state (Ctrough) [Baseline through Week 12]
To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations for dose selection in Fabry subjects with severe renal impairment.
- Average plasma migalastat concentration over the dosing interval (Cavg) [Baseline through Week 12]
To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations for dose selection in Fabry subjects with severe renal impairment.
- Time to maximum concentration (tmax) [Baseline through Week 12]
To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations for dose selection in Fabry subjects with severe renal impairment.
- Apparent terminal elimination half-life (t½) [Baseline through Week 12]
To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations for dose selection in Fabry subjects with severe renal impairment.
- Area under the concentration time curve at steady state during the dosing interval (AUC0-τ) [Baseline through Week 12]
To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations for dose selection in Fabry subjects with severe renal impairment. The PK parameter will be calculated from serial blood sampling based on the plasma concentrations of migalastat.
- Plasma clearance (CL/F) [Baseline through Week 12]
To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations for dose selection in Fabry subjects with severe renal impairment.
- peak and trough plasma migalastat concentrations [Baseline through Week 12]
To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations for dose selection in Fabry subjects with severe renal impairment.
- Change in Amount excreted urine [0-12 hours and 0-24 hours]
To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations for dose selection in Fabry subjects with severe renal impairment.
- Change in Fraction of the dose recovered in urine [0-12 hours and 0-24 hours]
To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations for dose selection in Fabry subjects with severe renal impairment.
Secondary Outcome Measures
- adverse events (AEs) [Screening through Week 14]
To assess the safety and tolerability of migalastat in Fabry subjects with severe renal impairment
- Number of subjects with abnormal clinical chemistry laboratory test results [Baseline through Week 14]
Blood samples will be collected for analysis of chemistry parameters.
- Number of subjects with abnormal hematology laboratory test results [Baseline through Week 14]
Blood samples will be collected for analysis of hematology parameters.
- Number of subjects with abnormal urinalysis laboratory test results [Baseline through Week 14]
Blood samples will be collected for analysis of urine parameters.
- Number of subjects with abnormal electrocardiogram (ECG) findings as a measure of safety and tolerability [Screening through Week 14]
A 12-lead ECG will be obtained
- change from baseline in estimated glomerular filtration rate (eGFR) based on the Modification of Diet in Renal Disease equation (eGFR MDRD) [Screening through Week 14]
To assess the safety and tolerability of migalastat in Fabry subjects with severe renal impairment
- change from baseline eGFR based on the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) [Screening through Week 14]
To assess the safety and tolerability of migalastat in Fabry subjects with severe renal impairment
- change from baseline in plasma globotriaosylsphingosine (lyso-Gb3) [Screening through Week 12]
To evaluate the pharmacodynamics (PD) of migalastat in subjects with Fabry disease and severe renal impairment
- Number of subjects with abnormal echocardiogram (ECHO) results [Screening through Week 12]
Echocardiogram parameters include left ventricular mass index (LVMi), ejection fraction, fractional shortening, left ventricular internal diameter end diastole and end systole, midwall fractional shortening, and wall thickness.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Male or female subjects aged 16 years or older, diagnosed with Fabry disease.
-
Subject (or legally authorized representative as applicable) is willing and able to provide written informed consent and authorization for use and disclosure of Personal Health Information
-
Subject has a GLA variant that is amenable to migalastat recorded in their medical records
-
Subject has at least 1 documented eGFR value of < 30 mL/min/1.73 m2
-
If of reproductive potential, both male and female patients agree to use a medically accepted method of contraception
Exclusion Criteria:
-
Subject has an eGFR of ≥ 30 mL/min/1.73 m2 at Visit 1 per the central laboratory.
-
Subject has undergone kidney transplantation or is currently on dialysis, or is planned to start dialysis within 3 months
-
Subject is treated or has been treated with another investigational drug (except migalastat) within the 30 days
-
Subject has undergone any gene therapy at any time prior to the study and anticipates undergoing gene therapy during the study.
-
Subject has had a documented transient ischemic attack, stroke, unstable angina, or myocardial infarction
-
Subject has clinically significant unstable cardiac disease
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Subject has any intercurrent illness or condition that may preclude the subject from fulfilling the protocol requirements
-
Subject has a history of allergy or sensitivity to migalastat (including excipients) or other iminosugars (eg, miglustat, miglitol).
-
Subject requires concurrent treatment with Glyset® (miglitol), Replagal® (agalsidase alfa), or Fabrazyme® (agalsidase beta).
-
Subject requires concurrent treatment with Zavesca® (miglustat) or has been treated with Zavesca
-
Female subject is pregnant or breast-feeding.
-
Subject is unable to comply with study requirements
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Emory SOM | Atlanta | Georgia | United States | 30322 |
| 2 | NYU School of Medicine | New York | New York | United States | 10017 |
| 3 | UPMC Children's Hospital of Pittsburgh | Pittsburgh | Pennsylvania | United States | 15224 |
| 4 | Antwerp University Hospital | Edegem | Belgium | ||
| 5 | Internal Medicine Unit Croix Saint Simon Hospital | Paris | France | 75020 | |
| 6 | Azienda Ospedalira Universitaria CAREGGI S.O.D.c. Nefrologia Dialisi Trapianto | Florence | Italy | ||
| 7 | S.C. Nefrologia - Clinica Nefrologica | Monza | Italy | 20900 | |
| 8 | Hospital Universitario Virgen del Rocio | Sevilla | C.p. | Spain | 41013 |
| 9 | Hospital General Universitario de Elda | Elda | Spain | 03600 | |
| 10 | Hospital General Universitario Gregorio Marañon | Madrid | Spain | 28007 | |
| 11 | Royal Free London NHS Foundation Trust | London | United Kingdom |
Sponsors and Collaborators
- Amicus Therapeutics
Investigators
- Study Director: Clinical Research, Amicus Therapeutics
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- AT1001-025