A Study to Evaluate Migalastat in Fabry Subjects With Amenable GLA Variant and Renal Disease

Study Overview
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Brief Summary
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An Open-label Study to Evaluate the Safety and Pharmacokinetics of Migalastat HCl in Subjects with Fabry Disease and Amenable GLA Variants and Severe Renal Impairment (SRI) or End Stage Renal Disease (ESRD)

Detailed Description
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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 equation (eGFRMDRD) value of < 30 mL/min/1.73 m2. Subjects may have had previous exposure to migalastat, either commercially or as a participant in a previous migalastat study. Two distinct populations of subjects with Fabry disease and renal impairment will be enrolled into this study: Cohort 1: Subjects with SRI not receiving any type of dialysis treatment Cohort 2: ESRD subjects who are receiving hemodialysis treatment, either standard hemodialysis (HD) or hemodiafiltration (HDF). Only subjects who can receive HD/HDF at the study clinic or at an affiliated center where the Investigator already has oversight should be enrolled into Cohort 2. Subjects entering into this study will undergo screening (Visit 1) to confirm enrollment eligibility including confirmatory GLA genotyping. Subjects who meet eligibility criteria will have a Baseline Visit (Visit 2) within 30 days of screening. Subjects who do not meet eligibility criteria (eg, subjects with an eGFR > 30 mL/min/1.73 m2) may be re-screened.

Official Title
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An Open-label Study to Evaluate the Safety and Pharmacokinetics of Migalastat HCl in Subjects With Fabry Disease and Amenable GLA Variants and Severe Renal Impairment or End-Stage Renal Disease Treated With Hemodialysis

Conditions
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Fabry Disease

Intervention / Treatment
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* Drug: migalastat HCl 150 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects aged 18 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 within the last 3 months and has an eGFRMDRD value of < 30 mL/min/1.73 m2 at Visit 1 Subjects with ESRD have been on a stable 2- or 3-times a week HD (standard or HDF) regimen for at least 2 months prior to the screening visit Subjects with ESRD must commit to completing at least 4 standard HD or HDF sessions during each 2-week dosing interval. Subjects with ESRD must commit to completing the entire prescribed duration for each dialysis session. If of reproductive potential, both male and female patients agree to use a medically accepted method of contraception Exclusion Criteria: Subject has undergone kidney transplantation Subject is on peritoneal dialysis 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 or 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 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 In France only, protected persons as defined by the Public Health Code

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Severe Renal Impairment<br>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<br>* migalastat HCl 150 mg capsule<br>* Other names: AT1001;|
| Experimental: Cohort 2: End-Stage Renal Disease<br>All hemodialysis subjects will receive migalastat 123 mg, equivalent to 150 mg migalastat HCl (hereafter, migalastat). Subjects will take 1 migalastat capsule orally with water every other week. | Drug: migalastat HCl 150 mg<br>* migalastat HCl 150 mg capsule<br>* Other names: AT1001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed concentration (Cmax) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations. | Baseline through Month 12 | 
| Time to maximum concentration (tmax) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations. | Baseline through Month 12 | 
| Apparent terminal elimination half-life (t½) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK | Baseline through Month 12 | 
| Concentration at the end of a dosing interval at steady state (Ctrough) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations. | Baseline through Month 12 | 
| Average plasma migalastat concentration over the dosing interval (Cavg) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations. | Baseline through Month 12 | 
| Area under the concentration-time curve at steady state during the dosing interval (AUC0-τ) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations. | Baseline through Month 12 | 
| Area under the concentration-time curve from zero time (pre-dose) extrapolated to infinite time (AUC0-∞) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations. | Baseline through Month 12 | 
| Apparent plasma clearance (CL/F) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK | Baseline through Month 12 | 
| Apparent terminal phase volume of distribution (Vz/F) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations. | Baseline through Month 12 | 
| Dialysis clearance (CLD) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations. | Baseline through Month 12 | 
| Volume of dialysate collected during the interval (VD) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations. | Baseline through Month 12 | 
| Mean migalastat concentration in dialysate (CD) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations. | Baseline through Month 12 | 
| Amount recovered in dialysate (AeD) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations. | Baseline through Month 12 | 
| Fraction of the dose recovered in dialysate (FeD) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations. | Baseline through Month 12 | 
| Mean migalastat plasma concentration during the dialysis interval (P) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations. | Baseline through Month 12 | 
| Mean inlet area under the curve (AUCinlet) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations. | Baseline through Month 12 | 
| Mean outlet area under the curve (AUCoutlet) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations. | Baseline through Month 12 | 
| Extraction ratio (ED) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations. | Baseline through Month 12 | 
| Dialyzer blood flow (QD) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations. | Baseline through Month 12 | 
| Cumulative amount excreted over all collection intervals (Ae0-τ) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations. | Baseline through Month 12 | 
| Fraction of the dose recovered after the last measurable time point postdose (Fe0-τ) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations. | Baseline through Month 12 | 
| Renal clearance (CLr) | To characterize the pharmacokinetics (PK) of migalastat and validate the population PK (popPK) model and simulations. | Baseline through Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events (AEs) | To assess the safety and tolerability of migalastat in Fabry subjects with severe renal impairment and end stage renal disease. | Baseline through Month 12 | 
| Number of subjects with abnormal clinical chemistry laboratory test results | Blood samples will be collected for analysis of chemistry parameters. | Baseline through Month 12 | 
| Number of subjects with abnormal hematology laboratory test results | Blood samples will be collected for analysis of hematology parameters. | Baseline through Month 12 | 
| Number of subjects with abnormal urinalysis laboratory test results | Blood samples will be collected for analysis of urine parameters. | Baseline through Month 12 | 
| Number of subjects with abnormal electrocardiogram (ECG) findings as a measure of safety and tolerability | A 12-lead ECG will be obtained | Baseline through Month 12 | 
| Change from baseline in estimated glomerular filtration rate (eGFR) based on the Modification of Diet in Renal Disease equation (eGFR MDRD) | To assess the safety and tolerability of migalastat in Fabry subjects with severe renal impairment and end stage renal disease | Baseline through Month 12 | 
| Change from baseline eGFR based on the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) | To assess the safety and tolerability of migalastat in Fabry subjects with severe renal impairment and end stage renal disease | Baseline through Month 12 | 
| Change from baseline in plasma globotriaosylsphingosine (lyso-Gb3) | To evaluate the pharmacodynamics (PD) of migalastat in subjects with Fabry disease and severe renal impairment | Baseline through Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal Disease, Severe Renal Impairment (SRI), End-Stage Renal Disease (ESRD)