Safety and Pharmacokinetics of AT1001 (Migalastat HCl) in Healthy Subjects and Subjects With Impaired Renal Function - Full Text View

Purpose

This study will assess the safety, tolerability, and pharmacokinetics (PK) study of a single dose of 150 mg AT1001 (migalastat HCl, GR181413A) administered orally to healthy subjects with normal renal function and to subjects with mild, moderate, and severe renal impairment.

Condition	Intervention	Phase
Fabry Disease	Drug: AT1001 150 mg	Phase 1

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	An Open-Label Study to Determine the Safety and Pharmacokinetics of AT1001 in Subjects With Impaired Renal Function and Healthy Subjects With Normal Renal Function (AT1001-015)

Resource links provided by NLM:

Genetics Home Reference related topics: Chanarin-Dorfman syndrome cholesteryl ester storage disease Fabry disease Farber lipogranulomatosis Schindler disease succinic semialdehyde dehydrogenase deficiency

U.S. FDA Resources

Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:

Number of subjects with adverse events to assess safety and tolerability [ Time Frame: Day 1 to Day 10 (+1) ] [ Designated as safety issue: No ]
Adverse events will be evaluated from Day 1 to the end of study (Day 10 +1).
Clinical laboratory test values to assess safety and tolerability [ Time Frame: Day -28 to Day 10 (+1) ] [ Designated as safety issue: No ]
Clinical laboratory evaluations (hematology, clinical chemistry, urinalysis, Hepatitis A and HIV screen) will be evaluated from screening to the end of the study.
Vital signs to assess safety and tolerability [ Time Frame: Day -28 to Day 10 (+1) ] [ Designated as safety issue: No ]
Vital signs (oral temperature, respiratory rate, and seated blood pressure) will be performed from screening to the end of the study.
Physician examination to assess safety and tolerability [ Time Frame: Day -28 to Day 10 (+1) ] [ Designated as safety issue: No ]
Physical examination (general appearance, skin, thorax/lungs, cardiovascular and abdomen) will be performed from screening to the end of the study.
Measure of ECG to assess safety and tolerability [ Time Frame: Day -28 to Day 10 (+1) ] [ Designated as safety issue: No ]
Electrocardiogram (ECG) measures the electrical activity of the heart and the hearts' rhythm. All subjects will undergo ECG testing.

Secondary Outcome Measures:

Maximum observed concentration (Cmax) of AT1001 [ Time Frame: Day 1 to Day 6 ] [ Designated as safety issue: No ]
Blood samples will be collected at predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 48, 72, 96, and 120 hours post-dose and the resultant maximum plasma concentration (Cmax) will be measured in subjects with impaired renal function and normal renal function.
Time to achieve maximum concentration (Tmax) of AT1001 [ Time Frame: Day 1 to Day 6 ] [ Designated as safety issue: No ]
Blood samples will be collected at predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 48, 72, 96, and 120 hours post-dose and time to maximum concentration (tmax) will be measured in subjects with impaired renal function and normal renal function.
Apparent terminal elimination half life (t1/2 ) of AT1001 [ Time Frame: Day 1 to Day 6 ] [ Designated as safety issue: No ]
Blood samples will be collected at predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 48, 72, 96, and 120 hours post-dose and and apparent terminal elimination half-life (t1/2) will be measured in subjects with impaired renal function and normal renal function.
Area under the concentration-time curve from time zero to the last measurable concentration (AUC 0-t ) of AT1001 [ Time Frame: Day 1 to Day 6 ] [ Designated as safety issue: No ]
Blood samples will be collected at predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 48, 72, 96, and 120 hours post-dose and AUC 0-t will be measured in subjects with impaired renal function and normal renal function
Area under the concentration-time curve extrapolated to infinity (AUC 0-inf) of AT1001 [ Time Frame: Day 1 to Day 6 ] [ Designated as safety issue: No ]
Blood samples will be collected at predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 48, 72, 96, and 120 hours post-dose and AUC 0-inf will be measured in subjects with impaired renal function and normal renal function
Apparent terminal elimination rate constant for AT1001 [ Time Frame: Day 1 to Day 6 ] [ Designated as safety issue: No ]
Blood samples will be collected at predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 48, 72, 96, and 120 hours post-dose and the apparent terminal elimination rate constant will be measured in subjects with impaired renal function and normal renal function
Oral clearance of AT1001 [ Time Frame: Day 1 to Day 6 ] [ Designated as safety issue: No ]
Blood samples will be collected at predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 48, 72, 96, and 120 hours post-dose and the oral clearance will be measured in subjects with impaired renal function and normal renal function
Oral volume of distribution of AT1001 [ Time Frame: Day 1 to Day 6 ] [ Designated as safety issue: No ]
Blood samples will be collected at predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 48, 72, 96, and 120 hours post-dose and the oral volume of distribution will be measured in subjects with impaired renal function and normal renal function

Enrollment:	32
Study Start Date:	August 2011
Study Completion Date:	April 2012
Primary Completion Date:	April 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: AT1001 150 mg Each subject will receive a single oral dose of AT1001 150 mg administered orally with 240 mL room temperature water after at least a 4-hour fast	Drug: AT1001 150 mg AT1001 150mg is available as a capsule Other Names: migalastat HCl GR181413A

Detailed Description:

This will be an open-label, non-randomized, multiple-center, sequential group, safety, tolerability, and PK study of a single dose of AT1001 (migalastat HCl, GR181413A) administered orally as a 150 mg dose in fasted healthy control male and female subjects with normal renal function compared to mild, moderate, and severe renally-impaired subjects (classified by level of creatinine clearance [CLcr] as determined by the Cockcroft-Gault formula).

Screening will occur from Day -28 to Day -2. Subjects will check-in to the clinic on Day -1 and receive a single oral dose of 150 mg AT1001 on Day 1. Subjects will be discharged from the clinic on Day 2 (if stable as determined by the Investigator) and return for daily visits on Day 3 through Day 6 for a safety assessment and PK sampling. Subjects will undergo a follow-up visit on Day 7 (+1) and an end of study visit on Day 10 (+1).

Eligibility

Ages Eligible for Study:	18 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria All subjects

males or females aged 18 to 70 years inclusive (subjects with normal renal function, mild or moderate renal impairment), and 18 to 75 years inclusive (subjects with severe renal impairment)
body mass index 18.0 to 40.0 kilogram (kg)/square meter (m^2) inclusive
females who are non-pregnant, non-lactating, or postmenopausal for >=1 year, surgically sterile for >= 90 days, or agree to use approved methods of contraception
males will be sterile or use approved methods of contraception
understands and signs informed consent form Healthy subjects with normal renal function
negative test for selected drugs of abuse (excludes alcohol) at Screening and Check-in
good health with no clinically significant medical history, physical examination, vital signs, or 12-lead ECG
clinical laboratory tests within the reference range or not clinically significant
normal renal function (estimated CLcr >90 mL/min) at Screening Subjects with mild, moderate or severe renal impairment
negative test for selected drugs of abuse (excludes alcohol) at Screening and Check-in or verification of a prescription for a positive test
renal impairment (estimated CLcr <90 mL/min)
evidence of stable renal impairment defined as two separate estimated CLcr values within 25%
clinical laboratory results consistent with their renal condition or of no clinical significance for the study
abnormal laboratory values must not be clinically significant. Anemia secondary to renal disease is acceptable if hemoglobin is ≥9 g/dL and no clinically significant symptoms. Liver enzymes and bilirubin must be below twice the upper normal level
subjects with renal impairment must have stable underlying medical conditions < 90 days before study start
stable medication regimen(s) (no new drug(s) or changed dosage(s) <30 days before study drug)
in good general health, allowing for concurrent illnesses associated with chronic kidney disease

Exclusion Criteria:

All subjects:

history of hypersensitivity or allergies to any drug, unless approved by the Investigator and reviewed by Sponsor/Medical Monitor
participation in a study with receipt of an investigational drug < 5 half-lives or 30 days (whichever is longer) before Check-in
use of alcohol, grapefruit, or caffeine-containing foods or beverages < 72 hours before Check-in, unless approved by the Investigator and reviewed by the Sponsor/Medical Monitor
poor peripheral venous access
whole blood donation < 56 days before dosing or plasma donation < 14 days before dosing
receipt of blood products < 2 months before Check-in
history or presence of any clinically significant abnormal ECG
history of alcoholism or drug addiction < 1 year before Check-in
positive test for HIV antibody, HBsAg or anti-HCV
pregnant or breastfeeding

Healthy subjects with normal renal function:

use of any tobacco- or nicotine-containing products < 6 months before Check-in
clinically significant (history of or active) cardiac, hepatic, pulmonary, endocrine, neurological, infectious, gastrointestinal, hematologic, oncologic, or psychiatric disease putting the subject at increased risk or could interfere with study objectives
screening laboratory values outside normal range and deemed clinically significant by the Investigator
use of a prescription drug < 14 days of dosing or a non-prescription drug < 7 days before dosing or need of concomitant medication during the study

Subjects with mild, moderate, or severe renal impairment:

unstable disease (concurrent medical conditions that have changed significantly < 90 days)
changes in concomitant prescription medications < 30 days before dosing or expected changes during study
use of new non-prescription medication < 30 days before dosing
renal transplant
acute or chronic non-renal condition limiting the subject's ability to complete and/or participate in the study

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01730469

Sponsors and Collaborators

GlaxoSmithKline

Amicus Therapeutics

Investigators

Study Director:

GSK Clinical Trials

GlaxoSmithKline

More Information

No publications provided

Responsible Party:	GlaxoSmithKline
ClinicalTrials.gov Identifier:	NCT01730469 History of Changes
Other Study ID Numbers:	116431
Study First Received:	November 8, 2012
Last Updated:	February 21, 2013
Health Authority:	United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:

Pharmacokinetics
GR181413
Safety
AT1001
Migalastat hydrochloride

Additional relevant MeSH terms:

Fabry Disease
Renal Insufficiency
Sphingolipidoses
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Genetic Diseases, X-Linked

Genetic Diseases, Inborn
Metabolism, Inborn Errors
Lipidoses
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders
Kidney Diseases
Urologic Diseases

ClinicalTrials.gov processed this record on May 23, 2013