A Study of AT1001 (Migalastat Hydrochloride) in Participants With Fabry Disease

Phase 2

Completed

• Conditions: Fabry Disease
• Interventions: Drug: migalastat HCl

• Registration Number: NCT00214500
• Lead Sponsor: Amicus Therapeutics

Brief Summary

Study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of migalastat hydrochloride (HCl) (migalastat) in participants with Fabry disease.

Detailed Description

This was a Phase 2, open-label study in male participants with Fabry disease. All participants who met initial eligibility criteria underwent a 28-day screening period, including a 14-day run-in with migalastat (150 milligrams \[mg\] migalastat once a day \[QD\] from Days -28 to -15) to assess eligibility for entering the treatment period of the study. Participants who entered the treatment period were required to have α-galactosidase A (α-Gal A) activity responsive to migalastat.

Fifteen participants received at least 1 dose of study drug, however, 6 of these participants did not demonstrate α-Gal A activity responsive to migalastat and were thus screen failures (these participants are hereafter referred to as "dosed screen failures") due to not meeting all inclusion criteria for treatment. Therefore, 9 participants were enrolled into the treatment period (these participants are hereafter referred to as "eligible-enrolled").

Eligible-enrolled participants (those who satisfied the criteria for inclusion in the study) received escalating doses of migalastat twice a day (BID) for 6 weeks (Days 1 to 42), followed by 6 weeks at 1 dose level BID (Days 43 to 84) during the treatment period. Participants could then opt to participate in the extension period. The study consisted of 2 optional extension periods, the first through Week 48 and the second through Week 96. For participants who did not continue into the optional treatment extension, the study included a 2-week follow-up period.

Study Timeline

• Study First Submitted: 2005-09-13
• Study First Submitted QC: 2005-09-14
• Study First Posted: 2005-09-22
• Study Start: 2006-01-02
• Primary Completion: 2008-01-29
• Study Completion: 2008-01-29
• Disposition First Submitted: 2010-08-17
• Disposition First Submitted QC: 2010-08-17
• Disposition First Posted: 2010-08-19
• Results First Submitted: 2018-08-10
• Results First Submitted QC: 2018-08-10
• Results First Posted: 2018-09-07
• Status Verified: 2018-10
• Last Update Submitted: 2018-10-01
• Last Update Posted: 2018-10-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 9

Inclusion Criteria

• Males between 18 and 55 years of age (inclusive)
• Hemizygous for Fabry disease
• Had a confirmed diagnosis of Fabry disease with a documented missense gene mutation (individual or familial)
• Had enhanceable enzyme activity
• In the judgment of the investigator, were either able to safely suspend ERT throughout the study, or be ERT naive
• Agreed to be sexually abstinent or use a condom with spermicide when engaging in sexual activity during the course of the study and for a period of 30 days following completion of the study
• Were willing and able to sign an informed consent form

Exclusion Criteria

• History of significant disease other than Fabry disease (for example, end-stage renal disease; Class III or IV heart disease [per the New York Heart Association classification]; current diagnosis of cancer, except for basal cell carcinoma of the skin; diabetes [unless hemoglobin A1c ≤8]; or neurological disease that would have impaired the participant's ability to participate in the study)
• History of organ transplant
• Serum creatinine >2 mg per deciliter on Day -2
• Screening 12-lead electrocardiogram demonstrating corrected QT interval >450 milliseconds prior to dosing
• Taking a medication prohibited by the protocol: Fabrazyme® (agalsidase beta), Replagal™ (agalsidase alfa), Glyset® (miglitol), Zavesca® (miglustat), or any experimental therapy for any indication
• Participated in a previous clinical trial in the last 30 days
• Any other condition, which, in the opinion of the investigator, would jeopardize the safety of the participant or impact the validity of the study results

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Migalastat	migalastat HCl	Migalastat was administered orally during the 12-week treatment period and then during the optional 2 treatment extension periods. Treatment Period: * Migalastat 25 mg BID for Weeks 1 and 2 (Day 1 through the morning dose on Day 14). * Migalastat 100 mg BID for Weeks 3 and 4 (Day 15 through the morning dose on Day 28). * Migalastat 250 mg BID for Weeks 5 and 6 (Day 29 through the morning dose on Day 42). * Migalastat 25 mg BID for Weeks 6 to 12 (Days 43 to 84). Extension Period: * Migalastat 25 mg BID for Weeks 12 through 48. * Migalastat 50 mg QD for Weeks 48 through 96.

Primary Outcome Measures

Name	Time	Method
Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs)	Day 1 (after dosing) through Week 96	TEAEs were defined as any adverse event with start date on or after administration of study drug or pre-existing conditions that worsened on or after the start of the first study drug administration (on Day 1). A severe adverse event was defined as an adverse event that was incapacitating and required medical intervention. The number of participants who experienced one or more severe TEAEs after dosing on Day 1 through Week 96 is presented. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.

Secondary Outcome Measures

Name	Time	Method
PK: Area Under The Concentration Versus Time Curve (AUC) After Administration Of Migalastat	0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, and 10 hr (postdose)	The AUC from time zero to 12 hours (hr) postdose (AUC0-12) was evaluated in plasma following a single dose of migalastat 25, 100, and 250 mg on Days 1, 15, and 29, respectively. In addition, AUC0-12 was assessed following multiple doses (14 days) of migalastat 25, 100, and 250 mg on Days 14, 28, and 42, respectively.
α-Galactosidase A (α-Gal A) Activity In Leukocytes At Baseline, Week 12, And Week 96	Baseline, Week 12 (end of treatment period), Week 96 (end of extension period)	Leukocytes were isolated from whole blood and lysed, and α-Gal A activity was measured using a validated fluorometric assay, with catalysis to fluorescent 4-methylumbelliferone (4-MU) as the activity measure. The activity values obtained were normalized to protein (measured using a colorimetric assay) and reported as enzyme activity (nanomole \[nmol\] 4-MU/hr) per mg of protein. On Day 1 of the first visit and at every visit thereafter, the samples were collected prior to dosing with migalastat. α-Gal A activity in leukocytes are presented by individual participants.