Fabry Disease
Conditions
Keywords
Amicus Therapeutics, AT1001, Galafold, Migalastat, Substrate
Brief summary
Study to evaluate the long-term safety, tolerability, and pharmacodynamics (PD) of migalastat hydrochloride (HCl) (migalastat) in participants with Fabry disease
Detailed description
This was a long-term open-label study of migalastat in participants with Fabry disease who were previously enrolled in a Phase 2 study of migalastat (FAB-CL-201 \[NCT00214500\], FAB-CL-202 \[NCT00283959\], FAB-CL-203 \[NCT00283933\], or FAB-CL-204 \[NCT00304512\]). Participants could enter this extension study immediately upon completion of participation in their previous study of migalastat, or at a later time point. Thus, some participants did not necessarily have continuous treatment with migalastat from the end of the original study to the time of enrollment into this extension study. Participants who enrolled before Protocol Amendment 2 received migalastat 150 milligrams (mg) orally once every other day (QOD). After the amendment, these participants entered a dose escalation period (DEP) at their next scheduled visit. During the DEP, participants received migalastat 250 mg (once daily \[QD\] for 3 days and 4 days off per week) for the first 2 months. If there were no safety concerns, the dose was then increased to 500 mg QD for 3 days and 4 days off per week). Participants received 500 mg (QD for 3 days and 4 days off per week) for up to 10 months, depending on the approval date of the protocol amendments at each site. An interim review of safety and PD data was performed after all enrolled participants had completed at least 4 months of treatment in the DEP. After the review, the dose and regimen of migalastat was returned to 150 mg QOD for all participants, except those who were on another dose as previously agreed by the investigator and medical monitor. The sponsor (Amicus Therapeutics) discontinued Study FAB-CL-205 for logistical reasons and not due to either safety concerns or lack of efficacy. Participants who were ongoing in Study FAB-CL-205 at the time of discontinuation were offered participation in another open-label, long-term treatment study of migalastat (AT1001-041 \[NCT01458119\]). Participants who did not enroll in Study AT1001-041 were contacted by telephone or another suitable method approximately 1 month after the End of Study (EOS) visit to inquire about adverse events and concomitant medications.
Interventions
DRUGmigalastat HCl
Sponsors
Amicus Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must have completed another Phase 2 study of migalastat in Fabry Disease * Women of childbearing potential must have had a negative result on their pregnancy test * Male and female participants agreed to use a reliable method of contraception during study treatment and for 4 weeks after study treatment termination * Were willing and able to provide written informed consent
Exclusion criteria
* Had not completed a Phase 2 study of migalastat in Fabry Disease * Had a major protocol violation in the preceding migalastat trial and was discontinued * Had undergone or was scheduled to undergo kidney transplantation or was currently on dialysis * Had been treated with another investigational drug (except migalastat) within 30 days of study start * Had been treated with Fabrazyme® (agalsidase beta), Replagal™ (agalsidase alfa), Glyset® (miglitol), or Zavesca® (miglustat) within 2 weeks prior to enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs) | Day 1 (after dosing) through EOS (up to 56 months) or follow-up (28 days after EOS) | A TEAE was defined as any adverse event (AE) 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 AE was defined as an AE that was incapacitating and required medical intervention. The number of participants who experienced one or more severe TEAEs after dosing on Day 1 through End of Study (EOS) or follow-up (for participants who did not enroll in Study AT1001-041) are presented. A summary of serious and all other non-serious AEs regardless of causality is located in the Reported Adverse Events module. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline In α-Galactosidase A (α-Gal A) Activity In Leukocytes To Month 42 | Baseline, Month 42 | The activity of the α-Gal A enzyme was measured in leukocyte lysate by a validated fluorometric assay method, using 4-methylumbelliferone as a reference. The activity values obtained were normalized to protein (measured using a colorimetric assay). Baseline was defined as the last non-missing pre-treatment value for each participant in his or her respective preceding migalastat Phase 2 study. A negative change from Baseline indicates that α-Gal A activity decreased. α-Gal A activity levels are presented for Baseline and Month 42. |
| Pharmacokinetics Of Migalastat As Assessed By Plasma Concentration | 0 (predose on Day 1; start of DEP), 3 hr (postdose at Month 2; during DEP]) | The concentration of migalastat was evaluated in plasma following a dose of 250 mg and 500 mg. Blood samples were taken at trough (predose or Time 0; just prior to the third dose during a 3 day on, 4 days off dosing regimen) and at peak (3 hr postdose; after the third dose during a 3 day on, 4 days off dosing regimen) during the Day 1 (250 mg) and Month 2 (500 mg) visits. This outcome presents the lowest and highest concentrations of migalastat measured in any of the participants for predose and 3 hr postdose. |
Countries
Australia, Brazil, France, United Kingdom, United States
Participant flow
Recruitment details
An open label, long-term extension study for participants who completed one of 4 preceding Phase 2 studies (FAB-CL-201 \[NCT00214500\], FAB-CL-202 \[NCT00283959\], FAB-CL-203 \[NCT00283933\], or FAB-CL-204 \[NCT00304512\]). Participants could enter this study directly upon completion of the previous study or at a later point.
Pre-assignment details
This study included a dose escalation period (DEP), in which migalastat was administered at 250 milligrams (mg) for 2 months. If there were no safety concerns the dose was increased to 500 mg for up to 10 months, depending on the date of amendment approval. Before and after the DEP, all but 1 participant (post-DEP 300 mg instead) received 150 mg.
Participants by arm
| Arm | Count |
|---|---|
| Migalastat Participants received migalastat 150 mg given orally QOD before and after the DEP. During the DEP participants received 250 mg QD for 3 days, 4 days off per week for 2 months then 500 mg QD for 3 days, 4 days off per week for up to 10 months, depending on the approval date of the protocol amendments at each site. One participant received migalastat 300 mg (QD for 3 days and 4 days off per week) until the end of the study. | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Lack of Response to Study Drug | 4 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Migalastat |
|---|---|
| Age, Continuous | 43.1 years STANDARD_DEVIATION 11.33 |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 23 / 23 |
| serious Total, serious adverse events | 7 / 23 |
Outcome results
Primary
Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs)
A TEAE was defined as any adverse event (AE) 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 AE was defined as an AE that was incapacitating and required medical intervention. The number of participants who experienced one or more severe TEAEs after dosing on Day 1 through End of Study (EOS) or follow-up (for participants who did not enroll in Study AT1001-041) are presented. A summary of serious and all other non-serious AEs regardless of causality is located in the Reported Adverse Events module.
Time frame: Day 1 (after dosing) through EOS (up to 56 months) or follow-up (28 days after EOS)
Population: Safety Population: all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Migalastat | Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs) | 9 Participants |
Secondary
Absolute Change From Baseline In α-Galactosidase A (α-Gal A) Activity In Leukocytes To Month 42
The activity of the α-Gal A enzyme was measured in leukocyte lysate by a validated fluorometric assay method, using 4-methylumbelliferone as a reference. The activity values obtained were normalized to protein (measured using a colorimetric assay). Baseline was defined as the last non-missing pre-treatment value for each participant in his or her respective preceding migalastat Phase 2 study. A negative change from Baseline indicates that α-Gal A activity decreased. α-Gal A activity levels are presented for Baseline and Month 42.
Time frame: Baseline, Month 42
Population: PD Population: all participants who received at least 1 dose of study drug and who had a baseline measurement and at least 1 postbaseline PD measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Migalastat | Absolute Change From Baseline In α-Galactosidase A (α-Gal A) Activity In Leukocytes To Month 42 | Month 42 | 7.88 nanomoles (nm)/hour (hr)/mg protein | Standard Deviation 8.691 |
| Migalastat | Absolute Change From Baseline In α-Galactosidase A (α-Gal A) Activity In Leukocytes To Month 42 | Baseline | 2.08 nanomoles (nm)/hour (hr)/mg protein | Standard Deviation 2.433 |
| Amenable Population; Women | Absolute Change From Baseline In α-Galactosidase A (α-Gal A) Activity In Leukocytes To Month 42 | Baseline | 16.84 nanomoles (nm)/hour (hr)/mg protein | Standard Deviation 7.955 |
| Amenable Population; Women | Absolute Change From Baseline In α-Galactosidase A (α-Gal A) Activity In Leukocytes To Month 42 | Month 42 | 18.31 nanomoles (nm)/hour (hr)/mg protein | Standard Deviation 14.186 |
| Non-amenable Population; Men | Absolute Change From Baseline In α-Galactosidase A (α-Gal A) Activity In Leukocytes To Month 42 | Baseline | 0.09 nanomoles (nm)/hour (hr)/mg protein | Standard Deviation 0.047 |
| Non-amenable Population; Women | Absolute Change From Baseline In α-Galactosidase A (α-Gal A) Activity In Leukocytes To Month 42 | Baseline | 14.62 nanomoles (nm)/hour (hr)/mg protein | Standard Deviation 8.944 |
| Non-amenable Population; Women | Absolute Change From Baseline In α-Galactosidase A (α-Gal A) Activity In Leukocytes To Month 42 | Month 42 | 9.77 nanomoles (nm)/hour (hr)/mg protein | Standard Deviation 5.071 |
Secondary
Pharmacokinetics Of Migalastat As Assessed By Plasma Concentration
The concentration of migalastat was evaluated in plasma following a dose of 250 mg and 500 mg. Blood samples were taken at trough (predose or Time 0; just prior to the third dose during a 3 day on, 4 days off dosing regimen) and at peak (3 hr postdose; after the third dose during a 3 day on, 4 days off dosing regimen) during the Day 1 (250 mg) and Month 2 (500 mg) visits. This outcome presents the lowest and highest concentrations of migalastat measured in any of the participants for predose and 3 hr postdose.
Time frame: 0 (predose on Day 1; start of DEP), 3 hr (postdose at Month 2; during DEP])
Population: Safety Population: all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Migalastat | Pharmacokinetics Of Migalastat As Assessed By Plasma Concentration | Predose Lowest Concentration | 5.94 nanograms/milliliter |
| Migalastat | Pharmacokinetics Of Migalastat As Assessed By Plasma Concentration | Predose Highest Concentration | 313 nanograms/milliliter |
| Migalastat | Pharmacokinetics Of Migalastat As Assessed By Plasma Concentration | 250 mg 3 hr Postdose Lowest Concentration | 908 nanograms/milliliter |
| Migalastat | Pharmacokinetics Of Migalastat As Assessed By Plasma Concentration | 250 mg 3 hr Postdose Highest Concentration | 5250 nanograms/milliliter |
| Migalastat | Pharmacokinetics Of Migalastat As Assessed By Plasma Concentration | 500 mg 3 hr Postdose Lowest Concentration | 113 nanograms/milliliter |
| Migalastat | Pharmacokinetics Of Migalastat As Assessed By Plasma Concentration | 500 mg 3 hr Postdose Highest Concentration | 8500 nanograms/milliliter |