Fabry Disease
Conditions
Keywords
Amicus Therapeutics, AT1001, Galafold, Migalastat
Brief summary
This was a long-term, open-label study of migalastat (123 milligrams \[mg\] of migalastat \[equivalent to 150 mg of migalastat hydrochloride\]) (migalastat) in participants with Fabry disease who completed treatment in a previous monotherapy trial with migalastat.
Detailed description
Study AT1001-041 was an open-label, noncomparative, multicenter, long-term extension study for participants with Fabry disease who completed treatment in one of three previous trials of migalastat (AT1001-011 \[NCT00925301\], AT1001-012 \[NCT01218659\], or FAB-CL-205 \[NCT00526071\]). In these trials, migalastat was given as monotherapy. This was an extension study designed to evaluate the long-term safety and efficacy of migalastat for the treatment of Fabry disease. Study visits occurred every 6 months (m). Visit evaluations included physical examinations, clinical laboratory parameters, adverse events, and participant reported outcomes. The study consisted of a Baseline Visit, which was performed at the time of the final visit of the previous study, followed by clinic visits every 6 m for each year of the study. Study assessments included a physical examination, echocardiography, laboratory parameters, and participant-reported outcomes. Since participants enrolled in the study at varying time points based on the completion of the preceding migalastat study, treatment duration varied among participants. No maximum treatment duration was defined. There were no control groups in this study; all participants received migalastat as a 150-mg capsule taken orally once every other day (QOD) and inactive reminder capsules on alternate days. The sponsor (Amicus Therapeutics) discontinued Study AT1001-041 for logistical reasons and not due to either safety concerns or lack of efficacy. For participants who were ongoing in Study AT1001-041 at the time of discontinuation, the investigators were offered participation in a similar open-label, long-term migalastat treatment study (AT1001-042 \[NCT02194985\]) for participants ongoing at discontinuation.
Interventions
Oral capsule QOD
Sponsors
Amicus Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Completed migalastat treatment in a previous Fabry disease protocol * Both male and female participants were enrolled * Age 16 years or older * Male and female participants had to agree to use protocol-identified acceptable contraception
Exclusion criteria
* Estimated glomerular filtration rate (eGFR) in the previous study was \<30 milliliters/minute/1.73 square meters (mL/min/1.73 m\^2) unless there was a measured GFR available within 3 m of the Baseline Visit that was \>30 mL/min/1.73 m\^2 * Had undergone, or was scheduled to undergo, kidney transplantation or was currently on dialysis * Pregnant or breast feeding * Treated with another investigational drug (except migalastat) within 30 days of study start * Unable to comply with study requirements, or deemed otherwise unsuitable for study entry, in the opinion of the investigator * Had documented transient ischemic attack, stroke, unstable angina, or myocardial infarction within the 12 m before the Baseline Visit * Had clinically significant, unstable cardiac disease in the opinion of the investigator * Had a history of allergy or sensitivity to migalastat (including excipients) or to other iminosugars * Required treatment with Glyset (miglitol) or Zavesca (miglustat) * Had any intercurrent illness or condition that may have precluded the participant from fulfilling the protocol requirements * Had a severe or unsuitable concomitant medical condition * Had a clinically significant abnormal laboratory value and a clinically significant electrocardiogram finding at the Baseline Visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number Of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) | Baseline to End of Follow-up (30 days after the end of this 42-month study), with AE reporting occurring at each study visit, which occurred once every 6 months. | An adverse event (AE) was defined as any untoward medical occurrence in a participant administered migalastat that did not necessarily have a causal relationship with the treatment. Each AE was recorded at the time of reporting; visits typically occurred every 6 months. A TEAE was defined as an AE starting on or after the first study drug administration date. Serious AEs were life-threatening or resulted in death, persistent or significant incapacitation, inpatient or prolonged hospitalization, or a congenital anomaly. The criteria for AE severity were: Mild: minimal discomfort, does not interfere with normal everyday activities; Moderate: sufficiently discomforting, interferes with normal everyday activities; Severe: prevents normal everyday activities. The number of participants experiencing TEAEs is presented for those who received migalastat treatment. 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 |
|---|---|---|
| Annualized Rate Of Change In The Estimated Glomerular Filtration Rate (eGFR) | Baseline, Every 6 m until the End of Study (42 m) | The annualized rate of change of the eGFR was assessed per participant by the slope of the simple linear regression between the observed values and the assessment times. It was calculated by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (eGFR \[CKD-EPI\]) and the Modification of Diet in Renal Disease (MDRD) equation (eGFR \[MDRD\]). The equations are as follows: eGFR \[MDRD\] = 175 \* (Serum Creatinine)\^-1.154 \* (Age)\^-0.203 \* 1.212 (if black or African American) \* 0.742 (if female); eGFR \[CKD-EPI\] = 141 \* min(serum creatinine/kappa,1)\^alpha \* max(serum creatinine/kappa, 1)\^-1.209 \* 0.993\^age \* 1.1018(if female) \* 1.159(if black or African American), where kappa is 0.7 for females and 0.9 for males, alpha is -0.329 for females and -0.411 for males, min is minimum of serum creatinine/kappa or 1, and max is the maximum of serum creatinine/kappa or 1. The number of participants with at least a Baseline and a post-Baseline value are presented. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Denmark, Egypt, France, Italy, Spain, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Eighty-five eligible participants with Fabry disease who completed treatment with migalastat in one of three previous studies (AT1001-011 \[NCT00925301\], AT1001-012 \[NCT01218659\], or FAB-CL-205 \[NCT00526071\]) were enrolled in this open-label extension study to enable the collection of long-term safety and efficacy data.
Participants by arm
| Arm | Count |
|---|---|
| Migalastat Participants received migalastat 150-mg capsule given orally QOD for a median duration of 23.5 m. Participants received an inactive reminder capsule on alternate days during the study. | 85 |
| Total | 85 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Consent Withdrawn by Participant | 8 |
| Overall Study | Death | 2 |
| Overall Study | Non-compliance With Study Drug | 3 |
| Overall Study | Physician Decision | 4 |
| Overall Study | Pregnancy | 1 |
| Overall Study | Withdrawal Due to Nonamenable Mutation | 1 |
Baseline characteristics
| Characteristic | Migalastat |
|---|---|
| Age, Continuous | 48.8 years STANDARD_DEVIATION 12.25 |
| Sex: Female, Male Female | 52 Participants |
| Sex: Female, Male Male | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 57 / 85 |
| serious Total, serious adverse events | 22 / 85 |
Outcome results
Primary
Number Of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) was defined as any untoward medical occurrence in a participant administered migalastat that did not necessarily have a causal relationship with the treatment. Each AE was recorded at the time of reporting; visits typically occurred every 6 months. A TEAE was defined as an AE starting on or after the first study drug administration date. Serious AEs were life-threatening or resulted in death, persistent or significant incapacitation, inpatient or prolonged hospitalization, or a congenital anomaly. The criteria for AE severity were: Mild: minimal discomfort, does not interfere with normal everyday activities; Moderate: sufficiently discomforting, interferes with normal everyday activities; Severe: prevents normal everyday activities. The number of participants experiencing TEAEs is presented for those who received migalastat treatment. A summary of serious and all other non-serious AEs regardless of causality is located in the Reported Adverse Events module.
Time frame: Baseline to End of Follow-up (30 days after the end of this 42-month study), with AE reporting occurring at each study visit, which occurred once every 6 months.
Population: Safety Population: All participants who received at least 1 dose of study drug after they enrolled into this open-label extension study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Migalastat | Number Of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) | Participants with at least 1 TEAE | 74 participants |
| Migalastat | Number Of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) | Participants with at least 1 serious TEAE | 22 participants |
| Migalastat | Number Of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) | Participants discontinued due to TEAEs | 1 participants |
| Migalastat | Number Of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) | Participants with adverse events leading to death | 2 participants |
| Migalastat | Number Of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) | Participants with TEAEs related to study drug | 14 participants |
| Migalastat | Number Of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) | Participants with TEAEs unrelated to study drug | 60 participants |
| Migalastat | Number Of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) | Participants with at least 1 mild TEAE | 22 participants |
| Migalastat | Number Of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) | Participants with at least 1 moderate TEAE | 40 participants |
| Migalastat | Number Of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) | Participants with at least 1 severe TEAE | 12 participants |
Secondary
Annualized Rate Of Change In The Estimated Glomerular Filtration Rate (eGFR)
The annualized rate of change of the eGFR was assessed per participant by the slope of the simple linear regression between the observed values and the assessment times. It was calculated by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (eGFR \[CKD-EPI\]) and the Modification of Diet in Renal Disease (MDRD) equation (eGFR \[MDRD\]). The equations are as follows: eGFR \[MDRD\] = 175 \* (Serum Creatinine)\^-1.154 \* (Age)\^-0.203 \* 1.212 (if black or African American) \* 0.742 (if female); eGFR \[CKD-EPI\] = 141 \* min(serum creatinine/kappa,1)\^alpha \* max(serum creatinine/kappa, 1)\^-1.209 \* 0.993\^age \* 1.1018(if female) \* 1.159(if black or African American), where kappa is 0.7 for females and 0.9 for males, alpha is -0.329 for females and -0.411 for males, min is minimum of serum creatinine/kappa or 1, and max is the maximum of serum creatinine/kappa or 1. The number of participants with at least a Baseline and a post-Baseline value are presented.
Time frame: Baseline, Every 6 m until the End of Study (42 m)
Population: ITT-Amenable Population: All participants who received at least 1 dose of study drug. Participants with mutant forms of α-Galactosidase (Gal) A determined to be amenable to migalastat based on the GLP-HEK assay are referred to as with amenable mutations. Number of participants analyzed are those with at least a Baseline and a post-Baseline value.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Migalastat | Annualized Rate Of Change In The Estimated Glomerular Filtration Rate (eGFR) | EGFR [CKD-EPI] | 1.54 milliliters/minute/1.73 meters^2 |
| Migalastat | Annualized Rate Of Change In The Estimated Glomerular Filtration Rate (eGFR) | eGFR [MDRD] | 1.40 milliliters/minute/1.73 meters^2 |