Clinical Trial Results:
An Open-Label Extension Study to Evaluate the Long-Term Safety and Efficacy of Migalastat Hydrochloride Monotherapy in Subjects With Fabry Disease
|
Summary
|
|
EudraCT number |
2011-004800-40 |
Trial protocol |
GB ES IT DK BE AT |
Global end of trial date |
17 Feb 2016
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
19 May 2017
|
First version publication date |
19 May 2017
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
AT1001-041
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT01458119 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Amicus Therapeutics, Inc.
|
||
Sponsor organisation address |
1 Cedarbrook Drive, Cranbury, United States, NJ 08512
|
||
Public contact |
Medical Information, Amicus Therapeutics, Inc., MedInfo_Amicus@quintiles.com
|
||
Scientific contact |
Medical Information, Amicus Therapeutics, Inc., MedInfo_Amicus@quintiles.com
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
17 Feb 2016
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
17 Feb 2016
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
17 Feb 2016
|
||
Was the trial ended prematurely? |
Yes
|
||
|
General information about the trial
|
|||
Main objective of the trial |
To assess the long-term safety of migalastat in the treatment of subjects with Fabry disease who completed treatment in a previous study of migalastat. The previous studies include AT1001-011, AT1001-012 and FAB-CL-205.
|
||
Protection of trial subjects |
The study was conducted in accordance with the principles of the Declaration of Helsinki including amendments in force up to and including the time the study was conducted. The study was conducted in compliance with the International Conference on Harmonisation E6 Guideline for Good Clinical Practice, and is compliant with the European Union Clinical Trial Directive 2001/20/EC. The study was also conducted in compliance with the United States Food and Drug Administration regulations in 21 Code of Federal Regulations.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
14 Oct 2011
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
No
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Argentina: 1
|
||
Country: Number of subjects enrolled |
Australia: 16
|
||
Country: Number of subjects enrolled |
Belgium: 1
|
||
Country: Number of subjects enrolled |
Brazil: 5
|
||
Country: Number of subjects enrolled |
Canada: 3
|
||
Country: Number of subjects enrolled |
Denmark: 12
|
||
Country: Number of subjects enrolled |
Egypt: 1
|
||
Country: Number of subjects enrolled |
France: 7
|
||
Country: Number of subjects enrolled |
Italy: 1
|
||
Country: Number of subjects enrolled |
Spain: 2
|
||
Country: Number of subjects enrolled |
Turkey: 4
|
||
Country: Number of subjects enrolled |
United Kingdom: 6
|
||
Country: Number of subjects enrolled |
United States: 26
|
||
Worldwide total number of subjects |
85
|
||
EEA total number of subjects |
29
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
76
|
||
From 65 to 84 years |
9
|
||
85 years and over |
0
|
||
|
|||||||||||||||||||||||
|
Recruitment
|
|||||||||||||||||||||||
Recruitment details |
85 eligible subjects with Fabry disease who had completed migalastat monotherapy treatment in a previous study (AT1001-011, AT1001-012 or FAB-CL-205) were enrolled in this open-label extension study to enable collection of longer term safety and efficacy data. First subject enrolled: 14 October 2011. Last subject completed: 17 February 2016. | ||||||||||||||||||||||
|
Pre-assignment
|
|||||||||||||||||||||||
Screening details |
Eligible subjects were enrolled if in the opinion of the investigator they could benefit from remaining on migalastat treatment. 85 subjects received at least 1 dose of study drug; of these 68 had amenable mutations in the gene encoding an alpha-galactosidase-A (α-Gal-A)(GLA) genotype that responds to migalastat in the migalastat amenability assay. | ||||||||||||||||||||||
|
Period 1
|
|||||||||||||||||||||||
Period 1 title |
Overall Trial (overall period)
|
||||||||||||||||||||||
Is this the baseline period? |
Yes | ||||||||||||||||||||||
Allocation method |
Non-randomised - controlled
|
||||||||||||||||||||||
Blinding used |
Not blinded | ||||||||||||||||||||||
|
Arms
|
|||||||||||||||||||||||
|
Arm title
|
Migalastat | ||||||||||||||||||||||
Arm description |
Subjects who completed migalastat monotherapy treatment in a previous study and who were eligible to participate were enrolled in this study to enable continued migalastat treatment on a dosing regimen of migalastat hydrochloride (migalastat HCl) 150 milligrams (mg) once every other day (QOD). Inactive reminder capsules were taken on alternate days. In order to ensure continuous treatment with migalastat during the transition from the previous study, subjects were given the first dose of either migalastat HCl or the inactive reminder capsule during the baseline visit to maintain the migalastat HCl 150 mg QOD dosing regimen. | ||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||
Investigational medicinal product name |
Migalastat HCl
|
||||||||||||||||||||||
Investigational medicinal product code |
AT1001
|
||||||||||||||||||||||
Other name |
Migalastat
|
||||||||||||||||||||||
Pharmaceutical forms |
Capsule, hard
|
||||||||||||||||||||||
Routes of administration |
Oral use
|
||||||||||||||||||||||
Dosage and administration details |
150 mg of migalastat HCl was administered orally QOD at approximately the same time each day. Subjects were required to fast 2 hours before and 2 hours after taking each dose.
|
||||||||||||||||||||||
|
|||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Migalastat
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects who completed migalastat monotherapy treatment in a previous study and who were eligible to participate were enrolled in this study to enable continued migalastat treatment on a dosing regimen of migalastat hydrochloride (migalastat HCl) 150 milligrams (mg) once every other day (QOD). Inactive reminder capsules were taken on alternate days. In order to ensure continuous treatment with migalastat during the transition from the previous study, subjects were given the first dose of either migalastat HCl or the inactive reminder capsule during the baseline visit to maintain the migalastat HCl 150 mg QOD dosing regimen. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Migalastat
|
||
Reporting group description |
Subjects who completed migalastat monotherapy treatment in a previous study and who were eligible to participate were enrolled in this study to enable continued migalastat treatment on a dosing regimen of migalastat hydrochloride (migalastat HCl) 150 milligrams (mg) once every other day (QOD). Inactive reminder capsules were taken on alternate days. In order to ensure continuous treatment with migalastat during the transition from the previous study, subjects were given the first dose of either migalastat HCl or the inactive reminder capsule during the baseline visit to maintain the migalastat HCl 150 mg QOD dosing regimen. | ||
|
|||||||||||||||||||||||||
End point title |
Number of subjects experiencing treatment emergent adverse events (TEAEs). [1] | ||||||||||||||||||||||||
End point description |
The long term safety of migalastat was assessed in the treatment of subjects with Fabry disease who completed treatment in a previous study of migalastat. The number of subjects experiencing TEAEs is presented for subjects who received migalastat treatment in this open-label extension study. The duration of migalastat exposure was from less than 6 months up to approximately 42 months, over a period of approximately 4 years and 4 months (52 months).
|
||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||
End point timeframe |
Up to 52 months
|
||||||||||||||||||||||||
| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The study analyses were performed using descriptive statistics. No statistical inference testing was performed for this end point. |
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||
End point title |
Annualized rate of change in the estimated glomerular filtration rate (eGFR) | ||||||||||||
End point description |
The annualized rate of change was assessed per subject by the slope of the simple linear regression between the observed values and the assessment times. The annualized rate of change in the eGFR was assessed in the following ways:
• by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (eGFR[CKD-EPI])
• by the Modification of Diet in Renal Disease equation (eGFR[MDRD]).
The mean change in eGFR[CKD-EPI] and eGFR[MDRD] from baseline to End of Study is presented for the Intention-to-Treat [ITT]-Amenable Population. The ITT-Amenable Population included all subjects with mutations amenable to migalastat in the migalastat amenability assay who took at least 1 dose of study drug after they enrolled into this open-label extension study. The number of subjects with at least a baseline and a post-baseline value are presented. The mean duration of this period was 2.03+/-0.691 years.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to End of Study (approximately 2 years mean duration)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||||
End point title |
Change from Baseline in 24-Hour Urine Protein | ||||||||||||||||||||
End point description |
The change from baseline at each visit in the 24 hour urine protein are presented.
The ITT-Amenable Population included all subjects with mutations amenable to migalastat in the migalastat amenability assay who took at least 1 dose of study drug after they enrolled into this open-label extension study. The number of subjects (n) with values at each timepoint are presented.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline to Month 36 visit
|
||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||||||||||||
End point title |
Change from Baseline in 24-Hour Urine Albumin:Creatinine Ratio | ||||||||||||||||||||
End point description |
The change from baseline at each visit in the 24 hour urine Albumin:Creatinine Ratio are presented.
The ITT-Amenable Population included all subjects with mutations amenable to migalastat in the migalastat amenability assay who took at least 1 dose of study drug after they enrolled into this open-label extension study. The number of subjects (n) with values at each timepoint are presented.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline to Month 36 visit
|
||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||||||
End point title |
Change from Baseline in Left Ventricular Mass Index (LVMi) | ||||||||||||||
End point description |
The change from baseline at the Month 12, 24 and 36 visits in the LVMi as measured by echocardiogram (ECHO) are presented.
The following are the LVMi ranges:
Female:
Normal: 43-95 g/m2; mildly abnormal: 96-108 g/m2; moderately abnormal: 109-121 g/m2; severely abnormal:>/=122 g/m2.
Male:
Normal: 49-115 g/m2; mildly abnormal: 116-131 g/m2; moderately abnormal: 132-148 g/m2; severely abnormal: >/=149 g/m2.
The ITT-Amenable Population included all subjects with mutations amenable to migalastat in the migalastat amenability assay who took at least 1 dose of study drug after they enrolled into this open-label extension study. The number of subjects (n) with values at each timepoint are presented.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Baseline to Month 36 visit
|
||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||||||||
End point title |
Change from Baseline in the White Blood Cell (WBC) α-Gal-A activity for male subjects | ||||||||||||||||||||
End point description |
The change from baseline at each visit in the α-Gal-A activity in WBCs is presented for male subjects in the ITT-Amenable Population. Higher values indicate less disability. As females are mosaic and express both mutant and wild-type α-Gal-A, the assessment of α-Gal-A activity is not relevant in female patients.
The ITT-Amenable Population included all subjects with mutations amenable to migalastat in the migalastat amenability assay who took at least 1 dose of study drug after they enrolled into this open-label extension study. The number of subjects (n) with values at each timepoint are presented.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline to Month 36 visit
|
||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
AEs were collected from the baseline visit to End of Study at each 6 monthly clinic visit. Treatment duration varied among subjects, ranging from under 6 months to approximately 42 months, over a period of approximately 4 years and 4 months (52 months).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
The Safety Population included all subjects who took at least 1 dose of study drug after they enrolled into this open-label extension study.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Migalastat
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects who completed migalastat monotherapy treatment in a previous study and who were eligible to participate were enrolled in this study to enable continued migalastat treatment on a dosing regimen of migalastat hydrochloride (migalastat HCl) 150 milligrams (mg) once every other day (QOD). Inactive reminder capsules were taken on alternate days. In order to ensure continuous treatment with migalastat during the transition from the previous study, subjects were given the first dose of either migalastat HCl or the inactive reminder capsule during the baseline visit to maintain the migalastat HCl 150 mg QOD dosing regimen. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
06 Feb 2012 |
1. Review of informed consent and inclusion/exclusion criteria at baseline added; clarified that labs, except for eGFR and pregnancy tests would be performed at the Follow-up visit, regardless of subject's withdrawal status, and removed the urine globotriaosylceramide (GL-3) assessment.
2. Clarified that subjects who met any withdrawal criteria and withdrew from the study were asked to return for a Follow-up visit within 30 days of the last treatment dose for assessments.
3. Footnote added to Table 1 (Time and Events) to clarify that an ECHO was to be performed for withdrawn subjects who did not have an ECHO performed in the previous 6 months.
4. Follow-Up visit defined as approximately 30 days after last treatment.
5. Clarified avoidance of certain drugs with potential for interaction with migalastat.
6. Removed urobilinogen for the urinalysis parameters. |
||
31 Jul 2012 |
1. Clarified the window time for collection of baseline visit assessments.
2. Clarified the assessments performed for Early Withdrawal. |
||
26 Nov 2012 |
1. Optional GLA genotyping added.
2. Etonogestrel implants included as a contraceptive method with a failure rate of <1% per year.
3. Language in Retained Urine and Serum Samples section altered to offer the option to decline. |
||
27 Jan 2014 |
1. Amicus added as sponsor and relevant updates made.
2. Urine GL-3 was removed as an assessment.
3. Data Safety Monitoring Board added to review safety data and stopping criteria.
4. Addition of cardiac measures to match previous studies.
5. Requirement to review inclusion/exclusion criteria every 6 months added.
6. Information about how long the protocol remained open added.
7. Reference to French subjects inclusion criteria removed.
8. Exclusion criteria updated to match previous studies.
9. Investigational Product text removed.
10. Prohibited medications and nondrug therapies updated and sites requested to avoid certain drugs that resulted in accumulation of phospholipids in lysosomes.
11. Critical baseline assessments updated to discuss conditions that had potential to impact subjects' condition on trial.
12. Safety assessments updated to include stopping criteria.
13. Addition of optional blood draw for testing of Fabry biomarkers for future exploratory analyses.
14. ITT efficacy Population removed. |
||
09 Jul 2014 |
1. New text added about study discontinuation for logistical reasons and not due to either safety concerns or lack of effiacy. Text on reasons for study conclusion deleted.
2. End of Study visit added.
3. Text on Early Withdrawal, End of Study and Follow-Up Visit added. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| The study was discontinued for logistical reasons and not due to either safety concerns or lack of efficacy. The investigators discussed participation in a similar long-term migalastat treatment study for subjects ongoing at time of discontinuation. | |||
