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Study to Compare the Efficacy and Safety of Oral AT1001 and Enzyme Replacement Therapy in Patients With Fabry Disease

Primary Purpose

Fabry Disease

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
migalastat hydrochloride
agalsidase
Sponsored by
Amicus Therapeutics
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Fabry Disease focused on measuring Amicus Therapeutics, Galafold, AT1001, Migalastat

Eligibility Criteria

16 Years - 74 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male or female between the ages of 16 and 74 diagnosed with Fabry disease
  • Confirmed α Gal-A mutation that is amenable to migalastat, based on the clinical trial HEK assay
  • Participant has been on ERT for at least 12 months before screening/baseline
  • Dose level and regimen of ERT have been stable for 3 months before screening/baseline and is at least 80% of the currently labeled dose and regimen for this time period
  • Glomerular filtration rate (GFR) ≥ 30 milliliter (mL)/minute (min) /1.73 m^2
  • Participants taking angiotensin converting enzyme inhibitors or angiotensin receptor blockers must be on a stable dose for at least 4 weeks before screening/baseline
  • Women who can become pregnant and all men agree to be sexually abstinent or use medically accepted methods of birth control throughout the duration of the study and for up to 30 days after last dose of study medication
  • Participant is willing and able to provide written informed consent and assent if applicable

Exclusion Criteria:

  • Participant has undergone, or is scheduled to undergo, kidney transplantation or any other solid organ transplantation
  • Participant is on regular dialysis that is specifically for the treatment of chronic kidney disease
  • Participant has had a documented transient ischemic attack, stroke, unstable angina, or myocardial infarction within the 3 months before screening/baseline
  • Participant has clinically significant unstable cardiac disease in the opinion of the investigator (for example, cardiac disease requiring active management, such as symptomatic arrhythmia, unstable angina, or New York Heart Association (NYHA) class III or IV congestive heart failure)
  • Pregnant or breast-feeding
  • History of allergy or sensitivity to study medication (including excipients) or other iminosugars (for example, miglustat, miglitol)
  • Participant has absolute contraindication to iohexol and/or inability to undergo iohexol GFR testing
  • Participant requires treatment with Glyset® (miglitol), or Zavesca® (miglustat)
  • Participant received any investigational/experimental drug, biologic or device within 30 days of screening/baseline
  • Any intercurrent illness or condition that may preclude the participant from fulfilling the study requirements or suggests to the investigator that the participant may have an unacceptable risk by participating in this study

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Migalastat

ERT

Arm Description

Participants received 150 mg migalastat orally QOD during the 18-month randomized treatment period and the optional 12-month OLE period. Participants received an inactive reminder capsule on alternate days during both treatment periods.

Participants received ERT (either agalsidase alfa or agalsidase beta) as prescribed by the participant's treating physician and administered in accordance with the approved prescribing information during the 18-month randomized treatment period. Participants were required to be given >80% of the currently labeled dose and regimen during the 18-month randomized treatment period. During the optional 12-month OLE period, participants received 150 mg migalastat orally QOD. Participants received an inactive reminder capsule on alternate days during the OLE.

Outcomes

Primary Outcome Measures

Annualized Rate Of Change From Baseline To Month 18 In Measured Glomerular Filtration Rate
To assess renal function, measured glomerular filtration rate (GFR) was measured by the plasma clearance of unlabeled iohexol (mGFR-iohexol), a non-ionic contrast agent. The annualized rate of change in mGFR-iohexol from Baseline to Month 18 was analyzed using an analysis of covariance (ANCOVA) model with the following factors as covariates: treatment group, sex, age, Baseline GFR (mGFR-iohexol), and Baseline 24-hour (hr) urine protein. A threshold of <2.2 milliliter (mL)/minute (min)/1.73 meter squared (m^2)/year was established to compare migalastat to ERT. This difference of 2.2 mL/min/1.73 m2/year is based on the smallest expected rate of decline in estimated glomerular filtration rate (eGFR) for participants treated with agalsidase alfa for 18 months.
Annualized Rate Of Change From Baseline To Month 18 In eGFR
The eGFR assessed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was calculated using the following: eGFR-CKD-EPI = 141 x min (Serum Creatinine/κ,1)^(α) x max(Serum Creatinine/κ,1)^(-1.209) x 0.993^(Age) x 1.1018 (if female) x 1.159 (if African American or black) where: κ is 0.7 for females and 0.9 for males; α is -0.329 for females and -0.411 for males; min indicates the minimum of Serum Creatinine/κ or 1; max indicates the maximum of Serum Creatinine/κ or 1. The annualized rate of change in eGFR-CKD-EPI from Baseline to Month 18 was analyzed using an ANCOVA model with the following factors as covariates: treatment group, sex, age, Baseline GFR (eGFR-CKD-EPI), and Baseline 24-hr urine protein. A threshold of <2.2 mL/min/1.73m^2/year was established to compare migalastat to ERT. This difference of 2.2 mL/min/1.73 m2/year is based on the smallest expected rate of decline in eGFR for participants treated with agalsidase alfa for 18 months.

Secondary Outcome Measures

Annualized Rate Of Change From Baseline To Month 18 In eGFR By The Modification Of Diet In Renal Disease Equation
The GFR estimated by the Modification Of Diet In Renal Disease equation (eGFR-MDRD) was calculated using the following equation: eGFR-MDRD = 175 x (Serum Creatinine)^(-1.154) x (Age)^(-0.203) x 1.212 (if participant's race is black or African American) x 0.742 (if participant is female). The eGFR-MDRD from Baseline to Month 18 was analyzed using an ANCOVA model with the following factors as covariates: treatment group, sex, age, Baseline GFR (eGFR-CKD-EPI), and Baseline 24-hr urine protein.

Full Information

First Posted
October 6, 2010
Last Updated
October 1, 2018
Sponsor
Amicus Therapeutics
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1. Study Identification

Unique Protocol Identification Number
NCT01218659
Brief Title
Study to Compare the Efficacy and Safety of Oral AT1001 and Enzyme Replacement Therapy in Patients With Fabry Disease
Official Title
A Randomized, Open-Label Study to Compare the Efficacy and Safety of AT1001 and Enzyme Replacement Therapy (ERT) in Patients With Fabry Disease and AT1001-Responsive GLA Mutations, Who Were Previously Treated With ERT
Study Type
Interventional

2. Study Status

Record Verification Date
October 2018
Overall Recruitment Status
Completed
Study Start Date
September 8, 2011 (Actual)
Primary Completion Date
May 27, 2014 (Actual)
Study Completion Date
May 28, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Amicus Therapeutics

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Study to compare the efficacy and safety of migalastat and enzyme replacement therapy (ERT) in male and female participants with Fabry disease who are currently receiving ERT and who have an alpha galactosidase-A (α Gal-A) mutation that is amenable to migalastat, based on the clinical trial human embryonic kidney cell (HEK) assay.
Detailed Description
This was a Phase 3, randomized, open-label, active-controlled study to evaluate the efficacy and safety of 150 milligrams (mg) of migalastat hydrochloride (migalastat) (equivalent to 123 mg of migalastat) once every other day (QOD) and ERT in male and female participants with Fabry disease who were receiving ERT and who have an α Gal-A mutation that is amenable to migalastat, based on the clinical trial HEK assay. This was a 2-part study. Part 1, the 18-month randomized phase, evaluated participants who received either migalastat 150 mg QOD or ERT per prescribing physicians' instructions for efficacy and safety. Part 2, the optional 12-month open-label extension (OLE) phase in which all participants received migalastat, also explored efficacy and safety. For Part 2, all participants who received ERT in Part 1 were given migalastat. Data presented in this posting include efficacy data from the 18-month randomized period and safety data from the entire study (18-month randomized period and 12-month optional OLE [total of 30 months]).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Fabry Disease
Keywords
Amicus Therapeutics, Galafold, AT1001, Migalastat

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
68 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Migalastat
Arm Type
Experimental
Arm Description
Participants received 150 mg migalastat orally QOD during the 18-month randomized treatment period and the optional 12-month OLE period. Participants received an inactive reminder capsule on alternate days during both treatment periods.
Arm Title
ERT
Arm Type
Active Comparator
Arm Description
Participants received ERT (either agalsidase alfa or agalsidase beta) as prescribed by the participant's treating physician and administered in accordance with the approved prescribing information during the 18-month randomized treatment period. Participants were required to be given >80% of the currently labeled dose and regimen during the 18-month randomized treatment period. During the optional 12-month OLE period, participants received 150 mg migalastat orally QOD. Participants received an inactive reminder capsule on alternate days during the OLE.
Intervention Type
Drug
Intervention Name(s)
migalastat hydrochloride
Other Intervention Name(s)
AT1001, Migalastat, Galafold
Intervention Description
150-mg capsule administered orally QOD
Intervention Type
Biological
Intervention Name(s)
agalsidase
Other Intervention Name(s)
agalsidase beta; Fabrazyme, agalsidase alfa; Replagal
Intervention Description
Agalsidase via intravenous infusion as prescribed by the participant's treating physician and in accordance with the approved prescribing information
Primary Outcome Measure Information:
Title
Annualized Rate Of Change From Baseline To Month 18 In Measured Glomerular Filtration Rate
Description
To assess renal function, measured glomerular filtration rate (GFR) was measured by the plasma clearance of unlabeled iohexol (mGFR-iohexol), a non-ionic contrast agent. The annualized rate of change in mGFR-iohexol from Baseline to Month 18 was analyzed using an analysis of covariance (ANCOVA) model with the following factors as covariates: treatment group, sex, age, Baseline GFR (mGFR-iohexol), and Baseline 24-hour (hr) urine protein. A threshold of <2.2 milliliter (mL)/minute (min)/1.73 meter squared (m^2)/year was established to compare migalastat to ERT. This difference of 2.2 mL/min/1.73 m2/year is based on the smallest expected rate of decline in estimated glomerular filtration rate (eGFR) for participants treated with agalsidase alfa for 18 months.
Time Frame
Baseline to Month 18
Title
Annualized Rate Of Change From Baseline To Month 18 In eGFR
Description
The eGFR assessed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was calculated using the following: eGFR-CKD-EPI = 141 x min (Serum Creatinine/κ,1)^(α) x max(Serum Creatinine/κ,1)^(-1.209) x 0.993^(Age) x 1.1018 (if female) x 1.159 (if African American or black) where: κ is 0.7 for females and 0.9 for males; α is -0.329 for females and -0.411 for males; min indicates the minimum of Serum Creatinine/κ or 1; max indicates the maximum of Serum Creatinine/κ or 1. The annualized rate of change in eGFR-CKD-EPI from Baseline to Month 18 was analyzed using an ANCOVA model with the following factors as covariates: treatment group, sex, age, Baseline GFR (eGFR-CKD-EPI), and Baseline 24-hr urine protein. A threshold of <2.2 mL/min/1.73m^2/year was established to compare migalastat to ERT. This difference of 2.2 mL/min/1.73 m2/year is based on the smallest expected rate of decline in eGFR for participants treated with agalsidase alfa for 18 months.
Time Frame
Baseline to Month 18
Secondary Outcome Measure Information:
Title
Annualized Rate Of Change From Baseline To Month 18 In eGFR By The Modification Of Diet In Renal Disease Equation
Description
The GFR estimated by the Modification Of Diet In Renal Disease equation (eGFR-MDRD) was calculated using the following equation: eGFR-MDRD = 175 x (Serum Creatinine)^(-1.154) x (Age)^(-0.203) x 1.212 (if participant's race is black or African American) x 0.742 (if participant is female). The eGFR-MDRD from Baseline to Month 18 was analyzed using an ANCOVA model with the following factors as covariates: treatment group, sex, age, Baseline GFR (eGFR-CKD-EPI), and Baseline 24-hr urine protein.
Time Frame
Baseline to Month 18

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Maximum Age & Unit of Time
74 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female between the ages of 16 and 74 diagnosed with Fabry disease Confirmed α Gal-A mutation that is amenable to migalastat, based on the clinical trial HEK assay Participant has been on ERT for at least 12 months before screening/baseline Dose level and regimen of ERT have been stable for 3 months before screening/baseline and is at least 80% of the currently labeled dose and regimen for this time period Glomerular filtration rate (GFR) ≥ 30 milliliter (mL)/minute (min) /1.73 m^2 Participants taking angiotensin converting enzyme inhibitors or angiotensin receptor blockers must be on a stable dose for at least 4 weeks before screening/baseline Women who can become pregnant and all men agree to be sexually abstinent or use medically accepted methods of birth control throughout the duration of the study and for up to 30 days after last dose of study medication Participant is willing and able to provide written informed consent and assent if applicable Exclusion Criteria: Participant has undergone, or is scheduled to undergo, kidney transplantation or any other solid organ transplantation Participant is on regular dialysis that is specifically for the treatment of chronic kidney disease Participant has had a documented transient ischemic attack, stroke, unstable angina, or myocardial infarction within the 3 months before screening/baseline Participant has clinically significant unstable cardiac disease in the opinion of the investigator (for example, cardiac disease requiring active management, such as symptomatic arrhythmia, unstable angina, or New York Heart Association (NYHA) class III or IV congestive heart failure) Pregnant or breast-feeding History of allergy or sensitivity to study medication (including excipients) or other iminosugars (for example, miglustat, miglitol) Participant has absolute contraindication to iohexol and/or inability to undergo iohexol GFR testing Participant requires treatment with Glyset® (miglitol), or Zavesca® (miglustat) Participant received any investigational/experimental drug, biologic or device within 30 days of screening/baseline Any intercurrent illness or condition that may preclude the participant from fulfilling the study requirements or suggests to the investigator that the participant may have an unacceptable risk by participating in this study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Monitor, Clinical Research
Organizational Affiliation
Amicus Therapeutics
Official's Role
Study Director
Facility Information:
City
Los Angeles
State/Province
California
ZIP/Postal Code
90048
Country
United States
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
City
Decatur
State/Province
Georgia
ZIP/Postal Code
30033
Country
United States
City
Grand Rapids
State/Province
Michigan
ZIP/Postal Code
49525
Country
United States
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
City
Fairfax
State/Province
Virginia
ZIP/Postal Code
22030
Country
United States
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States
City
Parkville
State/Province
Victoria
ZIP/Postal Code
03050
Country
Australia
City
Perth
State/Province
West Australia
ZIP/Postal Code
6000
Country
Australia
City
Vienna
ZIP/Postal Code
1090
Country
Austria
City
Edegem
ZIP/Postal Code
2650
Country
Belgium
City
Sao Paulo
ZIP/Postal Code
14048-900
Country
Brazil
City
Copenhagen
ZIP/Postal Code
2100
Country
Denmark
City
Garches
ZIP/Postal Code
92380
Country
France
City
Lille
ZIP/Postal Code
59037
Country
France
City
Firenze
ZIP/Postal Code
50129
Country
Italy
City
Niigata
ZIP/Postal Code
951-8520
Country
Japan
City
Osaka
ZIP/Postal Code
545-8586
Country
Japan
City
Osaka
ZIP/Postal Code
565-0871
Country
Japan
City
Tokyo
ZIP/Postal Code
105-8471
Country
Japan
City
Cambridge
ZIP/Postal Code
CB2 0QQ
Country
United Kingdom
City
London
ZIP/Postal Code
NW3 2QG
Country
United Kingdom
City
London
ZIP/Postal Code
WC1N 3BG
Country
United Kingdom
City
Salford
ZIP/Postal Code
M6 8HD
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
33012654
Citation
Feldt-Rasmussen U, Hughes D, Sunder-Plassmann G, Shankar S, Nedd K, Olivotto I, Ortiz D, Ohashi T, Hamazaki T, Skuban N, Yu J, Barth JA, Nicholls K. Long-term efficacy and safety of migalastat treatment in Fabry disease: 30-month results from the open-label extension of the randomized, phase 3 ATTRACT study. Mol Genet Metab. 2020 Sep-Oct;131(1-2):219-228. doi: 10.1016/j.ymgme.2020.07.007. Epub 2020 Aug 15.
Results Reference
derived
PubMed Identifier
32994552
Citation
Bichet DG, Aerts JM, Auray-Blais C, Maruyama H, Mehta AB, Skuban N, Krusinska E, Schiffmann R. Assessment of plasma lyso-Gb3 for clinical monitoring of treatment response in migalastat-treated patients with Fabry disease. Genet Med. 2021 Jan;23(1):192-201. doi: 10.1038/s41436-020-00968-z. Epub 2020 Sep 30. Erratum In: Genet Med. 2020 Nov 20;:
Results Reference
derived
PubMed Identifier
31934472
Citation
Haninger-Vacariu N, El-Hadi S, Pauler U, Foretnik M, Kain R, Prohaszka Z, Schmidt A, Skuban N, Barth JA, Sunder-Plassmann G. Pregnancy Outcome after Exposure to Migalastat for Fabry Disease: A Clinical Report. Case Rep Obstet Gynecol. 2019 Dec 21;2019:1030259. doi: 10.1155/2019/1030259. eCollection 2019.
Results Reference
derived
PubMed Identifier
31889231
Citation
Narita I, Ohashi T, Sakai N, Hamazaki T, Skuban N, Castelli JP, Lagast H, Barth JA. Efficacy and safety of migalastat in a Japanese population: a subgroup analysis of the ATTRACT study. Clin Exp Nephrol. 2020 Feb;24(2):157-166. doi: 10.1007/s10157-019-01810-w. Epub 2019 Dec 30.
Results Reference
derived
PubMed Identifier
27834756
Citation
Hughes DA, Nicholls K, Shankar SP, Sunder-Plassmann G, Koeller D, Nedd K, Vockley G, Hamazaki T, Lachmann R, Ohashi T, Olivotto I, Sakai N, Deegan P, Dimmock D, Eyskens F, Germain DP, Goker-Alpan O, Hachulla E, Jovanovic A, Lourenco CM, Narita I, Thomas M, Wilcox WR, Bichet DG, Schiffmann R, Ludington E, Viereck C, Kirk J, Yu J, Johnson F, Boudes P, Benjamin ER, Lockhart DJ, Barlow C, Skuban N, Castelli JP, Barth J, Feldt-Rasmussen U. Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study. J Med Genet. 2017 Apr;54(4):288-296. doi: 10.1136/jmedgenet-2016-104178. Epub 2016 Nov 10. Erratum In: J Med Genet. 2018 Apr 16;:
Results Reference
derived
PubMed Identifier
27657681
Citation
Benjamin ER, Della Valle MC, Wu X, Katz E, Pruthi F, Bond S, Bronfin B, Williams H, Yu J, Bichet DG, Germain DP, Giugliani R, Hughes D, Schiffmann R, Wilcox WR, Desnick RJ, Kirk J, Barth J, Barlow C, Valenzano KJ, Castelli J, Lockhart DJ. The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat. Genet Med. 2017 Apr;19(4):430-438. doi: 10.1038/gim.2016.122. Epub 2016 Sep 22.
Results Reference
derived

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Study to Compare the Efficacy and Safety of Oral AT1001 and Enzyme Replacement Therapy in Patients With Fabry Disease

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