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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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ClinicalTrials.gov Identifier: NCT01218659
Recruitment Status : Completed
First Posted : October 11, 2010
Results First Posted : November 1, 2018
Last Update Posted : November 1, 2018
Sponsor:
Information provided by (Responsible Party):
Amicus Therapeutics

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Fabry Disease
Interventions Drug: migalastat hydrochloride
Biological: agalsidase
Enrollment 68

Recruitment Details  
Pre-assignment Details The All Migalastat group was comprised of participants who received migalastat during the randomized treatment period (0-18 mo.) and who received enzyme replacement therapy (ERT) during the randomized treatment period (0-18 mo.) and switched to migalastat during the 12-mo. open-label extension (OLE). 8 participants enrolled but did not randomize.
Arm/Group Title Migalastat (0-18 Months) ERT (0-18 Months) All Migalastat (0-30 Months)
Hide Arm/Group Description Participants received 150 milligrams (mg) of migalastat hydrochloride (migalastat) (equivalent to 123 mg of migalastat) orally once every other day (QOD) during the 18-month randomized treatment period (0-18 months). 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 (0-18 months). Participants were required to be given >80% of the currently labeled dose and regimen during the 18-month randomized treatment period. Participants in this group are composed of participants from the Migalastat (0-18 months) and the ERT (0-18 months) groups. Therefore, participants in the All Migalastat group received at least 1 dose of 150 mg migalastat orally QOD during the 18-month randomization period or the optional 12-month OLE (for a total time period of up to 30 months), regardless of whether or not the participant discontinued the study early, and regardless of whether they were previously randomized to migalastat or ERT during the 18-month Randomized Period (0-18 months).
Period Title: 18-Month Randomized Period
Started 36 24 0 [1]
Safety Population [2] 36 21 0 [1]
Completed 34 18 0 [1]
Not Completed 2 6 0
Reason Not Completed
Withdrawal by Subject             2             3             0
Did not receive study drug             0             3             0
[1]
Zero participants are noted here because participants started in this group during the 12-month OLE.
[2]
Safety: received at least 1 dose of migalastat or ERT.
Period Title: 12-Month OLE
Started 0 [1] 0 [1] 52 [2]
Safety Population [3] 0 0 51
Modified Intent-to-Treat (mITT) [4] 0 [1] 0 [1] 46
Completed 0 [1] 0 [1] 42
Not Completed 0 0 10
Reason Not Completed
Withdrawal by Subject             0             0             2
Physician Decision             0             0             1
Lost to Follow-up             0             0             1
Pregnancy             0             0             1
Lack of Efficacy             0             0             1
Declined to participate in the OLE             0             0             4
[1]
Zero participants are noted here because they were combined in the All Migalastat (0-30 mo.) group.
[2]
Fifty-two participants completed the 18-mo. randomized treatment period.
[3]
Safety: ITT pop. who received ≥1 dose of study drug during the 18-mo randomized treatment period.
[4]
mITT: Eligibility based on Good Laboratory Practice (GLP) human embryonic kidney cell (HEK) assay.
Arm/Group Title Migalastat (0-18 Months) ERT (0-18 Months) Total
Hide Arm/Group Description Participants received 150 mg migalastat orally QOD during the 18-month randomized treatment 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. Participants received an inactive reminder capsule on alternate days during the OLE. Total of all reporting groups
Overall Number of Baseline Participants 36 21 57
Hide Baseline Analysis Population Description
Safety Population: All randomized participants who received at least 1 dose of migalastat or ERT.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 36 participants 21 participants 57 participants
50.5  (13.76) 46.3  (14.91) 48.9  (14.21)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 36 participants 21 participants 57 participants
Female
20
  55.6%
12
  57.1%
32
  56.1%
Male
16
  44.4%
9
  42.9%
25
  43.9%
1.Primary Outcome
Title Annualized Rate Of Change From Baseline To Month 18 In Measured Glomerular Filtration Rate
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
mITT Population: All randomized participants with an α Gal-A mutation that is amenable to migalastat, based on the GLP HEK assay, who received at least 1 dose of study drug, had Baseline and postbaseline mGFR-iohexol values, and postbaseline measure of the estimated GFR using the CKD-EPI equation.
Arm/Group Title Migalastat (0-18 Months) ERT (0-18 Months)
Hide Arm/Group Description:
Participants received 150 mg migalastat orally QOD during the 18-month randomized treatment 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.
Overall Number of Participants Analyzed 34 18
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mL/min/1.73 m^2/year
-4.35
(-7.65 to -1.06)
-3.24
(-7.81 to 1.33)
2.Primary Outcome
Title Annualized Rate Of Change From Baseline To Month 18 In eGFR
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
mITT Population: All randomized participants with an α Gal-A mutation that is amenable to migalastat, based on the GLP HEK assay, who received at least 1 dose of study drug, had Baseline and postbaseline mGFR-iohexol values, and postbaseline measure of the estimated GFR using the CKD-EPI equation.
Arm/Group Title Migalastat (0-18 Months) ERT (0-18 Months)
Hide Arm/Group Description:
Participants received 150 mg migalastat orally QOD during the 18-month randomized treatment 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.
Overall Number of Participants Analyzed 34 18
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mL/min/1.73 m^2/year
-0.40
(-2.27 to 1.48)
-1.03
(-3.64 to 1.58)
3.Secondary Outcome
Title Annualized Rate Of Change From Baseline To Month 18 In eGFR By The Modification Of Diet In Renal Disease Equation
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
mITT Population: All randomized participants with an α Gal-A mutation that is amenable to migalastat, based on the GLP HEK assay, who received at least 1 dose of study drug, had Baseline and postbaseline mGFR-iohexol values, and postbaseline measure of the estimated GFR using the CKD-EPI equation.
Arm/Group Title Migalastat (0-18 Months) ERT (0-18 Months)
Hide Arm/Group Description:
Participants received 150 mg migalastat orally QOD during the 18-month randomized treatment 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.
Overall Number of Participants Analyzed 34 18
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mL/min/1.73 m^2/year
-1.51
(-3.43 to 0.40)
-1.53
(-4.20 to 1.13)
Time Frame Adverse Event (AE) data were collected from the time of signing informed consent at screening/baseline through the follow-up visit (1 mo. after the last treatment in the optional OLE/after the 18-month Randomized Period if the participant did not enroll in the OLE), for up to 30 months. Because participants in the Migalastat (0-18 mo.) and ERT (0-18 mo.) groups were combined into the All Migalastat (0-30 mo.) group, AEs for those groups are included in the All Migalastat (0-30 mo.) group AEs.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Migalastat (0-18 Months) ERT (0-18 Months) All Migalastat (0-30 Months)
Hide Arm/Group Description Participants received 150 mg of migalastat orally QOD during the 18-month randomized treatment period (0-18 months). 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 (0-18 months). Participants were required to be given >80% of the currently labeled dose and regimen during the 18-month randomized treatment period. Participants in this group are composed of participants from the Migalastat (0-18 month) and the ERT (0-18 month) groups. Therefore, participants in the All Migalastat group received at least 1 dose of 150 mg migalastat orally QOD during the 18-month randomized treatment period or the optional 12-month OLE (for a total time period of up to 30 months), regardless of whether or not the participant discontinued the study early, and regardless of whether they were previously randomized to migalastat or ERT during the 18-month randomized phase (0-18 months).
All-Cause Mortality
Migalastat (0-18 Months) ERT (0-18 Months) All Migalastat (0-30 Months)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Migalastat (0-18 Months) ERT (0-18 Months) All Migalastat (0-30 Months)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   7/36 (19.44%)   7/21 (33.33%)   16/51 (31.37%) 
Cardiac disorders       
Ventricular tachycardia  1  1/36 (2.78%)  0/21 (0.00%)  1/51 (1.96%) 
Cardiac failure chronic  1  0/36 (0.00%)  1/21 (4.76%)  1/51 (1.96%) 
Atrial fibrillation  1  0/36 (0.00%)  0/21 (0.00%)  1/51 (1.96%) 
Ear and labyrinth disorders       
Vertigo  1  0/36 (0.00%)  1/21 (4.76%)  1/51 (1.96%) 
Eye disorders       
Vision blurred  1  0/36 (0.00%)  1/21 (4.76%)  1/51 (1.96%) 
Gastrointestinal disorders       
Hernial eventration  1  0/36 (0.00%)  1/21 (4.76%)  1/51 (1.96%) 
Abdominal pain  1  0/36 (0.00%)  1/21 (4.76%)  1/51 (1.96%) 
General disorders       
Chest pain  1  3/36 (8.33%)  0/21 (0.00%)  3/51 (5.88%) 
Device malfunction  1  0/36 (0.00%)  1/21 (4.76%)  1/51 (1.96%) 
Hepatobiliary disorders       
Bile duct stone  1  1/36 (2.78%)  0/21 (0.00%)  1/51 (1.96%) 
Infections and infestations       
Pneumonia  1  1/36 (2.78%)  0/21 (0.00%)  1/51 (1.96%) 
Endocarditis  1  0/36 (0.00%)  0/21 (0.00%)  1/51 (1.96%) 
Perineal abscess  1  0/36 (0.00%)  0/21 (0.00%)  1/51 (1.96%) 
Injury, poisoning and procedural complications       
Upper limb fracture  1  1/36 (2.78%)  0/21 (0.00%)  1/51 (1.96%) 
Metabolism and nutrition disorders       
Obesity  1  1/36 (2.78%)  1/21 (4.76%)  2/51 (3.92%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Phaeochromocytoma  1  1/36 (2.78%)  0/21 (0.00%)  1/51 (1.96%) 
Nervous system disorders       
Embolic stroke  1  0/36 (0.00%)  0/21 (0.00%)  1/51 (1.96%) 
Transient ischaemic attack  1  0/36 (0.00%)  1/21 (4.76%)  1/51 (1.96%) 
Hypoaesthesia  1  0/36 (0.00%)  0/21 (0.00%)  1/51 (1.96%) 
Psychiatric disorders       
Suicidal ideation  1  0/36 (0.00%)  0/21 (0.00%)  1/51 (1.96%) 
Renal and urinary disorders       
Proteinuria  1  0/36 (0.00%)  0/21 (0.00%)  1/51 (1.96%) 
Respiratory, thoracic and mediastinal disorders       
Haemoptysis  1  0/36 (0.00%)  0/21 (0.00%)  1/51 (1.96%) 
Atelectasis  1  0/36 (0.00%)  0/21 (0.00%)  1/51 (1.96%) 
Dyspnoea  1  0/36 (0.00%)  1/21 (4.76%)  1/51 (1.96%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (16.1)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Migalastat (0-18 Months) ERT (0-18 Months) All Migalastat (0-30 Months)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   34/36 (94.44%)   20/21 (95.24%)   50/51 (98.04%) 
Cardiac disorders       
Palpitations  1  2/36 (5.56%)  1/21 (4.76%)  5/51 (9.80%) 
Ear and labyrinth disorders       
Tinnitus  1  3/36 (8.33%)  0/21 (0.00%)  5/51 (9.80%) 
Vertigo  1  1/36 (2.78%)  2/21 (9.52%)  3/51 (5.88%) 
Gastrointestinal disorders       
Diarrhoea  1  5/36 (13.89%)  2/21 (9.52%)  11/51 (21.57%) 
Nausea  1  5/36 (13.89%)  2/21 (9.52%)  8/51 (15.69%) 
Vomiting  1  3/36 (8.33%)  3/21 (14.29%)  8/51 (15.69%) 
Abdominal pain  1  5/36 (13.89%)  2/21 (9.52%)  7/51 (13.73%) 
Constipation  1  3/36 (8.33%)  1/21 (4.76%)  4/51 (7.84%) 
Toothache  1  3/36 (8.33%)  0/21 (0.00%)  4/51 (7.84%) 
Abdominal pain upper  1  2/36 (5.56%)  1/21 (4.76%)  3/51 (5.88%) 
Dyspepsia  1  2/36 (5.56%)  1/21 (4.76%)  3/51 (5.88%) 
Flatulence  1  2/36 (5.56%)  0/21 (0.00%)  2/51 (3.92%) 
Dry mouth  1  1/36 (2.78%)  2/21 (9.52%)  1/51 (1.96%) 
Gastritis  1  1/36 (2.78%)  2/21 (9.52%)  1/51 (1.96%) 
General disorders       
Pyrexia  1  3/36 (8.33%)  1/21 (4.76%)  6/51 (11.76%) 
Influenza like illness  1  2/36 (5.56%)  0/21 (0.00%)  3/51 (5.88%) 
Oedema peripheral  1  2/36 (5.56%)  2/21 (9.52%)  2/51 (3.92%) 
Pain  1  1/36 (2.78%)  0/21 (0.00%)  5/51 (9.80%) 
Fatigue  1  1/36 (2.78%)  1/21 (4.76%)  4/51 (7.84%) 
Infections and infestations       
Nasopharyngitis  1  12/36 (33.33%)  7/21 (33.33%)  21/51 (41.18%) 
Influenza  1  5/36 (13.89%)  4/21 (19.05%)  12/51 (23.53%) 
Urinary tract infection  1  4/36 (11.11%)  1/21 (4.76%)  6/51 (11.76%) 
Bronchitis  1  2/36 (5.56%)  3/21 (14.29%)  5/51 (9.80%) 
Upper respiratory tract infection  1  4/36 (11.11%)  1/21 (4.76%)  5/51 (9.80%) 
Sinusitis  1  3/36 (8.33%)  3/21 (14.29%)  4/51 (7.84%) 
Herpes Zoster  1  2/36 (5.56%)  0/21 (0.00%)  3/51 (5.88%) 
Lower respiratory tract infection  1  2/36 (5.56%)  0/21 (0.00%)  3/51 (5.88%) 
Gastroenteritis  1  2/36 (5.56%)  1/21 (4.76%)  2/51 (3.92%) 
Pharyngitis  1  2/36 (5.56%)  0/21 (0.00%)  2/51 (3.92%) 
Cystitis  1  1/36 (2.78%)  1/21 (4.76%)  4/51 (7.84%) 
Injury, poisoning and procedural complications       
Fall  1  2/36 (5.56%)  1/21 (4.76%)  4/51 (7.84%) 
Procedural pain  1  0/36 (0.00%)  2/21 (9.52%)  0/51 (0.00%) 
Investigations       
Blood creatine phosphokinase increased  1  3/36 (8.33%)  1/21 (4.76%)  7/51 (13.73%) 
Protein urine present  1  3/36 (8.33%)  0/21 (0.00%)  4/51 (7.84%) 
White blood cell count decreased  1  2/36 (5.56%)  0/21 (0.00%)  2/51 (3.92%) 
Musculoskeletal and connective tissue disorders       
Arthralgia  1  3/36 (8.33%)  2/21 (9.52%)  6/51 (11.76%) 
Myalgia  1  3/36 (8.33%)  1/21 (4.76%)  6/51 (11.76%) 
Back pain  1  4/36 (11.11%)  3/21 (14.29%)  5/51 (9.80%) 
Neck pain  1  2/36 (5.56%)  0/21 (0.00%)  3/51 (5.88%) 
Muscle spasms  1  0/36 (0.00%)  0/21 (0.00%)  4/51 (7.84%) 
Musculoskeletal pain  1  0/36 (0.00%)  1/21 (4.76%)  3/51 (5.88%) 
Pain in extremity  1  1/36 (2.78%)  2/21 (9.52%)  3/51 (5.88%) 
Nervous system disorders       
Headache  1  9/36 (25.00%)  5/21 (23.81%)  16/51 (31.37%) 
Dizziness  1  6/36 (16.67%)  2/21 (9.52%)  8/51 (15.69%) 
Presyncope  1  2/36 (5.56%)  0/21 (0.00%)  2/51 (3.92%) 
Neuralgia  1  1/36 (2.78%)  1/21 (4.76%)  4/51 (7.84%) 
Paraesthesia  1  1/36 (2.78%)  0/21 (0.00%)  3/51 (5.88%) 
Tremor  1  1/36 (2.78%)  0/21 (0.00%)  3/51 (5.88%) 
Psychiatric disorders       
Insomnia  1  2/36 (5.56%)  0/21 (0.00%)  5/51 (9.80%) 
Depression  1  2/36 (5.56%)  1/21 (4.76%)  4/51 (7.84%) 
Respiratory, thoracic and mediastinal disorders       
Cough  1  3/36 (8.33%)  5/21 (23.81%)  8/51 (15.69%) 
Oropharyngeal pain  1  1/36 (2.78%)  0/21 (0.00%)  4/51 (7.84%) 
Epistaxis  1  2/36 (5.56%)  0/21 (0.00%)  2/51 (3.92%) 
Skin and subcutaneous tissue disorders       
Hyperhidrosis  1  3/36 (8.33%)  0/21 (0.00%)  3/51 (5.88%) 
Night sweats  1  2/36 (5.56%)  0/21 (0.00%)  2/51 (3.92%) 
Rash  1  2/36 (5.56%)  1/21 (4.76%)  2/51 (3.92%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (16.1)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The investigator can publish only the results from this trial, provided they supply the sponsor (or authorized entity) a copy of any proposed publication for review prior to submission for publication. If requested and prior to publication, the investigator will remove information deemed confidential or proprietary by the sponsor and will withhold publication an additional period of time to allow the sponsor to take appropriate measures to establish and preserve its proprietary rights.
Results Point of Contact
Name/Title: Medical Affairs
Organization: Amicus Therapeutics
Phone: +1-877-426-4287 (877-4-AMICUS)
Responsible Party: Amicus Therapeutics
ClinicalTrials.gov Identifier: NCT01218659     History of Changes
Other Study ID Numbers: AT1001-012
ATTRACT ( Other Identifier: Amicus Therapeutics )
2010-022636-37 ( EudraCT Number )
First Submitted: October 6, 2010
First Posted: October 11, 2010
Results First Submitted: August 10, 2018
Results First Posted: November 1, 2018
Last Update Posted: November 1, 2018