NCT01218659

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

Completed Phase 3 Results posted Last updated 1 November 2018

What this trial tests

Phase 3 trial testing migalastat hydrochloride in Fabry Disease in 68 participants. Completed in 28 May 2015.

Timeline

8 September 2011

Primary endpoint
27 May 2014

28 May 2015

Quick facts

Lead sponsor	Amicus Therapeutics
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	68
Start date	8 September 2011
Primary completion	27 May 2014
Estimated completion	28 May 2015
Sites	25 locations across Denmark, France, Italy, Japan, Belgium, Austria, United Kingdom, Australia

Drugs / interventions tested

• migalastat hydrochloride — full drug profile →
• agalsidase — full drug profile →

Conditions studied

• Fabry Disease — all drugs for Fabry Disease →

Sponsor

Amicus Therapeutics — full company profile →

Who can join

Adults 16 to 74, any sex, with Fabry Disease. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Annualized Rate Of Change From Baseline To Month 18 In Measured Glomerular Filtration Rate Primary · Baseline to Month 18

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.

Group	Value	95% CI
Migalastat (0-18 Months)	-4.35	-7.65 – -1.06
ERT (0-18 Months)	-3.24	-7.81 – 1.33

Annualized Rate Of Change From Baseline To Month 18 In eGFR Primary · Baseline to Month 18

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

Group	Value	95% CI
Migalastat (0-18 Months)	-0.40	-2.27 – 1.48
ERT (0-18 Months)	-1.03	-3.64 – 1.58

Annualized Rate Of Change From Baseline To Month 18 In eGFR By The Modification Of Diet In Renal Disease Equation Secondary · Baseline to Month 18

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.

Group	Value	95% CI
Migalastat (0-18 Months)	-1.51	-3.43 – 0.40
ERT (0-18 Months)	-1.53	-4.20 – 1.13

Adverse events — posted to ClinicalTrials.gov

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.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Migalastat (0-18 Months)

Serious: 7/36 (19%)

Deaths: —

ERT (0-18 Months)

Serious: 7/21 (33%)

Deaths: —

All Migalastat (0-30 Months)

Serious: 16/51 (31%)

Deaths: —

Serious adverse events (24 terms)

Reaction	System	Migalastat (0-18 Months)	ERT (0-18 Months)	All Migalastat (0-30 Months)
Chest pain	General disorders	—	—	—
Obesity	Metabolism and nutrition disorders	—	—	—
Pneumonia	Infections and infestations	—	—	—
Endocarditis	Infections and infestations	—	—	—
Perineal abscess	Infections and infestations	—	—	—
Proteinuria	Renal and urinary disorders	—	—	—
Suicidal ideation	Psychiatric disorders	—	—	—
Device malfunction	General disorders	—	—	—
Embolic stroke	Nervous system disorders	—	—	—
Transient ischaemic attack	Nervous system disorders	—	—	—
Hypoaesthesia	Nervous system disorders	—	—	—
Ventricular tachycardia	Cardiac disorders	—	—	—
Cardiac failure chronic	Cardiac disorders	—	—	—
Atrial fibrillation	Cardiac disorders	—	—	—
Haemoptysis	Respiratory, thoracic and mediastinal disorders	—	—	—
Atelectasis	Respiratory, thoracic and mediastinal disorders	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—
Bile duct stone	Hepatobiliary disorders	—	—	—
Hernial eventration	Gastrointestinal disorders	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—
Vision blurred	Eye disorders	—	—	—
Vertigo	Ear and labyrinth disorders	—	—	—
Upper limb fracture	Injury, poisoning and procedural complications	—	—	—
Phaeochromocytoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—

Other adverse events (56 terms — click to expand)

Reaction	System	Migalastat (0-18 Months)	ERT (0-18 Months)	All Migalastat (0-30 Months)
Nasopharyngitis	Infections and infestations	—	—	—
Headache	Nervous system disorders	—	—	—
Influenza	Infections and infestations	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—
Dizziness	Nervous system disorders	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—
Blood creatine phosphokinase increased	Investigations	—	—	—
Pyrexia	General disorders	—	—	—
Urinary tract infection	Infections and infestations	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—	—
Palpitations	Cardiac disorders	—	—	—
Tinnitus	Ear and labyrinth disorders	—	—	—
Bronchitis	Infections and infestations	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—
Insomnia	Psychiatric disorders	—	—	—
Pain	General disorders	—	—	—
Constipation	Gastrointestinal disorders	—	—	—
Toothache	Gastrointestinal disorders	—	—	—
Sinusitis	Infections and infestations	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—
Protein urine present	Investigations	—	—	—
Depression	Psychiatric disorders	—	—	—
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	—	—	—
Cystitis	Infections and infestations	—	—	—
Muscle spasms	Musculoskeletal and connective tissue disorders	—	—	—
Neuralgia	Nervous system disorders	—	—	—
Fatigue	General disorders	—	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—
Influenza like illness	General disorders	—	—	—
Herpes Zoster	Infections and infestations	—	—	—
Lower respiratory tract infection	Infections and infestations	—	—	—
Neck pain	Musculoskeletal and connective tissue disorders	—	—	—
Hyperhidrosis	Skin and subcutaneous tissue disorders	—	—	—
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	—	—	—

Most-reported serious reactions: Chest pain, Obesity, Pneumonia, Endocarditis, Perineal abscess, Proteinuria, Suicidal ideation, Device malfunction.

Data from ClinicalTrials.gov NCT01218659 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Drug development in the era of precision medicine.
   Dugger SA, Platt A, Goldstein DB. · · 2018 · cited 296× · PMID 29217837 · DOI 10.1038/nrd.2017.226
2. The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat.
   Benjamin ER, Della Valle MC, Wu X, Katz E, et al · · 2017 · cited 164× · PMID 27657681 · DOI 10.1038/gim.2016.122
3. Efficacy of the pharmacologic chaperone migalastat in a subset of male patients with the classic phenotype of Fabry disease and migalastat-amenable variants: data from the phase 3 randomized, multicenter, double-blind clinical trial and extension study.
   Germain DP, Nicholls K, Giugliani R, Bichet DG, et al · · 2019 · cited 73× · PMID 30723321 · DOI 10.1038/s41436-019-0451-z
4. 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.
   Feldt-Rasmussen U, Hughes D, Sunder-Plassmann G, Shankar S, et al · · 2020 · cited 56× · PMID 33012654 · DOI 10.1016/j.ymgme.2020.07.007
5. Assessment of plasma lyso-Gb₃ for clinical monitoring of treatment response in migalastat-treated patients with Fabry disease.
   Bichet DG, Aerts JM, Auray-Blais C, Maruyama H, et al · · 2021 · cited 38× · PMID 32994552 · DOI 10.1038/s41436-020-00968-z
6. Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients.
   Young-Gqamana B, Brignol N, Chang HH, Khanna R, et al · · 2013 · cited 33× · PMID 23472096 · DOI 10.1371/journal.pone.0057631
7. Coformulation of a Novel Human α-Galactosidase A With the Pharmacological Chaperone AT1001 Leads to Improved Substrate Reduction in Fabry Mice.
   Xu S, Lun Y, Brignol N, Hamler R, et al · · 2015 · cited 30× · PMID 25915924 · DOI 10.1038/mt.2015.87
8. Long-term follow-up of renal function in patients treated with migalastat for Fabry disease.
   Bichet DG, Torra R, Wallace E, Hughes D, et al · · 2021 · cited 26× · PMID 34401344 · DOI 10.1016/j.ymgmr.2021.100786