Open-Label Phase 3 Long-Term Safety Study of Migalastat (AT1001-041)

• ClinicalTrials.gov Identifier: NCT01458119
• Recruitment Status: Terminated
• First Posted: October 24, 2011
• Results First Posted: October 2, 2018
• Last Update Posted: October 2, 2018
• Sponsor: Amicus Therapeutics
• Information provided by (Responsible Party): Amicus Therapeutics

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Fabry Disease
• Intervention: Drug: migalastat hydrochloride
• Enrollment: 85

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.
Pre-assignment Details

Arm/Group Title	Migalastat
Arm/Group Description	Participants received migalastat hydrochloride (migalastat) 150-milligram (mg) capsule (equivalent to 123 mg of migalastat) given orally once every other day (QOD) for a median duration of 23.5 months (m). Participants received an inactive reminder capsule on alternate days during the study.
Period Title: Overall Study
Started	85
Received at Least 1 Dose of Study Drug	85
Safety Population	85
Intent to Treat (ITT) Population [1]	85
ITT-Amenable Population [2]	68
Completed	65
Not Completed	20
Reason Not Completed
Physician Decision	4
Withdrawal Due to Nonamenable Mutation	1
Pregnancy	1
Death	2
Adverse Event	1
Consent Withdrawn by Participant	8
Non-compliance With Study Drug	3
[1] Received at least 1 dose of study drug.; [2] Amenable mutations based on Good Laboratory Practice (GLP) Human Embryonic Kidney (HEK) assay.

Baseline Characteristics

Arm/Group Title		Migalastat
Arm/Group Description		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.
Overall Number of Baseline Participants		85
Baseline Analysis Population Description		ITT Population: All participants who received at least 1 dose of study drug after they enrolled into this open-label extension study.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	85 participants
		48.8 (12.25)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	85 participants
	Female	52 61.2%
	Male	33 38.8%

Outcome Measures

1. Primary Outcome

Title	Number Of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)
Description	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.

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least 1 dose of study drug after they enrolled into this open-label extension study.

Arm/Group Title	Migalastat
Arm/Group Description:	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.
Overall Number of Participants Analyzed	85
Measure Type: Number; Unit of Measure: participants
Participants with at least 1 TEAE	74
Participants with at least 1 serious TEAE	22
Participants discontinued due to TEAEs	1
Participants with adverse events leading to death	2
Participants with TEAEs related to study drug	14
Participants with TEAEs unrelated to study drug	60
Participants with at least 1 mild TEAE	22
Participants with at least 1 moderate TEAE	40
Participants with at least 1 severe TEAE	12

2. Secondary Outcome

Title	Annualized Rate Of Change In The Estimated Glomerular Filtration Rate (eGFR)
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Migalastat ITT-Amenable Population
Arm/Group Description:	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. The ITT-amenable population included all participants who received at least 1 dose of study drug after they enrolled into this open-label extension study. Participants with mutant forms of α-Gal A determined to be amenable to migalastat treatment based on the GLP-HEK assay are referred to as "with amenable mutations."
Overall Number of Participants Analyzed	47
Mean (95% Confidence Interval); Unit of Measure: milliliters/minute/1.73 meters^2
EGFR [CKD-EPI]	1.54; (-1.63 to 4.71)
eGFR [MDRD]	1.40; (-3.14 to 5.94)

Adverse Events

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.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Migalastat
Arm/Group Description	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.
All-Cause Mortality
	Migalastat
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events
	Migalastat
	Affected / at Risk (%)
Total	22/85 (25.88%)
Cardiac disorders
Angina pectoris † 1	1/85 (1.18%)
Atrial fibrillation † 1	2/85 (2.35%)
Endocrine disorders
Thyroid mass † 1	1/85 (1.18%)
Gastrointestinal disorders
Abdominal pain upper † 1	1/85 (1.18%)
Hiatus hernia † 1	1/85 (1.18%)
Pancreatitis † 1	1/85 (1.18%)
General disorders
Death † 1	1/85 (1.18%)
Device malfunction † 1	1/85 (1.18%)
Hepatobiliary disorders
Hepatic infarction † 1	1/85 (1.18%)
Infections and infestations
Pneumonia † 1	2/85 (2.35%)
Injury, poisoning and procedural complications
Foot fracture † 1	1/85 (1.18%)
Musculoskeletal and connective tissue disorders
Muscle spasms † 1	1/85 (1.18%)
Musculoskeletal chest pain † 1	1/85 (1.18%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer metastatic † 1	1/85 (1.18%)
Metastatic squamous cell carcinoma † 1	1/85 (1.18%)
Papillary thyroid cancer † 1	1/85 (1.18%)
Nervous system disorders
Brain stem ischaemia † 1	1/85 (1.18%)
Hemiplegic migraine † 1	1/85 (1.18%)
Presyncope † 1	1/85 (1.18%)
Psychiatric disorders
Conversion disorder † 1	1/85 (1.18%)
Renal and urinary disorders
Calculus urinary † 1	1/85 (1.18%)
Reproductive system and breast disorders
Priapism † 1	1/33 (3.03%)
Uterine polyp † 1	1/52 (1.92%)
Skin and subcutaneous tissue disorders
Angioedema † 1	1/85 (1.18%)
Skin lesion † 1	1/85 (1.18%)
Surgical and medical procedures
Implantable defibrillator insertion † 1	2/85 (2.35%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 16.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Migalastat
	Affected / at Risk (%)
Total	57/85 (67.06%)
Cardiac disorders
Atrial fibrillation † 1	7/85 (8.24%)
Palpitations † 1	5/85 (5.88%)
Ear and labyrinth disorders
Vertigo † 1	5/85 (5.88%)
Gastrointestinal disorders
Abdominal distension † 1	5/85 (5.88%)
Abdominal pain upper † 1	5/85 (5.88%)
Constipation † 1	6/85 (7.06%)
Nausea † 1	10/85 (11.76%)
Diarrhoea † 1	13/85 (15.29%)
General disorders
Fatigue † 1	9/85 (10.59%)
Oedema peripheral † 1	6/85 (7.06%)
Pain † 1	5/85 (5.88%)
Pyrexia † 1	7/85 (8.24%)
Infections and infestations
Influenza † 1	9/85 (10.59%)
Nasopharyngitis † 1	9/85 (10.59%)
Upper respiratory tract infection † 1	6/85 (7.06%)
Urinary Tract Infection † 1	8/85 (9.41%)
Injury, poisoning and procedural complications
Contusion † 1	5/85 (5.88%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	11/85 (12.94%)
Back pain † 1	6/85 (7.06%)
Pain in extremity † 1	11/85 (12.94%)
Nervous system disorders
Headache † 1	11/85 (12.94%)
Dizziness † 1	9/85 (10.59%)
Paraesthesia † 1	5/85 (5.88%)
Psychiatric disorders
Anxiety † 1	5/85 (5.88%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	6/85 (7.06%)
Vascular disorders
Hypertension † 1	6/85 (7.06%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 16.1

Limitations and Caveats

The study was discontinued for logistical reasons and not due to either safety concerns or lack of efficacy. The investigators were offered participation in a similar long-term migalastat study for participants ongoing at discontinuation.

More Information

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)
• EMail: MedInfoUSA@amicusrx.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Germain DP, Hughes DA, Nicholls K, Bichet DG, Giugliani R, Wilcox WR, Feliciani C, Shankar SP, Ezgu F, Amartino H, Bratkovic D, Feldt-Rasmussen U, Nedd K, Sharaf El Din U, Lourenco CM, Banikazemi M, Charrow J, Dasouki M, Finegold D, Giraldo P, Goker-Alpan O, Longo N, Scott CR, Torra R, Tuffaha A, Jovanovic A, Waldek S, Packman S, Ludington E, Viereck C, Kirk J, Yu J, Benjamin ER, Johnson F, Lockhart DJ, Skuban N, Castelli J, Barth J, Barlow C, Schiffmann R. Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat. N Engl J Med. 2016 Aug 11;375(6):545-55. doi: 10.1056/NEJMoa1510198.

• Responsible Party: Amicus Therapeutics
• ClinicalTrials.gov Identifier: NCT01458119
• Other Study ID Numbers: AT1001-041; 2011-004800-40 ( EudraCT Number )
• First Submitted: October 20, 2011
• First Posted: October 24, 2011
• Results First Submitted: August 10, 2018
• Results First Posted: October 2, 2018
• Last Update Posted: October 2, 2018