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

• Sponsor: Amicus Therapeutics (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01458119
• Collaborator: (none)
• Enrollment: 85
• Locations: 25
• Arm: 1
• Actual Duration (Months): 52.1
• Patients Per Site: 3.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This was a long-term, open-label study of migalastat (123 milligrams [mg] of migalastat [equivalent to 150 mg of migalastat hydrochloride]) (migalastat) in participants with Fabry disease who completed treatment in a previous monotherapy trial with migalastat.

Condition or Disease	Intervention/Treatment	Phase
Fabry Disease	Drug: migalastat hydrochloride	Phase 3

Detailed Description

Study AT1001-041 was an open-label, noncomparative, multicenter, long-term extension study for participants with Fabry disease who completed treatment in one of three previous trials of migalastat (AT1001-011 [NCT00925301], AT1001-012 [NCT01218659], or FAB-CL-205 [NCT00526071]). In these trials, migalastat was given as monotherapy. This was an extension study designed to evaluate the long-term safety and efficacy of migalastat for the treatment of Fabry disease. Study visits occurred every 6 months (m). Visit evaluations included physical examinations, clinical laboratory parameters, adverse events, and participant reported outcomes.

The study consisted of a Baseline Visit, which was performed at the time of the final visit of the previous study, followed by clinic visits every 6 m for each year of the study. Study assessments included a physical examination, echocardiography, laboratory parameters, and participant-reported outcomes. Since participants enrolled in the study at varying time points based on the completion of the preceding migalastat study, treatment duration varied among participants. No maximum treatment duration was defined. There were no control groups in this study; all participants received migalastat as a 150-mg capsule taken orally once every other day (QOD) and inactive reminder capsules on alternate days.

The sponsor (Amicus Therapeutics) discontinued Study AT1001-041 for logistical reasons and not due to either safety concerns or lack of efficacy. For participants who were ongoing in Study AT1001-041 at the time of discontinuation, the investigators were offered participation in a similar open-label, long-term migalastat treatment study (AT1001-042 [NCT02194985]) for participants ongoing at discontinuation.

Study Design

• Study Type: Interventional
• Actual Enrollment: 85 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label Extension Study to Evaluate the Long-Term Safety and Efficacy of Migalastat Hydrochloride Monotherapy in Subjects With Fabry Disease
• Actual Study Start Date: Oct 14, 2011
• Actual Primary Completion Date: Feb 17, 2016
• Actual Study Completion Date: Feb 17, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Migalastat Migalastat 150-mg capsule taken orally QOD. The median duration of exposure was 23.5 m.	Drug: migalastat hydrochloride; Oral capsule QOD; Other Names: AT1001 Galafold Migalastat

Outcome Measures

Primary Outcome Measures

1. Number Of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) [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.]

   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.

Secondary Outcome Measures

1. Annualized Rate Of Change In The Estimated Glomerular Filtration Rate (eGFR) [Baseline, Every 6 m until the End of Study (42 m)]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Completed migalastat treatment in a previous Fabry disease protocol

• Both male and female participants were enrolled

• Age 16 years or older

• Male and female participants had to agree to use protocol-identified acceptable contraception

Exclusion Criteria:

• Estimated glomerular filtration rate (eGFR) in the previous study was <30 milliliters/minute/1.73 square meters (mL/min/1.73 m^{2) unless there was a measured GFR available within 3 m of the Baseline Visit that was >30 mL/min/1.73 m}2

• Had undergone, or was scheduled to undergo, kidney transplantation or was currently on dialysis

• Pregnant or breast feeding

• Treated with another investigational drug (except migalastat) within 30 days of study start

• Unable to comply with study requirements, or deemed otherwise unsuitable for study entry, in the opinion of the investigator

• Had documented transient ischemic attack, stroke, unstable angina, or myocardial infarction within the 12 m before the Baseline Visit

• Had clinically significant, unstable cardiac disease in the opinion of the investigator

• Had a history of allergy or sensitivity to migalastat (including excipients) or to other iminosugars

• Required treatment with Glyset (miglitol) or Zavesca (miglustat)

• Had any intercurrent illness or condition that may have precluded the participant from fulfilling the protocol requirements

• Had a severe or unsuitable concomitant medical condition

• Had a clinically significant abnormal laboratory value and a clinically significant electrocardiogram finding at the Baseline Visit.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Atlanta	Georgia	United States	30322
2		Chicago	Illinois	United States	60611
3		Kansas City	Kansas	United States	66160
4		Boston	Massachusetts	United States	02114
5		Grand Rapids	Michigan	United States	49525
6		New York	New York	United States	10016
7		Portland	Oregon	United States	97239
8		Pittsburgh	Pennsylvania	United States	15213
9		Dallas	Texas	United States	75246
10		Fairfax	Virginia	United States	22030
11		Seattle	Washington	United States	98195
12		Pilar		Argentina	B1629ODT
13		Adelaide		Australia	5000
14		Parkville		Australia	3050
15		Edegem		Belgium	2650
16		Porto Alegre		Brazil	90035-903
17		Montreal		Canada	H4J 1C5
18		Copenhagen		Denmark	2100
19		Cairo		Egypt	11451
20		Garches		France	92380
21		Roma		Italy	00168
22		Barcelona		Spain	08025
23		Ankara		Turkey	06500
24		London		United Kingdom	NW3 2QG
25		Salford		United Kingdom	M6 8HD

Sponsors and Collaborators

• Amicus Therapeutics

Investigators

• Study Director: Medical Monitor, Clinical Research, Amicus Therapeutics

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Amicus Therapeutics
• ClinicalTrials.gov Identifier: NCT01458119
• Other Study ID Numbers: AT1001-041; 2011-004800-40
• First Posted: Oct 24, 2011
• Last Update Posted: Oct 2, 2018
• Last Verified: Oct 1, 2018

• Keywords provided by Amicus Therapeutics: Amicus Therapeutics; AT1001; Galafold; Migalastat
• Additional relevant MeSH terms: Fabry Disease

Study Results

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.

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	85
ITT-Amenable Population	68
COMPLETED	65
NOT COMPLETED	20

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 Participants	85
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.8 (12.25)
Sex: Female, Male (Count of 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.
Measure Participants	85
Participants with at least 1 TEAE	74 87.1%
Participants with at least 1 serious TEAE	22 25.9%
Participants discontinued due to TEAEs	1 1.2%
Participants with adverse events leading to death	2 2.4%
Participants with TEAEs related to study drug	14 16.5%
Participants with TEAEs unrelated to study drug	60 70.6%
Participants with at least 1 mild TEAE	22 25.9%
Participants with at least 1 moderate TEAE	40 47.1%
Participants with at least 1 severe TEAE	12 14.1%

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."
Measure Participants	47
EGFR [CKD-EPI]	1.54
eGFR [MDRD]	1.40

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.
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 (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Migalastat
	Affected / at Risk (%)	# Events
Total	22/85 (25.9%)
Cardiac disorders
Angina pectoris	1/85 (1.2%)
Atrial fibrillation	2/85 (2.4%)
Endocrine disorders
Thyroid mass	1/85 (1.2%)
Gastrointestinal disorders
Abdominal pain upper	1/85 (1.2%)
Hiatus hernia	1/85 (1.2%)
Pancreatitis	1/85 (1.2%)
General disorders
Death	1/85 (1.2%)
Device malfunction	1/85 (1.2%)
Hepatobiliary disorders
Hepatic infarction	1/85 (1.2%)
Infections and infestations
Pneumonia	2/85 (2.4%)
Injury, poisoning and procedural complications
Foot fracture	1/85 (1.2%)
Musculoskeletal and connective tissue disorders
Muscle spasms	1/85 (1.2%)
Musculoskeletal chest pain	1/85 (1.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer metastatic	1/85 (1.2%)
Metastatic squamous cell carcinoma	1/85 (1.2%)
Papillary thyroid cancer	1/85 (1.2%)
Nervous system disorders
Brain stem ischaemia	1/85 (1.2%)
Hemiplegic migraine	1/85 (1.2%)
Presyncope	1/85 (1.2%)
Psychiatric disorders
Conversion disorder	1/85 (1.2%)
Renal and urinary disorders
Calculus urinary	1/85 (1.2%)
Reproductive system and breast disorders
Priapism	1/33 (3%)
Uterine polyp	1/52 (1.9%)
Skin and subcutaneous tissue disorders
Angioedema	1/85 (1.2%)
Skin lesion	1/85 (1.2%)
Surgical and medical procedures
Implantable defibrillator insertion	2/85 (2.4%)
Other (Not Including Serious) Adverse Events
	Migalastat
	Affected / at Risk (%)	# Events
Total	57/85 (67.1%)
Cardiac disorders
Atrial fibrillation	7/85 (8.2%)
Palpitations	5/85 (5.9%)
Ear and labyrinth disorders
Vertigo	5/85 (5.9%)
Gastrointestinal disorders
Abdominal distension	5/85 (5.9%)
Abdominal pain upper	5/85 (5.9%)
Constipation	6/85 (7.1%)
Nausea	10/85 (11.8%)
Diarrhoea	13/85 (15.3%)
General disorders
Fatigue	9/85 (10.6%)
Oedema peripheral	6/85 (7.1%)
Pain	5/85 (5.9%)
Pyrexia	7/85 (8.2%)
Infections and infestations
Influenza	9/85 (10.6%)
Nasopharyngitis	9/85 (10.6%)
Upper respiratory tract infection	6/85 (7.1%)
Urinary Tract Infection	8/85 (9.4%)
Injury, poisoning and procedural complications
Contusion	5/85 (5.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	11/85 (12.9%)
Back pain	6/85 (7.1%)
Pain in extremity	11/85 (12.9%)
Nervous system disorders
Headache	11/85 (12.9%)
Dizziness	9/85 (10.6%)
Paraesthesia	5/85 (5.9%)
Psychiatric disorders
Anxiety	5/85 (5.9%)
Respiratory, thoracic and mediastinal disorders
Cough	6/85 (7.1%)
Vascular disorders
Hypertension	6/85 (7.1%)

Limitations/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.

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.