Clinical Trial Results:
An Open-label Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of 12 Month Treatment With Migalastat in Pediatric Subjects (Aged 12 to <18 Years) With Fabry Disease and Amenable GLA Variants
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Summary
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EudraCT number |
2017-000146-21 |
Trial protocol |
GB DE ES IT |
Global end of trial date |
02 Feb 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
04 Aug 2021
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First version publication date |
04 Aug 2021
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
AT1001-020
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03500094 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Amicus Therapeutics UK Limited
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Sponsor organisation address |
One Globeside, Fieldhouse Lane, Marlow, United Kingdom, SL7 1HZ
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Public contact |
Medical Affairs, Amicus Therapeutics, 001 609662-2000, clinicaltrials@amicusrx.com
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Scientific contact |
Medical Affairs, Amicus Therapeutics, 001 609662-2000, MedInfoUSA@amicusrx.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001194-PIP01-11 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
11 May 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
02 Feb 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
02 Feb 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Stage 1:
• to characterize the pharmacokinetics (PK) of migalastat in adolescents with Fabry disease and to validate extrapolation of migalastat plasma exposure in adults to adolescents weighing ≥ 45 kilograms (kg) for the 150 milligrams (mg) migalastat capsule administered every other day
• to evaluate the safety of migalastat treatment in pediatric participants diagnosed with Fabry disease and who have variants in the gene encoding α galactosidase A (α Gal A) (GLA) amenable to treatment with migalastat
Stage 2:
• to evaluate the safety of migalastat treatment in pediatric participants diagnosed with Fabry disease and who have GLA variants amenable to treatment with migalastat
Upon study completion, participants had the option to enroll in a long-term extension study conducted under a separate protocol (EudraCT number 2019-000222-21).
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Protection of trial subjects |
This study was conducted in accordance with International Council on Harmonisation Good Clinical Practice guidelines, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which the study was conducted.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 Sep 2018
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
5 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 4
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Country: Number of subjects enrolled |
United States: 18
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Worldwide total number of subjects |
22
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
22
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||
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Pre-assignment
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Screening details |
Participants must have been naïve to enzyme replacement therapy (ERT) or have stopped ERT at least 14 days at the time of screening. | ||||||||||||||||
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Period 1
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Period 1 title |
Overall (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||
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Arms
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Arm title
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Migalastat HCl 150 mg | ||||||||||||||||
Arm description |
Migalastat was administered every other day for 12 months. | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
Migalastat
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Investigational medicinal product code |
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Other name |
AT1001, Galafold
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
One migalastat 123 milligrams (mg) capsule equivalent to 150 mg migalastat hydrochloride (HCl) (herein referred to as “migalastat”) was administered every other day for 12 months.
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Baseline characteristics reporting groups
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Reporting group title |
Overall
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Reporting group description |
All participants who enrolled in the study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Migalastat HCl 150 mg
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Reporting group description |
Migalastat was administered every other day for 12 months. | ||
Subject analysis set title |
Migalastat HCl 150 mg
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Participants who received at least 1 dose of study drug.
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Subject analysis set title |
Migalastat HCl 150 mg: ERT Naive
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Migalastat was administered every other day for 12 months to ERT Naive participants.
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Subject analysis set title |
Migalastat HCl 150 mg: ERT Experienced
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Migalastat was administered every other day for 12 months to ERT experienced participants.
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End point title |
Number Of Participants Who Experienced Treatment-related Treatment-emergent Adverse Events (TEAEs) [1] | ||||||||
End point description |
TEAEs included adverse events that began after the first dose of study drug until 30 days after the last dose. Treatment-related TEAEs were defined as TEAEs that had an investigator-defined relationship to study drug of “Definite,” “Probable,” or “Possible.” A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Adverse Events section.
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End point type |
Primary
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End point timeframe |
Day 1 (after dosing) through Month 12 and follow-up (30 days after last dose)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive analysis was performed as per protocol. |
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| No statistical analyses for this end point | |||||||||
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End point title |
PK: Area Under The Plasma Concentration-time Curve Over The Dosing Interval (AUCtau) Of Migalastat [2] | ||||||||||||||||
End point description |
Four blood samples were collected during Stage 1 according to random 1:1:1 assignment to 1 of 3 PK sampling groups: Group 1: 1 hour (hr), 1.5 hr, 5 hr, 6.5 hr; Group 2: 1 hr, 2.75 hr, 5.25 hr, 10.75 hr; Group 3: 3.25 hr, 3.75 hr, 8.25 hr, 8.75 hr; and for all groups: one sample at Month 6 and at Month 12. Simulations were conducted to predict steady-state PK profiles and PK parameters for adolescent age subgroups 12 to <16 years, 16 to <18 years, and overall, 12 to <18 years. Population PK results are presented.
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End point type |
Primary
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End point timeframe |
Baseline to Month 12
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive analysis was performed as per protocol. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
PK: Maximum Observed Plasma Concentration (Cmax) Of Migalastat [3] | ||||||||||||||||
End point description |
Four blood samples were collected during Stage 1 according to random 1:1:1 assignment to 1 of 3 PK sampling groups: Group 1: 1 hour (hr), 1.5 hr, 5 hr, 6.5 hr; Group 2: 1 hr, 2.75 hr, 5.25 hr, 10.75 hr; Group 3: 3.25 hr, 3.75 hr, 8.25 hr, 8.75 hr; and for all groups: one sample at Month 6 and at Month 12. Simulations were conducted to predict steady-state PK profiles and PK parameters for pediatric age groups. Results by age group are presented.
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End point type |
Primary
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End point timeframe |
Baseline to Month 12
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive analysis was performed as per protocol. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Change In Estimated Glomerular Filtration Rate (eGFR) From Baseline To Month 12 | ||||||||||||
End point description |
Estimated GFR was calculated using the modified Schwartz formula for creatinine clearance.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 12 and last observation (up to Month 12)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Annualized Rate Of Change From Baseline | ||||||||
End point description |
Annualized rate of change from baseline of eGFR was defined as change from baseline to last visit divided by the duration from baseline to the last visit (Last assessment date – First dose date +1) and multiplied by 365.25. Baseline was defined as the last non-missing assessment prior to the first dose of study drug.
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End point type |
Secondary
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End point timeframe |
Baseline up to Month 12
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline In Total Urine Protein And Urine Albumin Levels At Month 12 | ||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline, Month 12 and last observation (up to Month 12)
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| Notes [4] - Month 12: n=19 |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Change From Baseline In Left Ventricular Mass Index (LVMi) | ||||||||||||||||
End point description |
LVMi was assessed as a measure of cardiac impairment in the study participants. LVMi values for both M Mode and 2D views are presented.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 12 and last observation (up to Month 12)
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Change In Plasma Levels Of Globotriaosylsphingosine (Lyso-Gb3) | ||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline, Month 12 and last observation (up to Month 12)
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| Notes [5] - Month 12: n=10 |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
FABPRO-GI And Pain Scores At Month 12 | ||||||||||||||||
End point description |
The Fabry Disease Patient-Reported Outcome – Gastrointestinal Signs And Symptoms (FABPRO-GI) And Pain Questionnaire For Clinical Trials (24-hr Version) consists of questions regarding gastrointestinal signs and symptoms and pain relative to the past 24 hours. Participants rated the severity of their symptoms and pain from 0 (none) to 10 (worst possible). The monthly average score at Month 12 is presented. A higher score indicated higher levels of symptoms and pain.
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End point type |
Secondary
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End point timeframe |
Month 12
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
FABPRO-GI And Pain Scores At Last Observation | ||||||||||||||||
End point description |
The Fabry Disease Patient-Reported Outcome – Gastrointestinal Signs And Symptoms (FABPRO-GI) And Pain Questionnaire For Clinical Trials (24-hr Version) consists of questions regarding gastrointestinal signs and symptoms and pain relative to the past 24 hours. Participants rated the severity of their symptoms and pain from 0 (none) to 10 (worst possible). The monthly average score at last observation is presented. A higher score indicated higher levels of symptoms and pain.
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End point type |
Secondary
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End point timeframe |
Last observation (up to Month 12)
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Patient’s Global Impression Of Change (PGI-C) Scores | ||||||||||||||||||||||||||||||||
End point description |
The PGI-C consists of 4 questions regarding diarrhea, abdominal pain, overall pain, and daily living. Participants rated their status based on improvement, worsening, or the same. Improved status includes “Much better”, “Better” and “A little better”; worsened status includes “A little worse”, “Worse” and “Much worse”.
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End point type |
Secondary
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End point timeframe |
Month 12
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
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End point title |
Number Of Participants Who Experienced Sudden Onset Of Pain As Assessed Using The Fabry-Specific Pediatric Health And Pain Questionnaire (FPHPQ) | ||||||||||||||||
End point description |
The assessment of “In the last 3 months how many times did you experience sudden onset of pain?” using the FPHPQ for ages 13 to 18 is presented.
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End point type |
Secondary
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End point timeframe |
Month 12
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Change From Baseline In FPHPQ Score For Pain Intensity | ||||||||||||
End point description |
The assessment of “How bad is your pain today?” using the FPHPQ for ages 13 to 18 is presented. Pain intensity was measured on a 10-point scale, 0 (no pain) to 10 (pain as bad as you can imagine). A decrease from baseline indicates an improvement in the condition.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 12 and last observation (up to Month 12)
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| Notes [6] - Month 12: n=16 |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline In Pediatric Quality Of Life (PedsQL) At Month 12 | ||||||||||||
End point description |
The PedsQL is a modular approach to measuring health-related quality of life in healthy children and adolescents and those with acute and chronic health conditions. The psychosocial score for the PedsQL encompassed 15 questions relating to the participants’ feelings, social interaction with others, and school. The physical score was derived from answers to 8 questions about the participants’ ease of managing physical activity.
All components of the PedsQL were scored based on a scale of 0 (never) to 4 (almost always) and linearly transformed to a 0-100 scale as follows: 0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0. Both categories were combined for a total score. Total scores for the child report ages 13 to 18 years old and parent report are presented at Month 12.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 12
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Day 1 (after dosing) through Month 12 and follow-up (30 days after last dose)
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.0
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Reporting groups
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Reporting group title |
Migalastat HCl 150 mg
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Reporting group description |
Migalastat was administered every other day for 12 months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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10 Sep 2018 |
• A change in terminology of GLA mutation to GLA variant was implemented.
• The inclusion requirement for subjects to be off ERT treatment for 6 months was reduced to 14 days.
• The number of participants targeted for enrollment was increased from 7 to 10 participants to 20 participants
• Prior or anticipated use of gene therapy was added as an exclusion criterion.
• The safety criteria of change in body weight and height was revised from percentile to absolute change.
• The procedure for GLA genotyping conducted at screening was clarified.
• Visit windows for Months 6, 9, and 12 (or early termination) were increased from ± 3 days to ± 6 days and the follow-up visit window was increased to + 6 days.
• Microalbumin was added as an alternative to albumin for urinalyses/urine chemistry parameters.
• Procedure and timing of PK blood sampling was clarified.
• The modified Schwartz formula was specified as the method of calculating eGFR.
• An alternate method of reporting serious adverse events via email was added as a back-up in the event that notification via fax failed.
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31 Oct 2018 |
• The design of the study was separated into 2 stages. Stage 1 was 1 month during which PK samples were collected and evaluated. Stage 2 was 11 months during which safety and efficacy were assessed. The total duration of the study (12 months) remained unchanged.
• A subpopulation of subjects aged 12 to < 16 years was planned for PK analysis since in some global markets 16 years of age is considered an adult.
• Duplicative exclusion criterion regarding prior ERT use was eliminated.
• Collection of PK samples was moved from between Days 1 to 15 to between Days 15 to 30 in order to capture steady-state data.
• Provision was made for 2 interim analyses in order to evaluate the subgroup of subjects aged 12 to < 16 years.
• The requirement for GLA genotype testing prior to migalastat administration was clarified.
• Plasma lyso-Gb3 was eliminated at screening, since it is also collected at baseline and does not impact inclusion criteria.
• Evaluation of PGI-C was moved from Month 2 to Month 3 and added to Month 9.
• Height measurement was added to every site visit in order to calculate eGFR.
• Questioning regarding the date of last menstrual period for menstruating females was added to all telephone contacts.
• Exploratory pharmcodynamic (PD) biomarkers were specified.
• A clarification was added to note that subjects enrolling in an extension study will not need to attend the follow-up visit.
• Procedures critical to collection of PK samples were specified and emphasized.
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
