Trial Outcomes & Findings for Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of Migalastat in Pediatric Subjects (Aged 12 to <18 Years) (NCT NCT03500094)

NCT ID: NCT03500094

Last Updated: 2021-11-30

Results Overview

TEAEs included adverse events that began on or 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 Reported Adverse Events module.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 22 participants
• Primary outcome timeframe: Day 1 (after dosing) through Month 12 and follow-up (30 days after last dose)
• Results posted on: 2021-11-30

Participant Flow

Participants must have been either naïve to enzyme replacement therapy (ERT) or have stopped ERT at least 14 days at the time of screening.

Participant milestones

Measure	Migalastat HCl 150 mg Migalastat was administered every other day for 12 months.
Overall Study STARTED	22
Overall Study Received At Least 1 Dose of Study Drug	21
Overall Study COMPLETED	19
Overall Study NOT COMPLETED	3

Reasons for withdrawal

Measure	Migalastat HCl 150 mg Migalastat was administered every other day for 12 months.
Overall Study Withdrawal by Subject	1
Overall Study Withdrawal by Parent or Legally-authorized Representative	1
Overall Study Lost to Follow-up	1

Baseline Characteristics

Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of Migalastat in Pediatric Subjects (Aged 12 to <18 Years)

Baseline characteristics by cohort

Measure	Migalastat HCl 150 mg n=22 Participants Migalastat was administered every other day for 12 months.
Age, Continuous	14.6 years STANDARD_DEVIATION 1.62 • n=5 Participants
Sex: Female, Male Female	12 Participants n=5 Participants
Sex: Female, Male Male	10 Participants n=5 Participants
Race/Ethnicity, Customized White	20 participants n=5 Participants
Race/Ethnicity, Customized Other	2 participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	3 participants n=5 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	19 participants n=5 Participants

PRIMARY outcome

Timeframe: Day 1 (after dosing) through Month 12 and follow-up (30 days after last dose)

Population: Participants who received at least 1 dose of study drug.

TEAEs included adverse events that began on or 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 Reported Adverse Events module.

Outcome measures

Measure	Migalastat HCl 150 mg n=21 Participants Migalastat was administered every other day for 12 months.	Migalastat HCl 150 mg: ERT Experienced Migalastat was administered every other day for 12 months to ERT experienced participants.
Number Of Participants Who Experienced Treatment-related Treatment-emergent Adverse Events (TEAEs)	5 Participants	—

PRIMARY outcome

Timeframe: 0 to 12 hours postdose during the first month of study and trough samples at Months 6 and 12

Population: Participants with at least 1 quantifiable concentration and a known weight and estimated glomerular filtration rate (eGFR). A population PK model was used for assessment. All migalastat concentration-time data were combined and included in a population PK analysis.

PK sampling was performed on 1 occasion at steady-state during the first month of the study. Adolescent participants were randomized to 3 sparse PK sampling groups based on optimal sampling theory. Each blood sample could have been taken at any time within the following time point ranges. Time point ranges for all 3 sparse sampling groups are arranged here in chronological order: 1 to 1.25 hours (h), 1.5 to 2h, 2.75 to 3.25h, 3.25 to 3.75h, 3.75 to 4.25h, 5 to 5.5h, 5.25 to 5.75h, 6.5 to 7h, 8.25 to 8.75h, 8.75 to 9.25h, and 10.75 to 11.25h post-dose. The combined sampling scheme resulted in rich data over an approximate 12-hour time course for AUC estimation. Additional trough samples were taken at Months 6 and 12. These trough samples (48h) assisted in estimating the terminal elimination phase for the AUC.

Simulations were conducted to predict steady-state PK profiles and parameters for adolescent age subgroups 12 to <16 years, 16 to <18 years, and overall, 12 to <18 years.

Outcome measures

Measure	Migalastat HCl 150 mg n=20 Participants Migalastat was administered every other day for 12 months.	Migalastat HCl 150 mg: ERT Experienced Migalastat was administered every other day for 12 months to ERT experienced participants.
Pharmacokinetics (PK): Area Under The Plasma Concentration-time Curve Over The Dosing Interval (AUCtau) Of Migalastat 12 to <16 years old	8920 h*ng/mL Geometric Coefficient of Variation 47.2	—
Pharmacokinetics (PK): Area Under The Plasma Concentration-time Curve Over The Dosing Interval (AUCtau) Of Migalastat 16 to <18 years old	8430 h*ng/mL Geometric Coefficient of Variation 41.7	—
Pharmacokinetics (PK): Area Under The Plasma Concentration-time Curve Over The Dosing Interval (AUCtau) Of Migalastat 12 to <18 years old	8740 h*ng/mL Geometric Coefficient of Variation 44.2	—

PRIMARY outcome

Timeframe: 0 to 12 hours postdose during the first month of study and trough samples at Months 6 and 12

Population: Participants with at least 1 quantifiable concentration and a known weight and eGFR. A population PK model was used for assessment. All migalastat concentration-time data were combined and included in a population PK analysis.

PK sampling was performed on 1 occasion at steady-state during the first month of the study. Adolescent participants were randomized to 3 sparse PK sampling groups based on optimal sampling theory. Each blood sample could have been taken at any time within the following time point ranges. Time point ranges for all 3 sparse sampling groups are arranged here in chronological order: 1 to 1.25h, 1.5 to 2h, 2.75 to 3.25h, 3.25 to 3.75h, 3.75 to 4.25h, 5 to 5.5h, 5.25 to 5.75h, 6.5 to 7h, 8.25 to 8.75h, 8.75 to 9.25h, and 10.75 to 11.25h post-dose. The combined sampling scheme resulted in rich data over an approximate 12-hour time course for AUC and Cmax estimation. Additional trough samples were taken at Months 6 and 12. These trough samples (48h) assisted in estimating the terminal elimination phase for the AUC.

Simulations were conducted to predict steady-state PK profiles and parameters for adolescent age subgroups 12 to <16 years, 16 to <18 years, and overall, 12 to <18 years.

Outcome measures

Measure	Migalastat HCl 150 mg n=20 Participants Migalastat was administered every other day for 12 months.	Migalastat HCl 150 mg: ERT Experienced Migalastat was administered every other day for 12 months to ERT experienced participants.
PK: Maximum Observed Plasma Concentration (Cmax) Of Migalastat 12 to <16 years old	1220 ng/mL Geometric Coefficient of Variation 60.9	—
PK: Maximum Observed Plasma Concentration (Cmax) Of Migalastat 16 to <18 years old	1160 ng/mL Geometric Coefficient of Variation 39.2	—
PK: Maximum Observed Plasma Concentration (Cmax) Of Migalastat 12 to <18 years old	1200 ng/mL Geometric Coefficient of Variation 52.7	—

SECONDARY outcome

Timeframe: Baseline, Month 12 and last observation (up to Month 12)

Population: Participants who received at least 1 dose of study drug and had evaluable data at the specified timepoints.

eGFR was calculated using the modified Schwartz formula for creatinine clearance.

Outcome measures

Measure	Migalastat HCl 150 mg n=20 Participants Migalastat was administered every other day for 12 months.	Migalastat HCl 150 mg: ERT Experienced Migalastat was administered every other day for 12 months to ERT experienced participants.
Change In eGFR From Baseline To Month 12 Month 12	-1.6 mL/min x 1.73 m^2 Standard Deviation 15.40	—
Change In eGFR From Baseline To Month 12 Last observation (up to Month 12)	-1.6 mL/min x 1.73 m^2 Standard Deviation 14.99	—

SECONDARY outcome

Timeframe: Baseline up to Month 12

Population: All participants who received study drug and had an assessment

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.

Outcome measures

Measure	Migalastat HCl 150 mg n=20 Participants Migalastat was administered every other day for 12 months.	Migalastat HCl 150 mg: ERT Experienced Migalastat was administered every other day for 12 months to ERT experienced participants.
Annualized Rate Of Change From Baseline	-1.5 mL/min x 1.73 m^2/year Standard Deviation 15.11	—

SECONDARY outcome

Timeframe: Baseline, Month 12 and last observation (up to Month 12)

Population: Participants who received at least 1 dose of study drug and had evaluable data at the specified timepoints.

Renal function was assessed by urine protein and urine albumin levels. Urine samples were collected as part of urinalysis to measure protein and albumin levels.

Outcome measures

Measure	Migalastat HCl 150 mg n=20 Participants Migalastat was administered every other day for 12 months.	Migalastat HCl 150 mg: ERT Experienced Migalastat was administered every other day for 12 months to ERT experienced participants.
Change From Baseline In Total Urine Protein And Urine Albumin Levels At Month 12 Total Urine Protein: Month 12	36.0 mg/L Standard Deviation 111.61	—
Change From Baseline In Total Urine Protein And Urine Albumin Levels At Month 12 Total Urine Protein: Last observation (up to Month 12)	36.2 mg/L Standard Deviation 108.64	—
Change From Baseline In Total Urine Protein And Urine Albumin Levels At Month 12 Urine Albumin: Month 12	16.2 mg/L Standard Deviation 28.27	—
Change From Baseline In Total Urine Protein And Urine Albumin Levels At Month 12 Urine Albumin: Last observation (up to Month 12)	15.6 mg/L Standard Deviation 27.67	—

SECONDARY outcome

Timeframe: Baseline, Month 12 and last observation (up to Month 12)

Population: Participants who received at least 1 dose of study drug and had evaluable data at the specified timepoints.

LVMi was assessed as a measure of cardiac impairment in the study participants. LVMi values for both M Mode and 2D views are presented.

Outcome measures

Measure	Migalastat HCl 150 mg n=20 Participants Migalastat was administered every other day for 12 months.	Migalastat HCl 150 mg: ERT Experienced Migalastat was administered every other day for 12 months to ERT experienced participants.
Change From Baseline In Left Ventricular Mass Index (LVMi) M Mode: Month 12	-3.9 g/m^2 Standard Deviation 13.53	—
Change From Baseline In Left Ventricular Mass Index (LVMi) 2D: Month 12	4.9 g/m^2 Standard Deviation 9.12	—
Change From Baseline In Left Ventricular Mass Index (LVMi) M Mode: Last observation (up to Month 12)	-4.4 g/m^2 Standard Deviation 13.31	—
Change From Baseline In Left Ventricular Mass Index (LVMi) 2D: Last observation (up to Month 12)	4.3 g/m^2 Standard Deviation 9.34	—

SECONDARY outcome

Timeframe: Baseline, Month 12 and last observation (up to Month 12)

Population: Participants who received at least 1 dose of study drug and had evaluable data at the specified timepoints.

Blood samples were collected for measurement of lyso-Gb3 levels in plasma. Plasma levels of lyso-Gb3 were measured using a validated liquid chromatography-mass spectrometry assay.

Outcome measures

Measure	Migalastat HCl 150 mg n=9 Participants Migalastat was administered every other day for 12 months.	Migalastat HCl 150 mg: ERT Experienced n=11 Participants Migalastat was administered every other day for 12 months to ERT experienced participants.
Change In Plasma Levels Of Globotriaosylsphingosine (Lyso-Gb3) Month 12	-14.0 ng/mL Standard Deviation 23.13	12.5 ng/mL Standard Deviation 36.33
Change In Plasma Levels Of Globotriaosylsphingosine (Lyso-Gb3) Last Observation (up to Month 12)	-14.0 ng/mL Standard Deviation 23.13	11.3 ng/mL Standard Deviation 34.67

SECONDARY outcome

Timeframe: Month 12 and last observation (up to Month 12)

Population: Participants who received at least 1 dose of study drug and had evaluable data at the specified timepoint.

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 and at last observation are presented. A higher score indicated higher levels of symptoms and pain.

Outcome measures

Measure	Migalastat HCl 150 mg n=18 Participants Migalastat was administered every other day for 12 months.	Migalastat HCl 150 mg: ERT Experienced Migalastat was administered every other day for 12 months to ERT experienced participants.
FABPRO-GI And Pain Scores Daily Ratings of Severity in Constipation: Month 12	0.9 units on a scale Standard Deviation 1.91	—
FABPRO-GI And Pain Scores Daily Ratings of Severity in Constipation: Last observation (up to Month 12)	0.4 units on a scale Standard Deviation 1.00	—
FABPRO-GI And Pain Scores Daily Ratings of Severity in Diarrhea: Month 12	1.0 units on a scale Standard Deviation 1.65	—
FABPRO-GI And Pain Scores Daily Ratings of Severity in Diarrhea: Last Observation (up to Month 12)	0.4 units on a scale Standard Deviation 0.91	—
FABPRO-GI And Pain Scores Overall Pain: Month 12	0.6 units on a scale Standard Deviation 0.71	—
FABPRO-GI And Pain Scores Overall Pain: Last Observation (up to Month 12)	1.2 units on a scale Standard Deviation 1.50	—
FABPRO-GI And Pain Scores Worst Tummy Pain: Month 12	0.3 units on a scale Standard Deviation 0.38	—
FABPRO-GI And Pain Scores Worst Tummy Pain: Last Observation (up to Month 12)	0.9 units on a scale Standard Deviation 1.52	—

SECONDARY outcome

Timeframe: Month 12

Population: Participants who received at least 1 dose of study drug and had evaluable data at the specified timepoint.

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".

Outcome measures

Measure	Migalastat HCl 150 mg n=19 Participants Migalastat was administered every other day for 12 months.	Migalastat HCl 150 mg: ERT Experienced Migalastat was administered every other day for 12 months to ERT experienced participants.
Patient's Global Impression Of Change (PGI-C) Scores Diarrhea: Status Improved	12 Participants	—
Patient's Global Impression Of Change (PGI-C) Scores Diarrhea: Status Same	7 Participants	—
Patient's Global Impression Of Change (PGI-C) Scores Diarrhea: Status Worse	0 Participants	—
Patient's Global Impression Of Change (PGI-C) Scores Abdominal pain: Status Improved	10 Participants	—
Patient's Global Impression Of Change (PGI-C) Scores Abdominal pain: Status Same	8 Participants	—
Patient's Global Impression Of Change (PGI-C) Scores Abdominal pain: Status Worse	1 Participants	—
Patient's Global Impression Of Change (PGI-C) Scores Overall pain: Status Improved	10 Participants	—
Patient's Global Impression Of Change (PGI-C) Scores Overall pain: Status Same	8 Participants	—
Patient's Global Impression Of Change (PGI-C) Scores Overall pain: Status Worse	1 Participants	—
Patient's Global Impression Of Change (PGI-C) Scores Daily living: Status Improved	10 Participants	—
Patient's Global Impression Of Change (PGI-C) Scores Daily living: Status Same	8 Participants	—
Patient's Global Impression Of Change (PGI-C) Scores Daily living: Status Worse	1 Participants	—

SECONDARY outcome

Timeframe: Month 12

Population: Participants who received at least 1 dose of study drug and had evaluable data at the specified timepoint.

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.

Outcome measures

Measure	Migalastat HCl 150 mg n=19 Participants Migalastat was administered every other day for 12 months.	Migalastat HCl 150 mg: ERT Experienced Migalastat was administered every other day for 12 months to ERT experienced participants.
Number Of Participants Who Experienced Sudden Onset Of Pain As Assessed Using The Fabry-Specific Pediatric Health And Pain Questionnaire (FPHPQ) 0 times	4 Participants	—
Number Of Participants Who Experienced Sudden Onset Of Pain As Assessed Using The Fabry-Specific Pediatric Health And Pain Questionnaire (FPHPQ) 1-3 times	5 Participants	—
Number Of Participants Who Experienced Sudden Onset Of Pain As Assessed Using The Fabry-Specific Pediatric Health And Pain Questionnaire (FPHPQ) 4-6 times	4 Participants	—
Number Of Participants Who Experienced Sudden Onset Of Pain As Assessed Using The Fabry-Specific Pediatric Health And Pain Questionnaire (FPHPQ) > 6 times	3 Participants	—

SECONDARY outcome

Timeframe: Baseline, Month 12 and last observation (up to Month 12)

Population: Participants who received at least 1 dose of study drug and had evaluable data at the specified timepoint.

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.

Outcome measures

Measure	Migalastat HCl 150 mg n=17 Participants Migalastat was administered every other day for 12 months.	Migalastat HCl 150 mg: ERT Experienced Migalastat was administered every other day for 12 months to ERT experienced participants.
Change From Baseline In FPHPQ Score For Pain Intensity Month 12	0.4 units on a scale Standard Deviation 1.82	—
Change From Baseline In FPHPQ Score For Pain Intensity Last observation (up to Month 12)	0.4 units on a scale Standard Deviation 1.77	—

SECONDARY outcome

Timeframe: Baseline, Month 12

Population: Participants who received at least 1 dose of study drug and had evaluable data at the specified timepoints.

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.

Outcome measures

Measure	Migalastat HCl 150 mg n=15 Participants Migalastat was administered every other day for 12 months.	Migalastat HCl 150 mg: ERT Experienced Migalastat was administered every other day for 12 months to ERT experienced participants.
Change From Baseline In Pediatric Quality Of Life (PedsQL) At Month 12 Child Report	2.2 units on a scale Standard Deviation 6.13	—
Change From Baseline In Pediatric Quality Of Life (PedsQL) At Month 12 Parent Report	3.1 units on a scale Standard Deviation 10.29	—

Adverse Events

Migalastat HCl 150 mg

Serious events: 1 serious events

Other events: 20 other events

Deaths: 0 deaths

Serious adverse events

Measure	Migalastat HCl 150 mg n=21 participants at risk Migalastat was administered every other day for 12 months.
Psychiatric disorders Suicidal ideation	4.8% 1/21 • Day 1 (after dosing) through Month 12 and follow-up (30 days after last dose)

Other adverse events

Measure	Migalastat HCl 150 mg n=21 participants at risk Migalastat was administered every other day for 12 months.
Gastrointestinal disorders Vomiting	9.5% 2/21 • Day 1 (after dosing) through Month 12 and follow-up (30 days after last dose)
General disorders Complication associated with device	9.5% 2/21 • Day 1 (after dosing) through Month 12 and follow-up (30 days after last dose)
Infections and infestations Influenza	14.3% 3/21 • Day 1 (after dosing) through Month 12 and follow-up (30 days after last dose)
Infections and infestations Nasopharyngitis	14.3% 3/21 • Day 1 (after dosing) through Month 12 and follow-up (30 days after last dose)
Infections and infestations Pharyngitis streptococcal	9.5% 2/21 • Day 1 (after dosing) through Month 12 and follow-up (30 days after last dose)
Infections and infestations Upper respiratory tract infection	28.6% 6/21 • Day 1 (after dosing) through Month 12 and follow-up (30 days after last dose)
Musculoskeletal and connective tissue disorders Back pain	14.3% 3/21 • Day 1 (after dosing) through Month 12 and follow-up (30 days after last dose)
Nervous system disorders Headache	14.3% 3/21 • Day 1 (after dosing) through Month 12 and follow-up (30 days after last dose)
Nervous system disorders Paraesthesia	9.5% 2/21 • Day 1 (after dosing) through Month 12 and follow-up (30 days after last dose)
Skin and subcutaneous tissue disorders Rash	9.5% 2/21 • Day 1 (after dosing) through Month 12 and follow-up (30 days after last dose)

Additional Information

Medical Affairs

Amicus Therapeutics

Phone: +1-877-426-4287 (877-4-AMICUS)

Email: MedInfoUSA@amicusrx.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER