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

Study Overview
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Brief Summary
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This was an open-label study to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of migalastat treatment in pediatric participants 12 to <18 years of age with Fabry disease and amenable gene encoding α-galactosidase A (GLA) variants.

Detailed Description
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This was a Phase 3b, 2-stage, open-label, uncontrolled, multicenter study to evaluate the safety, PK, PD, and efficacy of migalastat treatment in pediatric participants 12 to <18 years of age and weighing ≥ 45 kilograms (99 pounds) with Fabry disease and amenable GLA variants. Participants must have been naïve to enzyme replacement therapy (ERT) or have stopped ERT at least 14 days at the time of screening. Stage 1 was a treatment period of approximately 1 month (4 weeks); Stage 2 was a treatment period of 11 months and a 30-day (untreated) safety follow-up period. There was no break in treatment between Stages 1 and 2. Prior to Stage 1, there was a screening period lasting at least 14 days and up to 30 days (or more, if GLA genotyping was required). Stages 1 and 2 together consisted of a 12-month treatment period, and a 30-day safety follow-up period, for a total of approximately 13 months. Upon study completion, participants had the option to enroll in a long-term extension study conducted under a separate protocol (NCT04049760). Participants were randomly assigned 1:1:1 to 1 of 3 PK sampling groups using interactive response technology (IRT). Four blood samples for the determination of migalastat concentrations in plasma were collected during Stage 1 study drug administration, and 1 PK (trough) sample was collected at Month 6 and again at Month 12.

Official Title
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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

Conditions
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Fabry Disease

Intervention / Treatment
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* Drug: Migalastat HCl 150 mg


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria Willing and able to provide written consent or assent (participant and parent/legal guardian, as applicable) Male or female between 12 and <18 years of age diagnosed with Fabry disease Confirmed, amenable GLA variant Participant weighed at least 45 kg (99 pounds) at screening Participant had never been treated with ERT or had not received ERT for 14 days prior to screening Participant had at least 1 complication (such as, laboratory abnormality and/or sign/symptom) of Fabry disease Participant was able to swallow study medication whole Key Exclusion Criteria Had moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) <60 milliliter/minute/1.73 meter squared (m^2) at screening) Had advanced kidney disease requiring dialysis or kidney transplantation History of allergy or sensitivity to study medication (including excipients) or other iminosugars (for example, miglustat, miglitol) Had received any gene therapy at any time or anticipated starting gene therapy during the study period Required treatment with Glyset (miglitol) and/or Zavesca (miglustat) within 6 months before screening or throughout the study Required treatment with Replagal (agalsidase alfa), or Fabrazyme (agalsidase beta) within 14 days before screening or throughout the study Participant was treated or had been treated with any investigational/experimental drug, biologic or device within 30 days before screening Any intercurrent illness or condition or concomitant medication use considered to be a contraindication at screening or baseline or that may have precluded the participant from fulfilling the protocol requirements or suggested to the investigator that the potential participant may have had an unacceptable risk by participating in this study Pregnant or breast-feeding or planned to become pregnant during the study period Otherwise unsuitable for the study in the opinion of the investigator

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: migalastat HCl 150 mg<br>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. | Drug: Migalastat HCl 150 mg<br>* migalastat HCl 150 mg capsule<br>* Other names: Galafold;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number Of Participants Who Experienced Treatment-related Treatment-emergent Adverse Events (TEAEs) | 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. | Day 1 (after dosing) through Month 12 and follow-up (30 days after last dose) | 
| Pharmacokinetics (PK): Area Under The Plasma Concentration-time Curve Over The Dosing Interval (AUCtau) Of Migalastat | 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. | 0 to 12 hours postdose during the first month of study and trough samples at Months 6 and 12 | 
| PK: Maximum Observed Plasma Concentration (Cmax) Of Migalastat | 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. | 0 to 12 hours postdose during the first month of study and trough samples at Months 6 and 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change In eGFR From Baseline To Month 12 | eGFR was calculated using the modified Schwartz formula for creatinine clearance. | Baseline, Month 12 and last observation (up to Month 12) | 
| Annualized Rate Of Change From Baseline | 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. | Baseline up to Month 12 | 
| Change From Baseline In Total Urine Protein And Urine Albumin Levels At Month 12 | 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. | Baseline, Month 12 and last observation (up to Month 12) | 
| Change From Baseline In Left Ventricular Mass Index (LVMi) | LVMi was assessed as a measure of cardiac impairment in the study participants. LVMi values for both M Mode and 2D views are presented. | Baseline, Month 12 and last observation (up to Month 12) | 
| Change In Plasma Levels Of Globotriaosylsphingosine (Lyso-Gb3) | 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. | Baseline, Month 12 and last observation (up to Month 12) | 
| FABPRO-GI And Pain Scores | 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. | Month 12 and last observation (up to Month 12) | 
| Patient's Global Impression Of Change (PGI-C) Scores | 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. | Month 12 | 
| Number Of Participants Who Experienced Sudden Onset Of Pain As Assessed Using The Fabry-Specific Pediatric Health And Pain Questionnaire (FPHPQ) | 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. | Month 12 | 
| Change From Baseline In FPHPQ Score For Pain Intensity | 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. | Baseline, Month 12 and last observation (up to Month 12) | 
| Change From Baseline In Pediatric Quality Of Life (PedsQL) At Month 12 | 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. | Baseline, Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lysosomal storage disease, migalastat, AT1001, Galafold