A Phase 3 interventional study of Migalastat HCl 150 mg in Fabry Disease, sponsored by Amicus Therapeutics. Completed at 8 sites in 2 countries. Open to participants aged 12 Years to 17 Years. Per ClinicalTrials.gov, last updated 2021-11-30.
Sponsored by Amicus Therapeutics · Phase 3, Interventional, and Treatment
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.
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.
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Key Inclusion Criteria
Key Exclusion Criteria
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
migalastat HCl 150 mg capsule
Also known as: AT1001, Galafold
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.
Time frame: 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.
Time frame: 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.
Time frame: 0 to 12 hours postdose during the first month of study and trough samples at Months 6 and 12
Change In eGFR From Baseline To Month 12
eGFR was calculated using the modified Schwartz formula for creatinine clearance.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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".
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline, Month 12
Participants must have been either naïve to enzyme replacement therapy (ERT) or have stopped ERT at least 14 days at the time of screening.
| Milestone | Migalastat HCl 150 mg |
|---|---|
| Started | 22 |
| Received at least 1 dose of study drug | 21 |
| Completed | 19 |
| Not completed | 3 |
| Withdrew: Withdrawal by subject | 1 |
| Withdrew: Withdrawal by parent or legally-authorized representative | 1 |
| Withdrew: Lost to follow-up | 1 |
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.
| Participants | Migalastat HCl 150 mg |
|---|---|
| Number Of Participants Who Experienced Treatment-related Treatment-emergent Adverse Events (TEAEs) | 5 |
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.
| h*ng/mL | Migalastat HCl 150 mg |
|---|---|
| 12 to <16 years old | 8920 ± 47.2 |
| 16 to <18 years old | 8430 ± 41.7 |
| 12 to <18 years old | 8740 ± 44.2 |
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.
| ng/mL | Migalastat HCl 150 mg |
|---|---|
| 12 to <16 years old | 1220 ± 60.9 |
| 16 to <18 years old | 1160 ± 39.2 |
| 12 to <18 years old | 1200 ± 52.7 |
eGFR was calculated using the modified Schwartz formula for creatinine clearance.
| mL/min x 1.73 m^2 | Migalastat HCl 150 mg |
|---|---|
| Month 12 | -1.6 ± 15.40 |
| Last observation (up to Month 12) | -1.6 ± 14.99 |
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.
| mL/min x 1.73 m^2/year | Migalastat HCl 150 mg |
|---|---|
| Annualized Rate Of Change From Baseline | -1.5 ± 15.11 |
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.
| mg/L | Migalastat HCl 150 mg |
|---|---|
| Total Urine Protein: Month 12 | 36.0 ± 111.61 |
| Total Urine Protein: Last observation (up to Month 12) | 36.2 ± 108.64 |
| Urine Albumin: Month 12 | 16.2 ± 28.27 |
| Urine Albumin: Last observation (up to Month 12) | 15.6 ± 27.67 |
LVMi was assessed as a measure of cardiac impairment in the study participants. LVMi values for both M Mode and 2D views are presented.
| g/m^2 | Migalastat HCl 150 mg |
|---|---|
| M Mode: Month 12 | -3.9 ± 13.53 |
| 2D: Month 12 | 4.9 ± 9.12 |
| M Mode: Last observation (up to Month 12) | -4.4 ± 13.31 |
| 2D: Last observation (up to Month 12) | 4.3 ± 9.34 |
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.
| ng/mL | Migalastat HCl 150 mg: ERT Naive | Migalastat HCl 150 mg: ERT Experienced |
|---|---|---|
| Month 12 | -14.0 ± 23.13 | 12.5 ± 36.33 |
| Last Observation (up to Month 12) | -14.0 ± 23.13 | 11.3 ± 34.67 |
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.
| units on a scale | Migalastat HCl 150 mg |
|---|---|
| Daily Ratings of Severity in Constipation: Month 12 | 0.9 ± 1.91 |
| Daily Ratings of Severity in Constipation: Last observation (up to Month 12) | 0.4 ± 1.00 |
| Daily Ratings of Severity in Diarrhea: Month 12 | 1.0 ± 1.65 |
| Daily Ratings of Severity in Diarrhea: Last Observation (up to Month 12) | 0.4 ± 0.91 |
| Overall Pain: Month 12 | 0.6 ± 0.71 |
| Overall Pain: Last Observation (up to Month 12) | 1.2 ± 1.50 |
| Worst Tummy Pain: Month 12 | 0.3 ± 0.38 |
| Worst Tummy Pain: Last Observation (up to Month 12) | 0.9 ± 1.52 |
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".
| Participants | Migalastat HCl 150 mg |
|---|---|
| Diarrhea: Status Improved | 12 |
| Diarrhea: Status Same | 7 |
| Diarrhea: Status Worse | 0 |
| Abdominal pain: Status Improved | 10 |
| Abdominal pain: Status Same | 8 |
| Abdominal pain: Status Worse | 1 |
| Overall pain: Status Improved | 10 |
| Overall pain: Status Same | 8 |
| Overall pain: Status Worse | 1 |
| Daily living: Status Improved | 10 |
| Daily living: Status Same | 8 |
| Daily living: Status Worse | 1 |
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.
| Participants | Migalastat HCl 150 mg |
|---|---|
| 0 times | 4 |
| 1-3 times | 5 |
| 4-6 times | 4 |
| > 6 times | 3 |
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.
| units on a scale | Migalastat HCl 150 mg |
|---|---|
| Month 12 | 0.4 ± 1.82 |
| Last observation (up to Month 12) | 0.4 ± 1.77 |
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.
| units on a scale | Migalastat HCl 150 mg |
|---|---|
| Child Report | 2.2 ± 6.13 |
| Parent Report | 3.1 ± 10.29 |
Collected over Day 1 (after dosing) through Month 12 and follow-up (30 days after last dose). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Migalastat HCl 150 mg | 0/21 (0%) | 1/21 (4.8%) | 20/21 (95.2%) |
| Event | Migalastat HCl 150 mg |
|---|---|
| Suicidal ideationPsychiatric disorders | 1/21 |
| Event | Migalastat HCl 150 mg |
|---|---|
| Upper respiratory tract infectionInfections and infestations | 6/21 |
| InfluenzaInfections and infestations | 3/21 |
| NasopharyngitisInfections and infestations | 3/21 |
| Back painMusculoskeletal and connective tissue disorders | 3/21 |
| HeadacheNervous system disorders | 3/21 |
| VomitingGastrointestinal disorders | 2/21 |
| Complication associated with deviceGeneral disorders | 2/21 |
| Pharyngitis streptococcalInfections and infestations | 2/21 |
| ParaesthesiaNervous system disorders | 2/21 |
| RashSkin and subcutaneous tissue disorders | 2/21 |
All participants who enrolled in the study.
| Age, Continuous(years) | Migalastat HCl 150 mg |
|---|---|
| Mean | 14.6 ± 1.62 |
| Sex: Female, Male(Participants) | Migalastat HCl 150 mg |
|---|---|
| Female | 12 |
| Male | 10 |
| Race/Ethnicity, Customized(participants) | Migalastat HCl 150 mg |
|---|---|
| White | 20 |
| Other | 2 |
| Hispanic or Latino | 3 |
| Not Hispanic or Latino | 19 |
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Amicus Therapeutics