A Phase 3 interventional study of migalastat hydrochloride and Placebo in Fabry Disease, sponsored by Amicus Therapeutics. Completed at 28 sites in 13 countries. Open to participants aged 16 Years to 74 Years. Per ClinicalTrials.gov, last updated 2018-10-30.
Sponsored by Amicus Therapeutics · Phase 3, Interventional, and Treatment
The primary objective of this study was to compare the effect of migalastat (123 milligrams [mg] of migalastat [equivalent to 150 mg of migalastat hydrochloride]) (migalastat) versus placebo on kidney globotriaosylceramide (GL-3).
This double-blind, randomized, placebo-controlled study was conducted in 67 participants at 46 sites worldwide. The study consisted of 2 stages and an optional open-label treatment extension phase:
Stage 1 included a screening period of up to 2 months followed by a 6-month treatment period which involved 4 visits to the clinic. Participants were randomized in equal proportions to receive either migalastat or placebo.
After completing the 6-month double-blind phase, all participants entered Stage 2 of the study and received migalastat in an open-label manner. Stage 2 treatment lasted for 6 months and involved up to 4 visits to the clinic.
Participants who completed both Stage 1 and Stage 2 of the study as scheduled were offered the opportunity to participate in an open-label treatment extension phase with migalastat. The open-label treatment extension phase lasted 12 months and involved 2 visits to the clinic. A follow-up visit was undertaken 1 month following completion or discontinuation from the open-label treatment extension. Participants completing the 12-month open-label treatment extension and providing consent to enter a separate long-term extension were not required to complete this follow-up visit.
Study assessments included clinical laboratory tests, 12-lead electrocardiogram, kidney biopsy, kidney function testing, echocardiography, and patient-reported outcomes.
242 studies on the registry are indexed under Fabry Disease; 54 are open to participants now.
This study's enrollment of 67 is above the median of 22 across 105 interventional studies indexed under Fabry Disease.
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Exclusion Criteria:
Migalastat 150-mg capsule taken orally every other day (QOD) for 6 months and an open-label 6-month treatment extension, followed by an optional, 12-month, open-label treatment extension.
Drug: migalastat hydrochloride
Placebo capsule taken orally QOD for 6 months.
Drug: Placebo
Oral capsule QOD
Also known as: AT1001, Galafold, Migalastat
Oral capsule QOD
Percentage Of Participants With At Least A 50% Reduction From Baseline To Month 6 In The Average Number Of Kidney Interstitial Capillary (IC) Globotriaosylceramide (GL-3) Inclusions
Renal biopsies were taken at Baseline and Month 6 (Stage 1). The specimens were evaluated using virtual microscopy. The annotation, scoring, and adjudication of the kidney histology assessments were performed by the Clinical Pathology Endpoints Committee. The number of kidney IC GL-3 inclusions was assessed by 3 renal pathologists who were blinded to treatment assignments, participants' data, and biopsy sequence. One pathologist served as annotator and identified the 300 capillaries on up to 8 slides per specimen to be scored. Two pathologists served as scorers; these pathologists completed the blinded paired assessments. Each pathologist served as annotator/adjudicator for 1/3 of the cases. Paired assessments were undertaken at Baseline and Month 6. Assessments were made using digital images. A responder was defined as a participant with a ≥50% reduction from Baseline to Month 6 in the average number of kidney IC GL-3 inclusions.
Time frame: Baseline, Month 6
Percent Change In Kidney IC GL-3 Inclusions From Baseline To Month 6
Renal biopsies were taken at Baseline and Month 6. The specimens were evaluated using virtual microscopy. The annotation, scoring, and adjudication of the kidney histology assessments were performed by the Clinical Pathology Endpoints Committee. The number of kidney IC GL-3 inclusions was assessed by 3 renal pathologists who were blinded to treatment assignments, participants' data, and biopsy sequence. One pathologist served as annotator and identified the 300 capillaries on up to 8 slides per specimen to be scored. Two pathologists served as scorers; these pathologists completed the blinded paired assessments. Each pathologist served as annotator/adjudicator for 1/3 of the cases. Paired assessments were undertaken at Baseline and Month 6. Assessments were made using digital images.
Time frame: Baseline, Month 6
Change From Baseline Through Month 24 In Urine GL-3 Levels
The effect of migalastat versus placebo on urine GL-3 levels was measured by liquid chromatography-mass spectrometry/mass spectrometry. The 24-hour urine samples were collected at Baseline, Month 6 (Stage 1), Month 12 (Stage 2), and Month 24 (OLE). Results are presented as changes in nanograms (ng)/mg creatinine from Baseline to the end of the 3 stages.
Time frame: Baseline, Months 6, 12, and 24
Change From Month 6 To Month 12 In Average Number Of Kidney IC GL-3 Inclusions
Renal biopsies were taken at Month 6 and Month 12. The specimens were evaluated using virtual microscopy. The annotation, scoring, and adjudication of the kidney histology assessments were performed by the Clinical Pathology Endpoints Committee. The number of kidney IC GL-3 inclusions was assessed by 3 renal pathologists who were blinded to treatment assignments, participants' data, and biopsy sequence. One pathologist served as annotator and identified the 300 capillaries on up to 8 slides per specimen to be scored. Two pathologists served as scorers; these pathologists completed the blinded paired assessments. Each pathologist served as annotator/adjudicator for 1/3 of the cases. Paired assessments were undertaken at Month 6 and Month 12. Assessments were made using digital images.
Time frame: Month 6, Month 12
| Milestone | Migalastat (0-6 Months) | Placebo (0-6 Months) | Migalastat (>6-12 Months) | Migalastat (>12-24 Months) |
|---|---|---|---|---|
| Started | 34 | 33 | 0 | 0 |
| Received at least 1 dose of study drug | 34 | 33 | 0 | 0 |
| Intent-to-treat (itt) | 34 | 33 | 0 | 0 |
| Modified intent-to-treat (mitt) | 30 | 30 | 0 | 0 |
| Completed | 34 | 30 | 0 | 0 |
| Not completed | 0 | 3 | 0 | 0 |
| Withdrew: Withdrawal by subject | 0 | 2 | 0 | 0 |
| Withdrew: Pregnancy | 0 | 1 | 0 | 0 |
| Milestone | Migalastat (0-6 Months) | Placebo (0-6 Months) | Migalastat (>6-12 Months) | Migalastat (>12-24 Months) |
|---|---|---|---|---|
| Started | 0 | 0 | 63 | 0 |
| Itt-amenable | 0 | 0 | 47 | 0 |
| Completed | 0 | 0 | 60 | 0 |
| Not completed | 0 | 0 | 3 | 0 |
| Withdrew: Withdrawal by subject | 0 | 0 | 1 | 0 |
| Withdrew: Adverse event | 0 | 0 | 2 | 0 |
| Milestone | Migalastat (0-6 Months) | Placebo (0-6 Months) | Migalastat (>6-12 Months) | Migalastat (>12-24 Months) |
|---|---|---|---|---|
| Started | 0 | 0 | 0 | 57 |
| Itt-amenable | 0 | 0 | 0 | 42 |
| Completed | 0 | 0 | 0 | 54 |
| Not completed | 0 | 0 | 0 | 3 |
| Withdrew: Withdrawal by subject | 0 | 0 | 0 | 1 |
| Withdrew: Pregnancy | 0 | 0 | 0 | 1 |
| Withdrew: Lost to follow-up | 0 | 0 | 0 | 1 |
Renal biopsies were taken at Baseline and Month 6 (Stage 1). The specimens were evaluated using virtual microscopy. The annotation, scoring, and adjudication of the kidney histology assessments were performed by the Clinical Pathology Endpoints Committee. The number of kidney IC GL-3 inclusions was assessed by 3 renal pathologists who were blinded to treatment assignments, participants' data, and biopsy sequence. One pathologist served as annotator and identified the 300 capillaries on up to 8 slides per specimen to be scored. Two pathologists served as scorers; these pathologists completed the blinded paired assessments. Each pathologist served as annotator/adjudicator for 1/3 of the cases. Paired assessments were undertaken at Baseline and Month 6. Assessments were made using digital images. A responder was defined as a participant with a ≥50% reduction from Baseline to Month 6 in the average number of kidney IC GL-3 inclusions.
| Participants | Migalastat | Placebo |
|---|---|---|
| Responder | 13 | 9 |
| Non-Responder | 19 | 23 |
Renal biopsies were taken at Baseline and Month 6. The specimens were evaluated using virtual microscopy. The annotation, scoring, and adjudication of the kidney histology assessments were performed by the Clinical Pathology Endpoints Committee. The number of kidney IC GL-3 inclusions was assessed by 3 renal pathologists who were blinded to treatment assignments, participants' data, and biopsy sequence. One pathologist served as annotator and identified the 300 capillaries on up to 8 slides per specimen to be scored. Two pathologists served as scorers; these pathologists completed the blinded paired assessments. Each pathologist served as annotator/adjudicator for 1/3 of the cases. Paired assessments were undertaken at Baseline and Month 6. Assessments were made using digital images.
| percent change | Migalastat | Placebo |
|---|---|---|
| Percent Change In Kidney IC GL-3 Inclusions From Baseline To Month 6 | -7.948 ± 105.2736 | 12.985 ± 90.5131 |
The effect of migalastat versus placebo on urine GL-3 levels was measured by liquid chromatography-mass spectrometry/mass spectrometry. The 24-hour urine samples were collected at Baseline, Month 6 (Stage 1), Month 12 (Stage 2), and Month 24 (OLE). Results are presented as changes in nanograms (ng)/mg creatinine from Baseline to the end of the 3 stages.
| ng/mg creatinine | Migalastat-Migalastat | Placebo-Migalastat |
|---|---|---|
| Stage 1 | -234.80 ± 853.451 | -186.24 ± 957.119 |
| Stage 2 | -179.63 ± 699.157 | -537.95 ± 1169.883 |
| OLE | -62.37 ± 615.944 | -177.42 ± 288.224 |
Renal biopsies were taken at Month 6 and Month 12. The specimens were evaluated using virtual microscopy. The annotation, scoring, and adjudication of the kidney histology assessments were performed by the Clinical Pathology Endpoints Committee. The number of kidney IC GL-3 inclusions was assessed by 3 renal pathologists who were blinded to treatment assignments, participants' data, and biopsy sequence. One pathologist served as annotator and identified the 300 capillaries on up to 8 slides per specimen to be scored. Two pathologists served as scorers; these pathologists completed the blinded paired assessments. Each pathologist served as annotator/adjudicator for 1/3 of the cases. Paired assessments were undertaken at Month 6 and Month 12. Assessments were made using digital images.
| kidney IC GL-3 inclusions | Placebo-Migalastat |
|---|---|
| Change From Month 6 To Month 12 In Average Number Of Kidney IC GL-3 Inclusions | -0.320 (-0.5719 to -0.0677) |
Renal biopsies were taken at Baseline and Month 6. The specimens were evaluated using virtual microscopy. The annotation, scoring, and adjudication of the kidney histology assessments were performed by the Clinical Pathology Endpoints Committee. The number of kidney IC GL-3 inclusions was assessed by 3 renal pathologists who were blinded to treatment assignments, participants' data, and biopsy sequence. One pathologist served as annotator and identified the 300 capillaries on up to 8 slides per specimen to be scored. Two pathologists served as scorers; these pathologists completed the blinded paired assessments. Each pathologist served as annotator/adjudicator for 1/3 of the cases. Paired assessments were undertaken at Baseline and Month 6. Assessments were made using digital images. Treatment effect was estimated using the LS mean difference between treatments within the context of the ANCOVA model.
| kidney IC GL-3 inclusions | Migalastat |
|---|---|
| Change From Baseline To Month 6 In Average Number Of Kidney IC GL-3 Inclusions | -0.250 ± 0.5126 |
Collected over Adverse events (AEs) were monitored up to 25 months (±7 days) after the first dose of study drug. AEs were reported from the first dose of study medication at Baseline (Visit 1) in Stage 1 to 1 month (±7 days) after the date of the last study visit, whether during Stage 1, Stage 2, or the optional OLE, or after premature discontinuation from the study.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Migalastat (0-6 Months) | — | 2/34 (5.9%) | 31/34 (91.2%) |
| Placebo (0-6 Months) | — | 4/33 (12.1%) | 30/33 (90.9%) |
| All Migalastat (>6-12 Months) | — | 5/63 (7.9%) | 50/63 (79.4%) |
| All Migalastat (>12-24 Months) | — | 11/57 (19.3%) | 46/57 (80.7%) |
| Event | Migalastat (0-6 Months) | Placebo (0-6 Months) | All Migalastat (>6-12 Months) | All Migalastat (>12-24 Months) |
|---|---|---|---|---|
| Pulmonary EmbolismRespiratory, thoracic and mediastinal disorders | 0/34 | 0/33 | 2/63 | 0/57 |
| Post Procedural HaemorrhageInjury, poisoning and procedural complications | 0/34 | 1/33 | 0/63 | 0/57 |
| Anaplastic Large Cell Lymphoma T - and Null - Cell TypesNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 0/34 | 1/33 | 0/63 | 0/57 |
| Bacterial InfectionInfections and infestations | 0/34 | 1/33 | 0/63 | 0/57 |
| Meningitis ViralInfections and infestations | 0/34 | 1/33 | 0/63 | 0/57 |
| Post Procedural HaematomaInjury, poisoning and procedural complications | 1/34 | 0/33 | 0/63 | 0/57 |
| HydronephrosisRenal and urinary disorders | 1/34 | 0/33 | 0/63 | 0/57 |
| Multiple FracturesInjury, poisoning and procedural complications | 0/34 | 0/33 | 0/63 | 1/57 |
| PalpitationsCardiac disorders | 0/34 | 0/33 | 0/63 | 1/57 |
| PneumothoraxRespiratory, thoracic and mediastinal disorders | 0/34 | 0/33 | 0/63 | 1/57 |
| Event | Migalastat (0-6 Months) | Placebo (0-6 Months) | All Migalastat (>6-12 Months) | All Migalastat (>12-24 Months) |
|---|---|---|---|---|
| HeadacheNervous system disorders | 12/34 | 7/33 | 9/63 | 6/57 |
| NasopharyngitisInfections and infestations | 6/34 | 2/33 | 5/63 | 3/57 |
| ProteinuriaRenal and urinary disorders | 0/34 | 0/33 | 1/63 | 9/57 |
| FatigueGeneral disorders | 4/34 | 4/33 | 2/63 | 3/57 |
| ParaesthesiaNervous system disorders | 4/34 | 4/33 | 4/63 | 2/57 |
| Pain In ExtremityMusculoskeletal and connective tissue disorders | 0/34 | 4/33 | 2/63 | 2/57 |
| PyrexiaGeneral disorders | 4/34 | 1/33 | 1/63 | 0/57 |
| NauseaGastrointestinal disorders | 4/34 | 2/33 | 2/63 | 3/57 |
| Procedural PainInjury, poisoning and procedural complications | 2/34 | 1/33 | 7/63 | 0/57 |
| BronchitisInfections and infestations | 1/34 | 0/33 | 1/63 | 6/57 |
Safety Population: All randomized participants who received at least 1 dose of study drug.
| Age, Continuous(years) | Migalastat-Migalastat | Placebo-Migalastat | Total |
|---|---|---|---|
| Mean | 40.0 ± 13.29 | 44.5 ± 10.18 | 42.2 ± 11.99 |
| Sex: Female, Male(Participants) | Migalastat-Migalastat | Placebo-Migalastat | Total |
|---|---|---|---|
| Female | 22 | 21 | 43 |
| Male | 12 | 12 | 24 |
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