Study of the Effects of Oral AT1001 (Migalastat Hydrochloride) in Patients With Fabry Disease: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of the Effects of Oral AT1001 (Migalastat Hydrochloride) in Patients With Fabry Disease (NCT00925301), a randomized phase 3 study. The primary outcome is 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.

2. Clinical Question

3. Trial Design

This was a phase 3, randomized, double-blind, placebo-controlled, parallel-group study sponsored by Amicus Therapeutics. It enrolled 67 participants with Fabry disease and AT1001-responsive GLA mutations. The registry record lists the study as completed, with a start date of 2009-10-23 and primary completion date of 2012-06-12.

During the first 6 months, participants assigned to migalastat took a 150-mg capsule orally every other day; participants assigned to placebo took a placebo capsule on the same schedule. The official title identifies efficacy, safety, and pharmacodynamics as study aims. The primary objective in the study summary was to compare migalastat with placebo on kidney GL-3.

The migalastat arm description also includes an open-label 6-month treatment extension, followed by an optional 12-month open-label treatment extension. The placebo arm description specifies the 6-month placebo period and does not describe a subsequent regimen. Safety listings include initial and later periods labeled All Migalastat, but the registry record does not provide further details about how participants entered or continued through those periods.

The primary endpoint was assessed at baseline and Month 6 using renal biopsy specimens. The record describes a blinded pathology process involving annotation, scoring, and adjudication, with assessments made from digital images. It does not report the primary endpoint results, the allocation procedure in greater detail, or the planned statistical analysis beyond the stated primary analysis population.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: During Stage 1 (0-6 Months), all participants were randomized to either Migalastat or Placebo. After Stage 1, all participants progressed to Stage 2 where they received open-label migalastat for 6 months (\>6-12 Months). After Stage 2, participants were eligible to enter the optional, 12-month, open-label extension (OLE) (\>12-24 Months).

6-Month Double-blind (Stage 1)

Reasons for not completing this period:

6-Month Open-label (Stage 2)

Reasons for not completing this period:

12-Month Open-label Extension (Optional)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: ITT: All randomized participants regardless of their participation in the study beyond randomization. As per the statistical analysis plan, analysis excluded participants who were missing baseline kidney biopsy results.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: Safety Population: All randomized participants who received at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as 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, measured over Baseline, Month 6.

The primary endpoint is a binary participant-level response: whether a participant had at least a 50% reduction from baseline to Month 6 in the average number of kidney interstitial capillary GL-3 inclusions. A participant meeting that threshold is classified as a responder; one who does not meet it is not classified as a responder. The endpoint concerns the change in biopsy findings over the specified period, rather than a direct measurement of symptoms or a clinical event.

Kidney biopsies were taken at baseline and Month 6. The registry record says the specimens were evaluated using virtual microscopy and digital images. A Clinical Pathology Endpoints Committee performed annotation, scoring, and adjudication. Three renal pathologists assessed the inclusions while blinded to treatment assignments, participant data, and biopsy sequence. One pathologist annotated capillaries for scoring, and two served as scorers; paired assessments were undertaken at both time points.

In general, a threshold-based binary endpoint can make a response definition concrete and allow the proportion of responders to be compared between groups. It also compresses the underlying measurement: participants just above and well above the threshold are both counted as responders, while those just below it are not. The registry record does not report the primary responder counts or explain the rationale for choosing this threshold. It therefore supports describing the endpoint and its assessment, but not quantifying the observed treatment contrast.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General statistical explanation: a binary endpoint classifies each participant into one of two categories, such as meeting or not meeting a prespecified response definition. Here, response means at least a 50% reduction in average kidney interstitial capillary GL-3 inclusions between baseline and Month 6. The natural group-level summary for this endpoint is a responder proportion. A comparison of those proportions would describe how often the defined response occurred in each randomized group.

What does the response threshold capture?

The endpoint converts a measured change in biopsy findings into a yes-or-no classification. That can make the clinical question easier to state, but it loses information about the amount of change within each category. Participants with different degrees of reduction can receive the same responder classification if both meet the threshold. Conversely, a participant close to the threshold on either side receives a different classification. The registry record does not report continuous outcome summaries that would show the distribution of changes beneath this binary definition.

General statistical explanation: an effect estimate gives a concise account of the observed contrast between groups. For a binary outcome, analysts may report a difference between responder proportions or another measure of relative or absolute contrast. A confidence interval communicates uncertainty around that estimate. The registry record does not report a primary estimate, confidence interval, or p-value, so none of these quantities can be interpreted for the primary endpoint.

Why does the assessment process matter?

The primary endpoint depends on pathology measurements at two time points. The registry describes blinded assessment of digital images, paired baseline and Month 6 assessments, and a committee process for annotation, scoring, and adjudication. Blinding pathologists to treatment assignment, participant data, and biopsy sequence is intended, in general, to reduce the chance that expectations or knowledge of the time point influence scoring. The record describes these safeguards; it does not provide information about agreement between readers, reproducibility, or the frequency and handling of discrepant assessments.

The endpoint description says a pathologist identified 300 capillaries on up to 8 slides per specimen for scoring, while two pathologists served as scorers. These details clarify how the tissue assessments were organized. They do not provide the number of participants with evaluable paired biopsies, the distribution of the measured counts, or the response results.

What does the analysis population mean?

The primary population is described as all randomized participants, regardless of participation beyond randomization, with an exclusion for participants missing baseline kidney biopsy results. In general, an intention-to-treat approach seeks to preserve the randomized comparison by retaining participants according to their assigned group. The stated baseline-biopsy exclusion means the described primary analysis is not literally inclusive of every randomized participant. The record does not state how many participants were excluded for missing baseline biopsy results or how missing Month 6 biopsies were handled.

In general, missing outcome data can affect both the size and interpretation of an analysis. The impact depends on why data are missing and on the analysis method used to address them. The registry record does not report whether missing follow-up biopsies were imputed, excluded, or addressed by another method. It also does not report sensitivity analyses that might examine how conclusions change under alternative missing-data assumptions.

How should planning assumptions be read?

General statistical explanation: a sample-size calculation is a planning exercise based on assumptions about the target effect, variability or event frequency, significance level, and allocation. It is not a measure of the probability that a completed trial has detected an effect. The registry’s planning description specifies a two-sided significance level of 0.05, equal allocation as an assumption, and a normal approximation; it also says the planning effect is a stated fraction of the observed effect. These are planning assumptions, not a report of the trial’s original design rationale. The registry record does not report the protocol’s sample-size justification.

The registry’s sample-size description says the illustration is computed from the observed effect, but the primary endpoint has several categories or time points and is not reduced to one comparison. No numerical planning illustration for this endpoint is therefore described in the record. Any planning illustration based on an observed effect should be understood as conditional on that effect estimate and its assumptions, not as observed power or as proof that the study was adequately sized.

What do the safety summaries estimate?

The safety listings give participants at risk and participants affected for serious and other adverse events across specified treatment periods. In general, these counts describe the recorded event burden in the listed group and period; they do not by themselves establish that an event was caused by treatment. The meaning of a rate comparison depends on the event definitions, observation time, and analysis approach. The registry record does not report a comparative statistical analysis of these adverse-event counts.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary endpoint and two named secondary outcomes: percent change in kidney interstitial capillary GL-3 inclusions from baseline to Month 6, and change in urine GL-3 levels through Month 24. It also reports five outcome measures and three analyses. The record does not describe a multiplicity-control procedure, a hierarchy for testing outcomes, or whether secondary analyses were considered confirmatory or exploratory. Without that information and the outcome results, the role of multiple testing in interpreting any reported findings cannot be assessed.

The primary analysis population is described as all randomized participants, regardless of participation after randomization, excluding participants missing baseline kidney biopsy results in accordance with the statistical analysis plan. The number excluded for missing baseline biopsy results is not reported in the registry record. The record does not explain how participants with missing Month 6 biopsy data were treated, how partial or unusable specimens were handled, or whether imputation or sensitivity analyses were used.

In general, excluding participants with unavailable baseline measurements can make the analyzed group differ from the full randomized group. Missing follow-up measurements can also affect estimates if the reasons for missingness are related to treatment or outcome. These are general considerations, not claims about what occurred in this study. The registry record does not provide enough detail to assess the amount, pattern, or consequences of missing primary endpoint data.

Other details of the statistical analysis plan, including the planned effect measure, statistical test, adjustment variables, and interim analyses, are not reported in the registry record. The record’s description of the analysis population should therefore not be taken as a complete account of the prespecified analysis.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pulmonary embolism (3.2%), post procedural haemorrhage (3.0%), anaplastic large cell lymphoma t - and null - cell types (3.0%), bacterial infection (3.0%), meningitis viral (3.0%).

For the initial period labeled Migalastat (0-6 Months), the registry reports 2 serious adverse events among 34 participants at risk and 31 participants with other adverse events among 34 at risk. For Placebo (0-6 Months), it reports 4 serious adverse events among 33 participants at risk and 30 participants with other adverse events among 33 at risk. Serious and other adverse events are separate categories in the listing; the counts should not be added together or treated as primary endpoint outcomes.

Later safety periods are labeled All Migalastat. For >6-12 Months, the listing reports 5 serious adverse events among 63 participants at risk and 50 participants with other adverse events among 63 at risk. For >12-24 Months, it reports 11 serious adverse events among 57 participants at risk and 46 participants with other adverse events among 57 at risk. These periods should be read as separate registry summaries, not as a single randomized comparison with placebo. The registry record does not provide further detail on participant overlap or person-time for these periods.

Selected serious-event terms and percentages include Pulmonary Embolism (3.2%), Post Procedural Haemorrhage (3.0%), Anaplastic Large Cell Lymphoma T - and Null - Cell Types (3.0%), Bacterial Infection (3.0%), Meningitis Viral (3.0%), and Post Procedural Haematoma (2.9%). The record does not specify the denominator or further context for these term percentages in the information described. Death counts are not reported in the registry record. Adverse-event listings alone do not establish causation or provide a complete comparative safety analysis.

12. What the Result Does, and Does Not, Mean

The registry record establishes that a randomized, double-blind, placebo-controlled study was conducted in 67 participants and identifies a kidney biopsy response as its primary outcome. It also describes a pathology assessment process intended to keep readers blinded to treatment assignment and biopsy sequence. These details allow the study question and endpoint definition to be understood.

They do not establish what the study found on its primary comparison. The registry record does not report the number or proportion of responders in either group, an effect estimate, a confidence interval, or a p-value. It therefore cannot show the magnitude, direction, or precision of the difference in the defined kidney biopsy response between migalastat and placebo.

The response definition is specific: at least a 50% reduction in average kidney interstitial capillary GL-3 inclusions from baseline to Month 6. A result for this endpoint, if available, would address that measured tissue outcome over that period. By itself, such a result would not answer every question about symptoms, long-term outcomes, other disease manifestations, or later treatment periods. Those broader questions would require relevant outcome data and appropriate analysis.

The safety listings report event counts across an initial migalastat and placebo period and later periods labeled All Migalastat. They provide descriptive information, but the later periods are not a concurrent randomized comparison with placebo in the listings. The counts and selected serious-event terms do not establish that treatment caused an event, and the record does not provide a complete statistical comparison of safety outcomes.

In general, a missing result in a registry record should not be interpreted as a null result. It means the record does not support a quantitative conclusion about that outcome. The appropriate reading is therefore limited: the study design, endpoint, assessment procedures, and selected safety counts are described, while the primary efficacy result and several details needed for full statistical interpretation are not reported in the registry record.

13. Why This Trial Matters Statistically

This study is statistically notable for using a threshold-based response endpoint derived from paired kidney biopsies. The question is not simply whether a measured value changed, but whether a participant’s average kidney interstitial capillary GL-3 inclusion count met a specified reduction threshold by Month 6. That makes the endpoint definition and the reliability of the paired tissue assessments central to interpreting the comparison.

The registry describes several design features relevant to measurement quality: blinded pathology review, digital images, paired assessments at baseline and Month 6, and annotation, scoring, and adjudication procedures. In general, such safeguards matter because treatment knowledge or awareness of measurement order could influence subjective aspects of image assessment. The record, however, does not report reader agreement or other reproducibility results.

The study also illustrates an important distinction between a well-described endpoint and a reported result. The record gives substantial detail about how the responder classification was defined and assessed, yet does not report the responder counts or effect estimate. Without those results, the primary randomized comparison cannot be quantified, regardless of how clearly the outcome is specified.

Finally, the registry includes safety listings from treatment periods that extend beyond the initial randomized comparison. Reading those periods as if they were one continuous placebo-controlled analysis would go beyond the information reported. The initial randomized period and later All Migalastat periods have different labels and group structures. Separating endpoint definition, randomized comparison, extension safety summaries, and missing result information is essential for a statistically careful reading.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The main limitation for interpreting efficacy is that the primary outcome results are not reported in the registry record. There are no responder counts, group proportions, effect estimates, confidence intervals, or p-values for the primary comparison. The registry record therefore cannot support an estimate of the treatment contrast or its precision.

The analysis population excludes participants missing baseline kidney biopsy results, but the number excluded is not reported. The handling of missing Month 6 biopsies, incomplete specimens, and other missing endpoint data is also not reported in the registry record. Without these details, the completeness of the paired biopsy analysis and the potential influence of missing data cannot be evaluated.

The endpoint relies on kidney biopsy assessments. The registry describes blinded pathology review and adjudication but does not report reader agreement, repeatability, or how disagreements were resolved in practice. It also does not provide the distribution of the underlying inclusion counts or results for a continuous measure that might complement the responder threshold.

Although two secondary outcomes are named, their numerical results and the approach to multiplicity are not described. The statistical test, effect measure, adjustment strategy, and interim analyses are not reported in the registry record. The record also does not report the protocol’s sample-size justification.

Safety information is limited to counts for specified periods and selected serious-event terms. The registry does not provide a full comparative safety analysis, detail on person-time, or death counts. Later safety groups are labeled All Migalastat, and the record does not give enough information to treat those periods as a randomized comparison with placebo. These limitations constrain both efficacy and safety interpretation.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study of the Effects of Oral AT1001 (Migalastat Hydrochloride) in Patients With Fabry Disease — NCT00925301.
• Registry record last updated 2018-10-30; status last verified 2018-10.
• Results first posted 2018-10-30.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

The registry record describes NCT00925301, a completed phase 3 randomized, double-blind, placebo-controlled, parallel-group study sponsored by Amicus Therapeutics. It enrolled 67 participants with Fabry disease and AT1001-responsive GLA mutations. The initial treatment period compared oral migalastat 150 mg every other day with placebo every other day for 6 months.

The primary endpoint was the percentage of participants with at least a 50% reduction from baseline to Month 6 in average kidney interstitial capillary GL-3 inclusions, assessed using renal biopsy specimens and blinded pathology review. The record describes open-label extensions for migalastat and lists safety counts for initial and later periods.

Primary outcome results, including responder counts and a treatment-effect estimate, are not reported in the registry record. Details on missing Month 6 biopsy data, multiplicity, and several elements of the statistical analysis plan are also not reported.