Open Label, Study Of Efficacy and Safety Of AVR-RD-01 for Treatment-Naive Subjects With Classic Fabry Disease: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Open Label, Study Of Efficacy and Safety Of AVR-RD-01 for Treatment-Naive Subjects With Classic Fabry Disease (NCT03454893), a na phase 1, phase 2 study. The primary outcome is Incidence of and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs).

2. Clinical Question

3. Trial Design

NCT03454893 was a multinational, open-label Phase 1/Phase 2 study of AVR-RD-01 for treatment-naive subjects with classic Fabry disease. The registry describes a single-group model, with one assignment to AVR-RD-01. Allocation is listed as not applicable and masking as none. This design can describe events observed among participants receiving the intervention, but it does not provide a concurrent control group for separating intervention-associated events from events that might occur in the absence of the intervention.

The registry enrollment is 15. The brief summary describes an intended study of approximately 15 male subjects, aged 16 years or older and postpubertal, with confirmed classic Fabry disease based on deficient AGA enzyme activity. Treatment-naive status was specified in relation to prior ERT and/or chaperone therapy within 3 years of Screening. These eligibility details define a particular study population; they should not be generalized to people outside that description without additional evidence.

The primary endpoint was the incidence and severity of AEs and SAEs during baseline to Week 48 post gene therapy. The safety population is defined as all enrolled subjects who received any preparatory medication. The adverse-event listing reports a group at risk of 11 for both its serious and other adverse-event summaries. The record’s enrollment figure and its safety-population definition refer to different aspects of the study, and should not be treated as interchangeable denominators.

The study status is terminated. Its start date is 2018-02-21 and its primary completion date is 2022-03-14. The reason for termination is not reported in the registry record. The registry lists secondary outcomes concerning vector copy number, AGA enzyme activity, Gb3 biomarkers, skin substrate, and renal measures. The details of results for those outcomes are not reported in the registry record in the registry record for this analysis.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Safety population consists of all enrolled subjects who received any preparatory medication.

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 consists of all enrolled subjects who received any preparatory medication.

6. Primary Endpoint

The registry lists the primary outcome as Incidence of and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs), measured over Baseline to Week 48 post gene therapy.

The primary endpoint counts the incidence and severity of AEs and SAEs from baseline to Week 48 post gene therapy. An AE is defined as any untoward medical occurrence in a participant who received study drug, regardless of whether a causal relationship was considered possible. An SAE is an AE meeting specified seriousness criteria, including death, initial or prolonged inpatient hospitalization, a life-threatening experience, persistent or significant disability or incapacity, congenital anomaly, or another reason for being deemed significant. The definition also includes abnormalities in clinical laboratory tests, vital signs, and electrocardiographs.

Safety endpoints are used to characterize the kinds and frequency of unfavorable medical events observed during a study period. Recording all events, regardless of attributed cause, supports a broad description of what happened to participants. Separately recording seriousness identifies events that meet the registry’s criteria for greater clinical consequence. These measures do not by themselves establish that the intervention caused an event, nor do they compare risk with an untreated or alternative-treatment group.

The registry reports 13 SAEs and 354 AEs. It states that none of the reported SAEs and none of the reported AEs were considered related to AVR-RD-01. Those are event counts and attribution statements, not estimates of comparative risk. The endpoint description does not report a statistical model or an adjusted causal analysis.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study’s statistical structure is determined by its single-group, open-label design. A single-group study describes outcomes among participants assigned to the same intervention. Without a concurrent comparator, it cannot estimate a treatment contrast within the study. Open-label status means masking is listed as none; the registry record does not describe a blinded assessment procedure. These features shape how the safety counts should be interpreted, regardless of how clearly the endpoint is defined.

What is an event count?

An event count tallies occurrences, while a participant count tallies people with at least one occurrence. One participant may contribute multiple events. For that reason, the registry’s 13 SAEs and 354 AEs should not be read as counts of people. The adverse-event summary separately lists 8 participants with a serious event among 11 at risk, and 11 participants with another adverse event among 11 at risk. Those counts convey how many participants were affected according to the summary, while the larger event totals convey how many events were recorded.

Event counts can describe the workload and burden of events recorded during follow-up, but their interpretation depends on the observation period and event definitions. This primary endpoint spans baseline to Week 48 post gene therapy. A count does not, by itself, show when events occurred, whether they recurred in the same participant, or how long they lasted. Those details are not reported in the registry record. The record’s definitions also make clear that an AE is captured without requiring a suspected causal link, whereas an SAE meets specified seriousness criteria.

What does attribution mean?

The registry states that no reported AE and no reported SAE was considered related to AVR-RD-01. This is an attribution reported by the study, not a statistical test of causation. The endpoint definition deliberately includes untoward medical occurrences without regard to the possibility of a causal relationship. The record also attributes events to the conditioning agent, underlying disease, comorbid conditions, study procedures, and concomitant medications. In a single-group study, these observations cannot be contrasted with a concurrent group to assess how event occurrence might differ under another condition.

Why do denominators matter?

A participant proportion uses participants at risk as its denominator; an event total does not. The adverse-event summary gives 11 at risk for the serious and other event summaries. The registry separately gives enrollment as 15 and defines its safety population as enrolled subjects who received any preparatory medication. These figures refer to distinct registry concepts. The record does not explain the transition from enrollment to the group listed as at risk, so no further account of that difference should be inferred. The serious-term percentages are reported as 18.2% and 9.1%; their specific denominator and calculation details are not reported in the registry record.

In general, a confidence interval describes the range of values compatible with an estimate under a specified statistical procedure and its assumptions. It helps communicate precision, not certainty that a particular value is true. No confidence interval for the primary endpoint is reported in the registry record. Without one, and without a stated inferential model, the event summary should be treated as descriptive rather than as a precise estimate with quantified sampling uncertainty.

What would over-dispersion mean for event counts?

In general, a simple count model may assume that counts vary according to a particular probability distribution. Over-dispersion means the observed variation is greater than that model assumes; ignoring it can make uncertainty appear too small. Repeated events within the same participant can also make events statistically dependent rather than independent. These are general considerations for recurrent-event data, not methods documented for this study. The registry record does not report a model for recurrent events, an adjustment for within-participant dependence, or an analysis of event rates over time.

Are the planning assumptions part of the trial analysis?

Planning calculations are not observed outcomes and do not establish the power achieved by a completed study. The stated planning illustration assumptions use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with a target effect expressed as a fraction of an observed effect. They are planning assumptions, not a description of this trial’s single-group allocation. Any sample-size figures generated under such assumptions would be illustrations rather than observed power. The registry record does not report a sample-size justification or explain how those planning assumptions informed the original design.

The record lists no analysis entries. That fact does not establish that no analyses were performed; it means analysis entries are not recorded in the registry information represented. No inferential method, adjustment strategy, or model for the primary endpoint is reported in the registry record. Readers should therefore distinguish the available descriptive safety results from analyses that would require unreported methods or results.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 19 outcome measures, including a primary safety endpoint and secondary outcomes involving vector copy number, AGA enzyme activity, Gb3 biomarkers, skin substrate, and renal function measures. When a study assesses multiple outcomes, multiplicity can arise because many statistical questions are considered. In general, testing many hypotheses without an appropriate strategy can increase the chance of at least one apparently notable result arising by chance. The registry record does not report a multiplicity adjustment, a hierarchy among secondary outcomes, or a statistical analysis plan addressing multiple testing.

The record does not report how missing outcome data were handled, whether any participants discontinued follow-up, or whether any imputation or sensitivity analysis was used. The registry defines the safety population as enrolled subjects who received any preparatory medication, and the adverse-event summary lists 11 at risk. The record does not describe the analysis population for the secondary outcomes or clarify how participant availability differed across measures.

The endpoint spans baseline to Week 48 post gene therapy, but the registry record does not report the completeness of follow-up across that period or how events were handled for participants with incomplete observation. These omissions matter because the opportunity to observe an event may differ when follow-up is incomplete. The record reports no analysis entries, but that does not establish that no statistical analyses were conducted. The methods for missing data, multiplicity, and outcome-specific analysis populations are not reported in the registry record.

11. Safety Results

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

Deaths

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: febrile neutropenia (18.2%), thrombocytopenia (9.1%), nausea (9.1%), odynophagia (9.1%), vomiting (9.1%).

The safety summary reports 13 SAEs and 354 AEs over baseline to Week 48 post gene therapy. It states that none of these reported serious or other adverse events were considered related to AVR-RD-01. The record attributes events to the conditioning agent, the underlying disease, comorbid conditions, study procedures, and concomitant medications. These are reported judgments, not a controlled estimate of causation.

The adverse-event listing gives 8 of 11 participants at risk with at least one SAE, and 11 of 11 with at least one other AE. The serious-event count is an event total, whereas the participant count indicates how many people experienced at least one such event. Multiple events can occur in a participant, so the two summaries are not interchangeable.

The listed serious terms include febrile neutropenia at 18.2%; thrombocytopenia, nausea, odynophagia, vomiting, and mucosal inflammation are each listed at 9.1%. The specific denominator and term-counting method are not reported in the registry record. With no comparator group, these findings describe the study’s recorded safety experience rather than a comparative risk. Detailed timing, duration, and individual event courses are not reported in the registry record.

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

The results establish that the registry records adverse events during the specified safety period in a single-group study of AVR-RD-01. It reports 354 AEs and 13 SAEs and gives participant counts of 11 with at least one other AE and 8 with at least one SAE, among 11 at risk in each summary. The registry says that no reported AE or SAE was considered related to AVR-RD-01. These are meaningful descriptive details about the record, but they do not answer a comparative treatment question.

The event counts do not show how many events would have occurred in a similar group receiving another intervention or no study intervention. Because there was no comparator and no random allocation, the observed events cannot be used to estimate a between-group difference. The attribution that events were not considered related is the study’s reported assessment; it is not proof that the intervention could not have contributed, nor is it a causal estimate.

The safety results also do not establish efficacy. The registry lists secondary outcomes concerning AGA activity, Gb3 biomarkers, skin substrate, and renal measures, but their results are not reported in the registry record in the registry record for this analysis. No efficacy conclusion should be drawn from a primary endpoint that measures adverse events and serious adverse events.

The results do not describe the reason for termination, provide detailed event timing or duration, or report uncertainty intervals for the safety counts. The endpoint’s baseline-to-Week 48 period gives a defined observation window, but the completeness of participant follow-up is not reported in the registry record. The record therefore supports a bounded interpretation: these are the reported safety observations and attribution statements for the study, not a complete causal or comparative evaluation.

In general, a safety profile is interpreted by considering event type, seriousness, timing, recurrence, attribution, follow-up completeness, and an appropriate comparison when available. The record contains some of these elements, including event definitions, counts, participant summaries, and attribution statements. Other details are not reported in the registry record. Those limits should remain visible when interpreting what the study can establish.

13. Why This Trial Matters Statistically

This study illustrates why a statistical reading should separate event totals from participant counts. The registry reports 13 SAEs and 354 AEs, while the adverse-event summary separately reports how many participants experienced at least one event. Keeping those quantities distinct prevents a count of repeated events from being mistaken for the number of people affected.

It also illustrates the limits of causal interpretation in a single-group, open-label study. Events can be described, classified by seriousness, and assigned a reported relationship to the intervention, but without a comparator the study cannot estimate how those outcomes differ under another condition. The registry’s statement that no AE or SAE was considered related is important as an attribution, but it does not replace a controlled comparison.

The endpoint definition is another important part of interpretation. AEs include untoward medical occurrences regardless of whether a causal relationship was considered possible, and SAEs are defined by specified seriousness criteria. The broad AE definition supports recording events without requiring a causal judgment, while the separate SAE category identifies events meeting the seriousness criteria. Readers need both the definition and the reported counts to understand what was measured.

Finally, the record distinguishes enrollment from the safety population and the participants listed at risk. It reports enrollment of 15, defines the safety population by receipt of preparatory medication, and lists 11 at risk in the adverse-event summary. Recognizing these distinctions is essential for reading denominators accurately. The study is therefore useful for illustrating how design, endpoint definition, event-versus-participant counts, and reporting completeness constrain statistical interpretation.

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 single-group design has no concurrent comparator, and the study is open label. Event occurrence and reported attribution can be described, but the design does not estimate a comparative safety effect. The registry record does not report a reason for termination, so the termination status should not be used to infer why the study ended.

The registry enrollment is 15, whereas the adverse-event summary lists 11 at risk, and the safety population is defined as enrolled subjects who received any preparatory medication. The record does not explain the difference among these figures or provide a detailed account of follow-up and participant disposition. The denominator for the serious-term percentages and the method used to count terms are not reported in the registry record.

The reported endpoint covers baseline to Week 48 post gene therapy, but detailed event timing, duration, recurrence, and severity grades are not reported in the registry record. The record also does not report confidence intervals, a statistical model, an analysis plan, or an inferential comparison for the primary safety endpoint. Although 19 outcome measures are listed, outcome-specific analysis populations, multiplicity handling, and missing-data methods are not reported.

The study population is described as treatment-naive male subjects who were 16 years of age or older and postpubertal, with confirmed classic Fabry disease. Results from this defined population should not automatically be generalized to other populations. Secondary outcomes are listed, but their results are not reported in the registry record in the registry record for this analysis.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Open Label, Study Of Efficacy and Safety Of AVR-RD-01 for Treatment-Naive Subjects With Classic Fabry Disease — NCT03454893.
• Registry record last updated 2024-01-05; status last verified 2023-09.
• Results first posted 2024-01-05.
• 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

NCT03454893 is a multinational, open-label Phase 1/Phase 2, single-group study of AVR-RD-01 in treatment-naive subjects with classic Fabry disease. The registry lists enrollment of 15, status as terminated, a start date of 2018-02-21, and a primary completion date of 2022-03-14. The primary endpoint measures AEs and SAEs from baseline to Week 48 post gene therapy.

The registry reports 354 AEs and 13 SAEs and states that none of the reported events were considered related to AVR-RD-01. Its adverse-event summary lists 8 participants with at least one SAE and 11 with at least one other AE, with 11 at risk in each summary. The study has no comparator group, so these results are descriptive rather than a comparative treatment estimate. The reason for termination, inferential methods, missing-data methods, and detailed secondary-outcome results are not reported in the registry record.