Long-Term Follow-up Study of ADVM-043: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Long-Term Follow-up Study of ADVM-043 (NCT03804021), a registered phase not stated study. The primary outcome is Number of Participants With Adverse Events of Special Interest and of Serious Adverse Events Related to ADVM-043.

2. Clinical Question

3. Trial Design

ADVM-043-03 is described as a long-term follow-up study of subjects who participated in ADVM-043-01, the parent study identified as ADVANCE. The parent study evaluated ADVM-043 for Alpha-1 Antitrypsin Deficiency. In this follow-up, participants had already received ADVM-043 in the parent study; the registry lists “No Intervention” for the follow-up. The design is therefore observational follow-up after treatment, rather than a new randomized comparison of treatment and control.

The registry lists an enrollment of 6. It separates the posted safety counts into Study ADVM-043-01 Part A Dose Level 1, Dose Level 2, and Dose Level 3. The count at risk is 2 for each listed group. These are reported group counts and should not be read as evidence of randomized allocation. The record explicitly does not state allocation, and the dose-level groups are not a like-for-like control comparison.

The study started on 2018-12-27, reached primary completion on 2021-12-06, and has status COMPLETED. The primary outcome timeframe is described as 2 years from the start of the long-term follow-up study, with a parenthetical reference to 2 years from completion of the parent study. The record does not explain how follow-up time was handled for people with incomplete observation or whether all participants had the same opportunity for event detection.

The primary endpoint is a count of participants with adverse events of special interest and serious adverse events related to ADVM-043. The registry lists one outcome measure and zero analyses. It does not report a statistical analysis plan, a sample-size justification, interim analyses, or further details about how events were attributed to ADVM-043. As a follow-up record, its role is to describe reported safety observations after parent-study treatment, not to estimate a randomized treatment effect.

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: Completion of Study ADVM-043-01

Overall Study

Analysis population for the primary outcome, as defined in the registry: Subjects who received ADVM-043 in Study ADVM-043-01

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: \[Not Specified\]

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Adverse Events of Special Interest and of Serious Adverse Events Related to ADVM-043, measured over 2 years from start of long-term follow-up study ADVM-043-03 (NCT03804021) (2 years from completion of the parent study (ADVM-043-01, NCT02168686).

The primary endpoint counts participants with adverse events of special interest and serious adverse events related to ADVM-043. It is a participant count, not a count of all event episodes. A person with more than one event could still contribute as a participant with an event; the registry record does not explain event-level counting or whether repeat events were handled separately. It describes the events of interest as all adverse events of special interest and all serious adverse events related to ADVM-043.

Safety follow-up uses this kind of endpoint to document events that may warrant particular attention after treatment, including events classified as serious. In a long-term follow-up, the aim is to maintain observation after the parent study's treatment period. That can add descriptive information about events reported during the stated follow-up timeframe. It does not, by itself, determine whether treatment caused an event, since attribution and causal inference require more than observing an event after treatment.

The posted results separate serious events from other adverse events and provide counts by dose level. They report zero participants with related serious events and zero with other related adverse events in each group. The record does not give a separate numerical result for adverse events of special interest as distinct from those categories, nor does it provide event descriptions for the primary outcome. The endpoint should therefore be read as a registered safety question with limited posted detail, rather than as a complete account of every safety outcome.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

For a binary safety endpoint, each participant is classified according to whether the event definition was met during the relevant observation period. A participant count is different from an event count: multiple episodes in a single participant need not increase the number of participants with an event. The registry defines the primary measure as the number of participants with adverse events of special interest and serious adverse events related to ADVM-043. Its posted safety rows also separate serious adverse events from other adverse events. The registry record does not explain whether repeated events were counted once per participant, how event overlap was handled, or how adverse events of special interest map to the posted categories.

What does a zero count mean?

A zero observed count means that no participant in the listed group was recorded as having the specified event category in the posted results. It does not establish a true risk of zero. In general, rare events may not appear in a small observed group even when the underlying risk is not zero. The strength of a safety conclusion also depends on observation time, completeness of event reporting, and consistent event definitions. Those details are not reported in the registry record, so the counts cannot be converted into a precise estimate of risk over a common person-time scale.

Why does the design matter?

The follow-up includes participants who received ADVM-043 in the parent study, with results presented by parent-study dose level. A comparison between groups is most informative when the groups are sufficiently comparable and the allocation process supports causal interpretation. Here, allocation is not stated, and the registry says these groups are not a like-for-like control comparison. Any differences may reflect group composition, follow-up, or other factors rather than dose level. The posted counts should therefore be treated as descriptive rather than as a randomized comparison.

What can an interval or test add?

In general, a confidence interval describes the range of effect values reasonably compatible with an estimate under the method's assumptions. It communicates precision, which a point estimate alone cannot do. A statistical test assesses compatibility with a specified null hypothesis under a model; a p-value is not the probability that a treatment works or that a result arose by chance. For event counts with sparse data, conventional approximations may be unreliable, and exact or otherwise suitable methods may be considered. No confidence interval, test, p-value, or model result is reported in the registry record, so none can be attributed to this study.

What is over-dispersion, and does it apply?

In general, over-dispersion means that observed variability is greater than a statistical model expects. It can matter for count outcomes when events vary more across participants or settings than a simple model assumes, affecting uncertainty estimates. The primary measure is described as participants with an event, rather than a repeated-event rate, and the registry does not report a count model or an over-dispersion assessment. There is no basis to claim that an over-dispersion adjustment was used or needed.

How should planning calculations be read?

In general, a sample-size calculation asks how much information a future study would need to detect a specified effect under stated assumptions. Such a calculation is conditional on the assumed effect, significance level, allocation, and statistical method; it is not a finding about the current study. The planning assumptions associated with this record describe a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect expressed as a fraction of the observed effect. For non-time-to-event outcomes, planning quantities are expressed as participants per arm. These are planning illustrations, not observed power, and the registry does not report that these assumptions were the study's original design plan. Since the record lists zero analyses and does not post an effect estimate for the endpoint, a planning illustration should not be used as evidence of a treatment effect.

Statistical methods beyond these general concepts are not reported in the registry record. In particular, the record does not provide an analysis population definition beyond the stated population of subjects who received ADVM-043 in the parent study, an approach to incomplete follow-up, a missing-data method, or an adjustment plan. Those omissions limit how far readers can reproduce or evaluate an inferential analysis.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists one outcome measure and zero analyses. It does not report whether the endpoint was designated as the sole primary outcome in a prespecified statistical analysis plan, whether additional outcomes were tested elsewhere, or how multiple hypotheses, dose-level comparisons, or event categories would be handled. Because no analyses are posted, there is no reported multiplicity adjustment to assess. In general, testing many outcomes or comparisons can increase the chance of a false-positive finding; methods for controlling that risk depend on the planned family of questions. The record does not report such a plan.

Missing data and incomplete observation are also important in a long-term follow-up. If participants differ in how long they are observed or in whether events are captured, simple counts may not represent comparable observation periods. The registry does not report participant-level follow-up completeness, reasons for loss to follow-up, missing outcome handling, or a method for accounting for different observation time. These details should not be inferred from the status COMPLETED.

The primary outcome population is described as subjects who received ADVM-043 in Study ADVM-043-01. The registry does not report further analysis-population rules, such as how eligibility for the follow-up analysis was determined or how participants with incomplete information were treated. The posted counts are therefore best read as descriptive registry results, not as the output of a documented inferential analysis. No missing-data strategy or multiplicity procedure is 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 0% reporting threshold.

The safety results are organized by parent-study dose level. For Dose Level 1, the count at risk is 2, with zero serious adverse events and zero other adverse events recorded. For Dose Level 2, the count at risk is 2, with zero serious adverse events and zero other adverse events recorded. For Dose Level 3, the count at risk is 2, with zero serious adverse events and zero other adverse events recorded. The death count is zero in Dose Level 1, zero in Dose Level 2, and one in Dose Level 3.

These are counts, not rates adjusted for follow-up duration. The registry does not state whether the death was related to ADVM-043, and it does not provide a cause or timing. The absence of related adverse events in the posted categories should not be interpreted as proof that the treatment has no risk. The groups are not a like-for-like control comparison, and the registry does not report the completeness or duration of observation for each participant. The figures describe the events recorded, with those interpretive limits.

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

The result documents the safety counts recorded for a follow-up of participants who received ADVM-043 in the parent study. For each listed dose-level group, the posted counts are zero for serious adverse events and zero for other adverse events. The record also reports a death in the Dose Level 3 group. It does not state that the death was related to ADVM-043, so the death count should be kept distinct from the related adverse-event counts.

These observations do not show that treatment caused or prevented an event. All participants in the follow-up population had received ADVM-043 in the parent study, and the registry does not describe a concurrent control group. The dose-level groups are not a like-for-like control comparison, and allocation is not stated. Their counts therefore cannot support a causal comparison of dose levels or a treatment-versus-control conclusion.

The zero counts also do not prove that the underlying risk is absent. The record does not report confidence intervals, inferential tests, detailed follow-up completeness, or event-level descriptions. Without information on observation time and how missing information was handled, the precision and scope of the findings are difficult to assess. The posted results should be read as a limited descriptive account of recorded outcomes within the stated follow-up, not as a comprehensive estimate of safety.

The study nevertheless addresses a distinct statistical question: whether specified adverse events were recorded after treatment during longer-term observation. That question differs from whether treatment is effective or whether its risk is lower than another option. Neither an efficacy conclusion nor comparative safety evidence is reported by these counts. The registry record does not report a statistical analysis plan, sample-size justification, or analyses that would broaden the interpretation beyond the descriptive results.

13. Why This Trial Matters Statistically

Long-term follow-up addresses a statistical challenge that differs from evaluating outcomes during a treatment study. Events may be of interest after the parent study's treatment period, so continued observation can document later safety outcomes among people who received the intervention. This record identifies that aim for ADVM-043 and specifies a follow-up timeframe of 2 years from the start of the long-term follow-up study, also described in relation to completion of the parent study.

The record also illustrates why event counts need context. A zero count is a direct description of what was recorded, but it is not a precise estimate of underlying risk without information about observation and completeness. A death count likewise requires context about cause and attribution before it can be connected to treatment. Here, the registry reports a death in the Dose Level 3 group but does not report its relationship to ADVM-043.

Finally, the study highlights the boundary between descriptive follow-up and causal comparison. The dose-level groups come from the parent study, and allocation is not stated; they are not a like-for-like control comparison. A count by group can support a factual description of the record but cannot by itself isolate the effect of dose level or treatment. The registry lists one outcome measure and zero analyses, leaving no posted inferential results to quantify precision or test a comparative hypothesis. Those distinctions are important when interpreting sparse safety data.

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 posted results are limited to counts by parent-study dose level. The registry record does not provide event narratives, event timing, severity detail beyond the serious-event category, or a distinct numerical result for adverse events of special interest. It also does not explain how events were judged to be related to ADVM-043. This limits interpretation of both the outcome definition and the clinical meaning of the recorded categories.

The record does not report individual follow-up duration, completeness of follow-up, reasons for incomplete observation, or a missing-data approach. Counts across groups may therefore reflect different opportunities to observe events; the record does not provide the information needed to evaluate that possibility. It also does not report confidence intervals, statistical tests, adjusted estimates, or a documented analysis plan. The registry lists zero analyses.

The follow-up population consists of participants who received ADVM-043 in the parent study. There is no described untreated control group, and the dose-level groups are not a like-for-like comparison. Allocation is not stated. The counts cannot establish comparative risk or attribute a difference to dose level. The death recorded in Dose Level 3 has no reported cause or relationship to ADVM-043. These limitations are specific to the posted record and should temper conclusions drawn from its descriptive safety results.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Long-Term Follow-up Study of ADVM-043 — NCT03804021.
• Registry record last updated 2024-09-20; status last verified 2023-09.
• Results first posted 2024-09-20.
• 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

NCT03804021, titled “Long-Term Follow-up Study of ADVM-043,” is a completed long-term follow-up study of subjects who received ADVM-043 in Study ADVM-043-01. The condition is Alpha-1 Antitrypsin Deficiency. The registry lists enrollment of 6, a start date of 2018-12-27, and primary completion on 2021-12-06. The follow-up intervention is listed as “No Intervention.”

The primary outcome concerns participants with adverse events of special interest and serious adverse events related to ADVM-043, within a timeframe described as 2 years from the start of follow-up. Posted results are grouped by parent-study dose level. Each group has a count at risk of 2 and zero reported serious and other adverse events; one death is recorded in Dose Level 3, with no stated relationship to ADVM-043. The registry lists one outcome measure and zero analyses. Allocation and a like-for-like control comparison are not reported.