Long-term Safety of Alpha1-Proteinase Inhibitor (Human) in Japanese Subjects With Alpha1 Antitrypsin Deficiency (GTI1401-OLE): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Long-term Safety of Alpha1-Proteinase Inhibitor (Human) in Japanese Subjects With Alpha1 Antitrypsin Deficiency (GTI1401-OLE) (NCT02870348), a na phase 1, phase 2 study. The primary outcome is Number of Participants With Treatment-Emergent Adverse Events (TEAEs).

2. Clinical Question

3. Trial Design

This was a multi-center, open-label, single-group study in Japanese adults with alpha1-antitrypsin deficiency. Participants had completed Study GTI1401 before entering the extension. The study evaluated long-term safety during weekly intravenous infusions of Alpha-1 MP at 60 mg/kg. Its phase is listed as Phase 1 and Phase 2, and its status is completed.

The registry records 4 participants enrolled. The safety population includes all participants who received any amount of Alpha-1 MP, and the adverse-event listing records 4 at risk. The treatment description reports a mean duration of 213 weeks. The primary outcome's timeframe extends from the start of study-drug administration through 30 days after the final infusion, with an upper limit of 228 weeks.

Because this is an open-label study without a concurrent control group, participants and study staff were not masked to the treatment, and there is no randomized allocation between treatment arms. The design can describe events observed during treatment and follow-up, but it cannot separate treatment-associated events from the background occurrence of illness or other causes by comparing groups within the study. Its extension setting also means the population consisted of people who had completed the preceding study, rather than a newly enrolled comparison population.

The registry does not report a protocol-level statistical plan, a sample-size justification, or details of interim analyses. The record lists no analysis entries. These omissions limit what can be said about prespecified analyses or the rationale for the enrollment target. The record's design details support a descriptive safety reading, not a comparative efficacy interpretation.

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: Participants with diagnosis of alpha1-antitrypsin deficiency (AATD) who completed the Study GTI1401 (NCT02870309) were eligible to enroll in this open-label extension study. The Screening / Extension (Ext) Week 1 Visit and initiation of treatment for the current study (GTI1401-OLE) occurred on the same day as the Week 9 Visit of GTI1401 only for those participants who gave the consent for participation in the Study GTI1401-OLE.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Population included all participants who received any amount of Alpha-1 MP.

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 included all participants who received any amount of Alpha-1 MP.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment-Emergent Adverse Events (TEAEs), measured over From start of study drug administration through 30 days after last study drug infusion (Up to 228 weeks).

The primary endpoint is the number of participants with treatment-emergent adverse events. It is a participant count, not a measure of how many total events occurred or how frequently events occurred per unit of treatment time. A participant can experience more than one event, so a count of affected participants and a count of event episodes answer different questions.

The registry defines an adverse event as an untoward medical occurrence in a participant given a medicinal product or study treatment; the event need not have a causal relationship to the treatment. Treatment-emergent events are defined as events occurring after or on the first Alpha-1 MP infusion, through the final study visit. The stated observation period runs from treatment initiation through 30 days after the last infusion, up to 228 weeks.

A participant-based safety endpoint is used to describe how many people experienced an event during the defined observation window. It is useful for identifying whether events occurred among those receiving the study drug, while the event definitions and timeframe clarify which occurrences count. It does not, by itself, establish that treatment caused an event, describe event severity, or quantify the total number of episodes. The numerical result for this primary endpoint is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count measure?

A participant count records how many people met an outcome definition during the specified observation period. For this study, the primary outcome concerns participants with at least one treatment-emergent adverse event. That is distinct from counting every event episode: a participant with several events still contributes a participant-level outcome rather than becoming several participants.

Counts are most interpretable when the population at risk and event definition are clear. The registry identifies the safety population as participants who received any amount of Alpha-1 MP. It also states the adverse-event timeframe, from the first infusion through the final visit, with follow-up through 30 days after the last infusion. Those details determine who is included and which events qualify. The primary-outcome count itself is not reported in the registry record.

Why does the denominator matter?

A count should be read alongside the number of participants at risk. The adverse-event listing gives 4 at risk for serious events and 4 at risk for other events. A denominator helps readers understand the group to which the affected-participant count applies. It does not, on its own, solve the uncertainty that comes with a small study or establish that treatment caused the outcome.

Event percentages can communicate the share of a defined group associated with a listed term, but their precision depends on the amount of information available. With a very small group, a change in the experience of a participant can materially alter the descriptive percentage. Percentages in this setting should not be treated as precise estimates of what would occur in a wider population, and they do not convey the number of repeated episodes unless the record reports that separately.

What can a confidence interval add?

In general, a confidence interval describes uncertainty around an estimated quantity under a specified statistical method. It gives readers a range of values compatible with the data and method, rather than a single estimate alone. In a small safety group, uncertainty can be substantial, and an interval may help make that imprecision visible. The registry record does not report a confidence interval for the primary endpoint, so no interval-based precision claim can be made for it.

A confidence interval would not remove limitations of the study design. It quantifies statistical uncertainty under its assumptions; it does not account automatically for lack of a comparator, open-label assessment, incomplete reporting, or differences between this extension population and other populations. Nor would it prove causality.

Why does the design limit comparisons?

Randomized comparative trials use assigned groups to support estimates of differences between treatment strategies. This study is listed as single-group, with allocation not applicable and no masking. It therefore has no concurrent control arm. The posted adverse-event counts can describe what was recorded during Alpha-1 MP exposure, but there is no within-trial control estimate to distinguish treatment effects from background risk, underlying disease, or other influences.

Open-label knowledge of treatment can also influence event recognition, reporting, and assessment. The record does not report a method for adjusting for such influences. This is not evidence that reporting was biased; it is a design feature to keep in mind when interpreting subjective or clinically assessed outcomes.

How should planning illustrations be read?

General sample-size calculations estimate the number of participants that might be needed to detect a specified effect under a set of assumptions. The planning assumptions described for this record use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They describe hypothetical planning, not the design of this single-group study. The stated effect is a fraction of an observed effect, and the illustrations are not observed power.

Such calculations cannot turn a single-group safety description into a randomized comparison. They are sensitive to the effect assumed, the statistical model, and the target precision or power. They do not show that the study was designed with those assumptions, and the registry record does not report its own sample-size justification. Any planning value should therefore be understood as an illustration rather than an observed trial result or a retrospective measure of success.

What does an event count not tell us?

A count of participants with an event does not state the event's duration, intensity, recurrence, or relationship to study treatment unless those features are separately reported. Seriousness is a classification distinct from causality. A serious adverse event can occur during treatment without being caused by it, and an event that is not serious may still be relevant to the participant's experience. The registry's definitions and listed counts support descriptive reporting, not an individual clinical conclusion.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Alpha-1 MP")
n      <- c(4)
events <- c(4)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Alpha-1 MP  4  4  100.0  39.8  100.0  51.0  100.0  47.8  99.5

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 9 outcome measures, while no analysis entries are listed. It does not report a statistical plan describing how outcomes were prioritized beyond identifying the primary outcome, or how multiple statistical tests, if any, would be handled. Multiplicity matters when many outcomes or comparisons are tested: repeated testing can increase the chance of at least one apparently notable result by chance. Without a reported analysis plan, it is not possible to determine whether or how that issue was addressed.

The registry record does not report a missing-data strategy for the primary endpoint. It also does not describe whether participants had incomplete follow-up, how missing adverse-event information was handled, or whether any sensitivity analyses were planned. Missing information should not be treated as evidence that no event occurred. The primary outcome's numerical result is not reported, so the extent to which outcome data were available cannot be assessed from the record.

The stated safety population includes all participants who received any amount of Alpha-1 MP. This defines the population for safety reporting, but the record does not provide additional details about analysis populations or rules for excluding observations. The adverse-event listing gives at-risk and affected counts, but does not provide a full accounting of follow-up completeness or event-level data in the information reported.

These gaps limit assessment of the analysis process and the robustness of the reported safety summary. They do not establish that data were missing or that multiplicity affected any result; they mean those matters are not reported in the registry record.

12. 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.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pulmonary hypertension (25.0%), pneumonia (25.0%), cellulitis (25.0%), large intestine polyp (25.0%), pneumothorax (25.0%).

The adverse-event record lists the Alpha-1 MP group with 4 participants at risk for serious adverse events and 2 affected. For other adverse events, it lists 4 at risk and 4 affected. The recorded number of deaths is 0. These are descriptive participant counts, not estimates from a comparison with another group.

The listed serious-event terms are pulmonary hypertension, pneumonia, cellulitis, large intestine polyp, and pneumothorax, each reported as 25.0%. The percentages do not show whether events were repeated, how long they lasted, or whether they were considered related to treatment. The record's definition of an adverse event explicitly allows events without a causal relationship to study treatment.

Seriousness and causality are separate concepts: a serious event is not automatically treatment-caused. Likewise, counts do not identify background rates or indicate what would have happened without Alpha-1 MP. The small group size means the listing should be read as the experience recorded in this study, not as a precise prediction for a broader population. The primary treatment-emergent adverse-event count is not reported in the registry record.

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

The record documents a completed, long-term, open-label extension study of weekly intravenous Alpha-1 MP in Japanese adults with alpha1-antitrypsin deficiency who had completed Study GTI1401. Its safety information gives participant counts for serious and other adverse events, lists serious-event terms, and reports 0 deaths. These observations describe what the registry records for the study group during the stated period.

The central limitation is that the numerical result for the primary endpoint, the number of participants with treatment-emergent adverse events, is not reported in the registry record. The available serious and other event counts do not replace that primary result, because they describe different categories. The record also does not supply a comparative treatment estimate, confidence interval, or analysis record.

Because there was no concurrent comparator and treatment was open-label, the safety observations cannot establish that Alpha-1 MP caused the events or that event experience differed from what would occur under another treatment or without treatment. The study's extension population and long exposure period are relevant context, but they do not remove the limitations of a single-group design.

These data should not be interpreted as proof that treatment is safe or unsafe, or as proof that an event was or was not related to treatment. They are a limited descriptive record. The absence of a posted primary-outcome result is a reporting gap, not a result of zero events. Similarly, the reported 0 deaths applies to the registry's death count and should not be generalized beyond the recorded study population and observation period.

14. Why This Trial Matters Statistically

Long-term safety studies address a different statistical question from trials designed to compare treatment effects. Extended observation can capture events occurring during prolonged exposure, and a participant-level safety endpoint can describe how many people experienced an event under the study's definitions. For researchers, the value of such a record depends on clear event definitions, a stated timeframe, an identified safety population, and transparent reporting of counts and their uncertainty.

This study provides several of those design details: the safety population definition, the treatment-emergent event definition, and an observation window extending through 30 days after the last infusion, up to 228 weeks. It also records serious and other adverse-event counts and a list of serious-event terms. These details permit a bounded descriptive reading of long-term exposure in the enrolled group.

At the same time, the primary endpoint result is not reported, and the design has no control group. The record therefore illustrates why event counts should not be confused with a causal estimate. Even a complete count of events in a treated group cannot establish what would have occurred under a different treatment strategy. Small enrollment also limits the precision and generalizability of descriptive estimates.

Statistically, the record is a reminder that reporting completeness is part of interpretation. A stated endpoint without its numerical result cannot answer the endpoint question, and a completed study status does not fill that gap. Clear reporting of analysis methods, missing-data handling, and uncertainty would be needed for a fuller evaluation. The available information supports attention to the study's design and reporting boundaries rather than a broad efficacy conclusion.

15. 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 study enrolled 4 participants and used a single-group, open-label design. There was no randomized comparator, so the observed safety experience cannot be contrasted with a concurrent control group. The design does not support attributing events to Alpha-1 MP or estimating a treatment effect against an alternative.

The population was specific: Japanese adults with alpha1-antitrypsin deficiency who had completed Study GTI1401. Findings from an extension population may not represent people who did not complete the preceding study or other populations. The registry describes mean treatment duration as 213 weeks, but does not report participant-level exposure durations or the distribution of follow-up.

The primary outcome's numerical result is not reported in the registry record. The record also does not report confidence intervals, detailed analysis methods, missing-data handling, interim-analysis procedures, or the trial's sample-size justification. No analysis entries are listed. These gaps make it difficult to assess statistical precision, prespecification, and the completeness of outcome reporting.

Serious-event terms and percentages are descriptive, and the record does not provide event-level details such as recurrence, timing, or causal assessments. A small group can describe experiences observed in that group, but cannot precisely characterize uncommon events or establish how frequently they would occur in a wider population. The absence of a reported death in the record does not resolve these limitations or determine the overall safety profile.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Long-term Safety of Alpha1-Proteinase Inhibitor (Human) in Japanese Subjects With Alpha1 Antitrypsin Deficiency (GTI1401-OLE) — NCT02870348.
• Registry record last updated 2022-03-31; status last verified 2022-03.
• Results first posted 2022-03-21.
• 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.

19. Record Summary

NCT02870348 is a completed Phase 1 and Phase 2, multi-center, open-label, single-group study of weekly intravenous Alpha-1 MP in Japanese adults with alpha1-antitrypsin deficiency who had completed Study GTI1401. The registry lists 4 enrolled participants and a mean treatment duration of 213 weeks. The primary outcome is the number of participants with treatment-emergent adverse events, assessed from the first infusion through the final visit, with follow-up through 30 days after the last infusion, up to 228 weeks.

The adverse-event listing records 2 of 4 at risk with serious adverse events, 4 of 4 at risk with other adverse events, and 0 deaths. Five serious-event terms are listed, each at 25.0%. The primary endpoint result, comparative estimates, and detailed statistical analysis methods are not reported in the registry record. The single-group, open-label design supports descriptive safety reporting but not a causal comparison.