Safety and Pharmacokinetics of Alpha-1 MP (Alpha1-proteinase Inhibitor (Human), Modified Process) in Participants With Alpha1-Antitrypsin Deficiency: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Pharmacokinetics of Alpha-1 MP (Alpha1-proteinase Inhibitor (Human), Modified Process) in Participants With Alpha1-Antitrypsin Deficiency (NCT02870309), a na phase 1, phase 2 study. The primary outcome is Number of Participants With Treatment-Emergent Adverse Events (TEAEs).

2. Clinical Question

The trial was open-label and designed to evaluate safety and pharmacokinetics, rather than to compare Alpha-1 MP with another treatment or control. Its primary endpoint is a participant count: it concerns whether participants experienced a TEAE during the specified observation period. The registry definition includes adverse events occurring on or after the first infusion through the final study visit, whether or not the event was considered related to the medicinal product.

The clinical question is therefore descriptive. The posted adverse-event summary can indicate how many participants were recorded with serious and other adverse events in the treatment group. It cannot, on its own, estimate how the event experience would compare with an untreated or alternative-treatment group. The record lists a pharmacokinetic outcome as well, but results for that outcome are not reported in the registry record.

3. Trial Design

This is a multicenter, open-label Phase I/II trial of Alpha-1 MP in participants with alpha1-antitrypsin deficiency. The registry record lists a single treatment group, no masking, and allocation as not applicable. The single-group design means all participants in the described arm received Alpha-1 MP; the record does not describe a control arm or a randomized treatment comparison.

The intervention was weekly intravenous Alpha-1 MP at 60 mg/kg for 8 weeks. The arm description states that participants received 8 infusions, administered at an infusion rate not exceeding 0.08 mL/kg/min over approximately 15 minutes, up to Week 8. The brief study description characterizes the trial as an evaluation of safety and pharmacokinetics.

The registry lists enrollment as 4. The study status is completed, with a start date of 2016-07-29 and a primary completion date of 2017-03-15. The primary safety outcome is the number of participants with TEAEs, with a timeframe of up to Week 12. The safety population includes all participants who received any amount of Alpha-1 MP.

The record also lists a secondary outcome measuring trough levels of total alpha1-PI for weekly intravenous infusions of 60 mg/kg Alpha-1 MP. The number of outcome measures is listed as 6, but the registry entries in this record do not give results for the pharmacokinetic outcome. The number of participating centers, the approach to selecting participants, and a detailed statistical analysis plan are not reported in the registry record.

Because the trial is open-label and has no comparator, its design supports a descriptive account of the experience in the treated group. It does not separate treatment-associated changes from changes that might occur over time or from other influences. The design and enrollment also do not establish how precisely the observed event experience represents a broader 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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Safety population included all the 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 the 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 Up to Week 12.

The primary endpoint is the number of participants with treatment-emergent adverse events (TEAEs), measured through the period stated as up to Week 12. The registry defines an adverse event as an unfavorable and unintended sign, symptom, disease, or abnormal laboratory finding temporally associated with use of an investigational product, regardless of whether it is considered related to the medicinal product. A TEAE is defined as an adverse event occurring on or after the first Alpha-1 MP infusion until the final study visit.

This endpoint is used to describe the safety experience observed during treatment and follow-up. Counting participants with an event focuses on how many people experienced an event, rather than how many separate events occurred. The distinction matters because a participant may experience more than one event, while a participant count records that person as an affected participant rather than representing each event separately.

The safety population consists of all participants who received any amount of Alpha-1 MP. The registry record names the primary endpoint and its definition, but a result for the primary TEAE count is not reported in the registry record. The posted adverse-event summary separately lists serious and other adverse-event counts; those categories should be read as the adverse-event summary and not assumed to supply an unreported primary endpoint result.

As a general statistical matter, event counts help describe what was observed, while uncertainty estimates would indicate how much precision can be attached to those observations. Such estimates and a method for deriving them are 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 describe?

The primary outcome is defined as a count of participants with TEAEs. In a binary outcome, each participant is classified according to whether the event of interest was recorded during the specified period. The count answers a direct descriptive question about the observed group. It is not the same as a total event count: repeated events in one participant do not necessarily correspond to additional participants with an event.

For interpretation, the population used as the denominator matters. The registry defines the safety population as participants who received any amount of Alpha-1 MP. That definition makes the safety analysis population treatment-exposed, rather than simply everyone who may have been enrolled. The record lists enrollment as 4, and the adverse-event summary lists 4 at risk for both serious and other adverse events.

Why does the single-group design matter?

A single-group study can describe what was observed among treated participants. Without a comparator group, it cannot estimate a between-group treatment contrast. A count in the treatment arm does not tell what would have occurred to comparable participants without Alpha-1 MP or under another treatment. This is why the record's adverse-event data should be read descriptively, rather than as a comparative estimate of harm or benefit.

Open-label status means the study was not masked. The registry record does not report a blinded assessment process. In general, knowledge of treatment assignment can affect how symptoms are noticed, reported, evaluated, or classified. This is a design consideration, not evidence that any particular event classification in this trial was affected.

What can uncertainty estimates add?

In general, a confidence interval expresses the statistical uncertainty around an estimate under a specified method and assumptions. For a binary outcome, an interval around an event proportion can help communicate that the observed group count does not determine the underlying event frequency with certainty. With a small observed group, uncertainty can remain substantial even when the count is clear. The registry record does not report confidence intervals for the primary endpoint or adverse-event categories, nor does it identify an interval method.

Over-dispersion is a general concern when observed variation is greater than a model assumes. It is more pertinent to certain count or clustered-data models than to the simple participant-level binary endpoint. The registry record does not report a model for the primary endpoint, so it is not possible to assess whether over-dispersion was evaluated or whether a model-based adjustment was planned.

What does the planning illustration represent?

The sample-size assumptions describe a planning illustration based on the observed effect, not the trial's original design. The stated assumptions include a two-sided significance level of 0.05, equal allocation between two hypothetical arms, and a normal approximation. The planning illustration is therefore not evidence that this single-group trial was designed as a two-arm study. It also is not observed power. A planning sample size asks how many participants per arm might be needed under stated assumptions to detect a specified effect; it does not measure the probability that the completed trial has demonstrated an effect.

In general, planning estimates depend on the target effect, outcome variability, significance level, power target, allocation, and statistical method. A planning exercise based on an observed effect is particularly dependent on that estimate and should be treated as an illustration, not as an independent confirmation. The registry record does not report the original sample-size justification or a protocol-based sample-size calculation.

What analyses are reported?

The record lists 0 analysis entries. It does not report an inferential test, an adjusted model, a confidence interval, or a detailed analysis plan for the primary endpoint. No recalculated comparative result is appropriate from the posted single-group counts. General statistical explanations do not fill in those missing analysis details: only the registry's stated design and outcome information can characterize the trial-specific methods.

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(3)
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  3  75.0  19.4  99.4  30.1  95.4  28.4  94.7

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 6 outcome measures, including the primary TEAE endpoint and a secondary outcome for trough levels of total alpha1-PI. A study with multiple outcomes can raise multiplicity questions because interpreting several statistical tests together may increase the chance of a misleading positive result. The record does not report a multiplicity adjustment, a hierarchy among secondary outcomes, or a strategy for controlling the interpretation of multiple tests. It also lists 0 analysis entries, so no outcome-specific testing procedure is available in the registry record.

The registry defines the safety population as all participants who received any amount of Alpha-1 MP. This definition identifies the population for safety assessment, but the record does not provide additional analysis-population definitions or explain how participants with incomplete outcome information were handled.

Missing-data methods are not reported in the registry record. In general, missing observations can affect an estimate if the participants with available outcome information differ from those without it. The record does not describe imputation, a complete-case approach, sensitivity analyses, or the amount of missing information for the primary endpoint. No assumptions about missing outcomes should therefore be inferred.

The primary endpoint's result is not reported in the registry record, and no statistical analysis plan or hypothesis-testing results are listed. These omissions limit assessment of how outcomes were selected, how missingness was treated, and whether analyses were adjusted for multiple outcomes. They do not change the descriptive adverse-event counts that are posted, but they constrain what can be concluded from them.

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 non-serious adverse event terms

The adverse-event summary lists 0 participants with serious adverse events among 4 at risk, 3 participants with other adverse events among 4 at risk, and 0 deaths. These figures describe the Alpha-1 MP group; they are not comparisons against a control group. The registry record lists no top serious adverse-event terms.

Serious and other adverse events are presented as separate categories in the summary. A count of 0 for serious adverse events means no participant was recorded in that category in the posted summary; it does not mean that serious events cannot occur. The count of 3 for other adverse events is a participant count, not a total number of event episodes. The record does not provide event-level descriptions for those participants in the registry record for this analysis.

The primary endpoint is defined as participants with TEAEs, but its result is not reported in the registry record. The other-adverse-event count should not automatically be treated as the TEAE endpoint result because the record does not explicitly identify those categories as equivalent. In general, adverse-event counts are descriptive and do not establish causation. The endpoint definition includes events whether or not they were considered related to the medicinal product.

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

The posted results offer a limited description of adverse events recorded in the Alpha-1 MP group. The summary reports 0 participants with serious adverse events, 3 with other adverse events, and 0 deaths. These counts can be read as the observed safety summary for this study group, using the categories and denominators stated in the registry record.

They do not establish the rate of events in a broader population. Enrollment was 4, and a small group provides limited information about how often uncommon or variable outcomes might occur elsewhere. The record does not report uncertainty intervals, so the precision of a population-level estimate cannot be assessed from the posted information. The counts should not be converted into a claim about the likelihood of an event for an individual.

Nor do the counts establish that Alpha-1 MP caused or prevented an event. The trial had no comparator, was open-label, and defines TEAEs without requiring that an event be judged related to the medicinal product. Without a control group, there is no direct estimate of how the observed event experience differs from what might otherwise have occurred.

The primary TEAE endpoint is specified, but its result is not reported in the registry record. The secondary trough-level outcome is listed, but its result is also not reported. As a result, the posted adverse-event summary cannot answer the full safety and pharmacokinetic question posed by the study title and design.

In general, a trial's findings apply most directly to the participants, intervention, and follow-up actually described. Here, the treatment schedule was weekly intravenous Alpha-1 MP at 60 mg/kg for 8 weeks, with the primary outcome timeframe stated as up to Week 12. The record does not establish effects beyond that setting or observation period. The appropriate reading is therefore a cautious, descriptive account of a small treated group, not a definitive comparative or long-term conclusion.

14. Why This Trial Matters Statistically

This trial matters statistically because it illustrates the difference between describing an observed safety experience and estimating a comparative treatment effect. The record describes a single treatment group and reports adverse-event counts. Those counts are useful as a record of what was observed, but they cannot supply the contrast that a control group would provide.

It also shows why endpoint definitions and results should be read separately. The primary endpoint is a count of participants with TEAEs through the stated follow-up, while the adverse-event summary reports serious and other event categories. The primary endpoint result is not reported in the registry record, so the listed categories should not be assumed to replace it. A clear definition tells readers what was intended to be measured; a posted result is needed to describe the outcome on that measure.

The enrollment of 4 makes precision central to interpretation. In general, observations from a small group can be highly sensitive to the experience of each participant. Reporting uncertainty estimates and explaining the analysis approach can help readers distinguish a precise estimate from a count that remains uncertain as a guide to wider populations. Neither confidence intervals nor a detailed analysis plan are reported in the registry record.

Finally, the sample-size illustration is not the study's design or an indication of observed power. Its assumptions describe a hypothetical two-arm planning exercise, whereas this study is single-group. Keeping that distinction clear prevents planning calculations from being mistaken for evidence that the trial established a treatment effect. The record is most informative when its design, endpoint, and descriptive safety data are interpreted together.

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 most direct limitation is the absence of a comparator. The study is listed as single-group, with allocation not applicable, so the posted adverse-event counts cannot show how the safety experience compares with another treatment or with no treatment. The open-label design is another consideration; the registry record does not report masking or a blinded outcome-assessment procedure.

Enrollment was 4, limiting the amount of information available about event patterns and the precision of any estimate for a wider population. The stated primary outcome timeframe is up to Week 12, and the described treatment period is 8 weeks. The record does not report longer-term safety outcomes.

The primary TEAE endpoint is defined but its result is not reported in the registry record. The listed secondary outcome is trough level of total alpha1-PI, but its numerical result is not reported in the registry record either. The adverse-event summary supplies counts for serious events, other events, and deaths, but does not provide event-level descriptions or top serious-event terms.

The statistical analysis plan, missing-data approach, and multiplicity strategy are not reported in the registry record. The number of centers, participant characteristics beyond the condition, and details of the recruitment process are also not reported in the registry record. These omissions restrict assessment of generalizability and analytic choices. They do not justify assuming that unreported procedures or results were absent; they mean that those details cannot be evaluated from the record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Pharmacokinetics of Alpha-1 MP (Alpha1-proteinase Inhibitor (Human), Modified Process) in Participants With Alpha1-Antitrypsin Deficiency — NCT02870309.
• Registry record last updated 2021-10-28; status last verified 2021-10.
• Results first posted 2021-02-18.
• 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

The registry record describes NCT02870309, a completed, multicenter, open-label Phase I/II single-group trial sponsored by Grifols Therapeutics LLC. It evaluated weekly intravenous Alpha-1 MP at 60 mg/kg for 8 weeks in participants with alpha1-antitrypsin deficiency. Enrollment was listed as 4.

The primary outcome was the number of participants with TEAEs, with a timeframe of up to Week 12. The safety population included participants who received any amount of Alpha-1 MP. The adverse-event summary lists 0 participants with serious adverse events, 3 with other adverse events, and 0 deaths. The primary endpoint result and the result for the listed trough-level outcome are not reported in the registry record.

Because there was no comparator and the trial was open-label, the posted counts are descriptive rather than comparative. The record lists 0 analysis entries and does not report a detailed statistical analysis plan, uncertainty estimates, or missing-data methods.