Efficacy and Safety Study of Augmentation Therapy With ARALAST Fraction IV-1 (Human Alpha 1 - Proteinase Inhibitor): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety Study of Augmentation Therapy With ARALAST Fraction IV-1 (Human Alpha 1 - Proteinase Inhibitor) (NCT00396006), a non-randomized phase 4 study. The primary outcome is Change in Bronchoalveolar Lavage (BAL) Epithelial Lining Fluid (ELF) Alpha1-Proteinase Inhibitor (α1-PI) Level.

2. Clinical Question

The study also aimed to assess other epithelial lining fluid analytes and safety. Secondary outcomes include measures involving antineutrophil elastase capacity, the α1-PI to human neutrophil elastase complex concentration, plasma α1-PI and antineutrophil elastase capacity, and clinically significant vital-sign changes. The registry lists 12 outcome measures overall, but it does not report a full set of numerical efficacy results in the record summarized for this analysis.

3. Trial Design

This was a completed Phase 4 study with a single-group, non-randomized design and no masking. The registry lists enrollment of 21. Participants with severe congenital alpha 1-antitrypsin deficiency were to receive intravenous ARALAST Fraction IV-1 once weekly for 8 consecutive weeks at 60 mg/kg/week. The study description specifies two bronchoscopies with bronchoalveolar lavage: one at study initiation and another at study termination. Imaging and laboratory assessments were also part of the planned safety evaluation. Each subject was to participate for a minimum of 12 weeks.

The recorded start date is 2006-10-27, the primary completion date is 2007-12-14, and the study status is completed. The primary endpoint was the median change from baseline in BAL epithelial lining fluid antigenic α1-PI level, expressed in μM. Its analysis population is listed as per protocol. The record does not state the number of participants included in that primary analysis, nor does it give the endpoint’s observed median change or full range.

Because the study had a single group, the baseline and post-treatment observations are measurements from the same treatment group rather than outcomes from randomized treatment and control arms. Such a design can describe within-group change over time, but it does not by itself separate a treatment-associated change from other explanations, such as changes over time or measurement variability. This is a general design consideration, not a conclusion about what caused any change in this study.

The registry does not report a detailed protocol for handling departures from the treatment regimen, the timing of each participant’s post-treatment measurement, or the number of participants who completed each assessment. Those details should not be inferred from the planned schedule. The enrollment figure is not necessarily the number contributing data to each outcome; the relevant analysis counts are not reported in the registry record.

The intervention is identified as a biological alpha1-proteinase inhibitor. The registry lists Baxalta now part of Shire as the sponsor. No randomized comparison is described, and the listed design does not support a like-for-like comparison between treatment arms. Interpretation should therefore remain focused on the endpoint definition and the information actually reported for the treated group.

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: 21 participants enrolled: 4 were screen failures (i.e., did not meet inclusion/exclusion criteria), 3 were discontinued due to unevaluable baseline bronchoalveolar lavage (BAL) samples, and 1 subject withdrew consent prior to receiving investigational product.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Per protocol

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.

6. Primary Endpoint

The registry lists the primary outcome as Change in Bronchoalveolar Lavage (BAL) Epithelial Lining Fluid (ELF) Alpha1-Proteinase Inhibitor (α1-PI) Level, measured over BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks).

The primary endpoint is the change in bronchoalveolar lavage epithelial lining fluid α1-PI level from baseline to post-treatment. The registry describes the measure as antigenic α1-PI, reports the unit as μM, and specifies the median and full range as the summary approach. BAL obtains a sample of material from the lower respiratory tract; the endpoint concerns α1-PI measured in the epithelial lining fluid rather than a blood concentration. The registry separately lists plasma α1-PI as a secondary outcome.

A pre-treatment and post-treatment measurement can describe whether the measured level changed during the study period. Using a median is a way to characterize the center of observed values that is less sensitive to extreme observations than an arithmetic mean. Reporting the full range conveys the span from the lowest to the highest observed values, though it does not show how values are distributed between those endpoints. These are general statistical explanations.

The endpoint is relevant to the study’s stated aim of evaluating effects on epithelial lining fluid α1-PI levels. It is a laboratory measure, not by itself a direct measure of symptoms, functioning, or clinical events. The observed median change, range, and analysis sample size are not reported in the registry record, so the magnitude and precision of the endpoint result cannot be assessed from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The design determines which statistical questions the data can answer. This study is listed as non-randomized, unmasked, and single-group. Its primary endpoint compares a baseline measure with a post-treatment measure within the treated group. In general, paired measurements can describe within-person change and then summarize those changes across participants. A separate randomized comparison would be needed to directly estimate how outcomes differ between assigned treatment conditions; no such comparison is listed for this study.

What does the median describe?

The primary endpoint is summarized by a median change. In general, the median is the middle value after observations are ordered. It can be useful when values are skewed or when a small number of extreme values could strongly affect an arithmetic mean. The median does not describe every participant’s response, and it can conceal variation among individual changes. The registry specifies a full range as the accompanying dispersion summary. A range gives the lowest and highest observed values, but not the concentration or pattern of observations between those limits. The endpoint’s median and range are not reported in the registry record.

What does a confidence interval add?

In general, a confidence interval gives a range of estimates compatible with the data and the method used to construct it. It communicates uncertainty around an estimate, whereas a point estimate alone gives only one summary value. A narrow interval generally indicates greater precision than a wide interval under the same method and assumptions. The registry record summarized for this study does not report a confidence interval for the primary endpoint. Therefore, the precision of its estimated change cannot be assessed from a reported interval.

What does a p-value answer?

In general, a p-value describes how unusual data at least as inconsistent with a specified null hypothesis would be if that hypothesis and the analysis assumptions were true. It does not measure the size or clinical importance of an effect, and it does not give the probability that a treatment works. A p-value is also not a substitute for an effect estimate and an uncertainty interval. The registry record does not report a primary-endpoint p-value or identify the statistical test used for the primary analysis. No test or result should be inferred.

Why does the single-group structure matter?

With measurements collected before and after treatment in one group, the observed change combines any treatment-associated change with other changes occurring over time and with measurement variability. A control group can help distinguish those influences when the comparison is appropriately designed and analyzed. Here, the registry lists no comparator arm. The non-randomized allocation and absence of masking are further design features to consider, but the record does not describe their practical effects on measurement or conduct. They should not be treated as proof that bias occurred.

What is over-dispersion?

In general, over-dispersion occurs when observed variability is greater than a statistical model assumes. If a model understates variability, standard errors may be too small and confidence intervals may be too narrow. This issue is often relevant to count or event data, depending on the model. The primary endpoint is a continuous laboratory measure summarized by median and full range; the registry does not report a model or an over-dispersion assessment for it. It would therefore be inappropriate to claim that over-dispersion was present or that a particular correction was used.

How should planning illustrations be read?

The registry describes planning illustrations computed from an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. For time-to-event calculations, the stated quantity is a total number of events; other calculations are stated as participants per arm. These are planning assumptions for hypothetical comparisons, not the actual single-group allocation in this study. They are not observed power and do not show that the trial was adequately or inadequately powered. The record does not report a trial-specific sample-size justification, the effect used as the planning reference, or a prespecified target sample size.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 12 outcome measures and 5 analyses. It does not report a testing hierarchy, identify which outcomes were treated as confirmatory, or describe whether statistical significance thresholds were adjusted for multiple outcomes or analyses. When many hypotheses are tested, the chance of at least one apparently unusual result can increase; this is a general statistical concern, not evidence that a particular finding in this study is false. Without a stated analysis plan, the role of any individual secondary result cannot be determined from the registry record.

The primary endpoint population is labeled per protocol, while the adverse-event group is labeled intent to treat. These labels refer to different analysis populations and should not be assumed to contain the same participants. The registry reports enrollment of 21 and lists 13 participants at risk in each of the serious and other adverse-event categories. It does not explain the relationship between those counts and overall enrollment or give the primary endpoint analysis count. Reasons for any difference are not reported in the registry record.

The handling of missing baseline or post-treatment measurements, incomplete BAL procedures, and other missing outcome data is not reported in the registry record. The record also does not state whether all participants received the planned treatment schedule or how deviations were handled. Missing-data methods can affect an estimate when observations are incomplete, so the absence of this information limits assessment of the endpoint analysis. No imputation method, sensitivity analysis, or analysis-population reconciliation should be inferred.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hepatitis a antibody positive (7.7%).

The registry lists an intent-to-treat safety group. For serious adverse events, it reports 13 participants at risk and 1 affected. For other adverse events, it reports 13 at risk and 7 affected. These are separate categories in the record; the counts should not be added or treated as mutually exclusive without further information. The registry does not report the number of events per affected participant or give event-level details for the other adverse events.

The leading serious adverse event term is Hepatitis A antibody positive, listed as 7.7%. The registry’s category counts and term listing are descriptive safety information. They do not, by themselves, establish that an event was caused by treatment, and the record does not provide a comparison group for estimating a treatment-related excess. Deaths are not reported in the registry record.

The risk period, definitions used for event attribution, severity grading, and details of clinical review are not reported in the registry record. Therefore, the figures should be read as counts and a listed term rather than as a complete account of safety. The number of participants at risk is not the same as the number of events, and a listed percentage does not convey the clinical context or timing of the event.

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

The registry describes a study designed to measure change in BAL epithelial lining fluid α1-PI after a course of ARALAST Fraction IV-1 augmentation therapy. It establishes the endpoint definition, unit, summary approach, intended measurement times, and the single-group design. It also records enrollment of 21 and provides limited safety counts. These registry entries describe the study structure and some posted safety information.

The numerical primary endpoint result is not reported in the registry record. As a result, the posted record does not establish the size or direction of the median change, the range of changes, or the precision of the estimate. It also does not report a p-value or confidence interval for that endpoint. A conclusion about the magnitude of the observed laboratory change cannot be drawn from the endpoint description alone.

Even if a pre-to-post change estimate were available, the single-group, non-randomized design would support description of change during the study rather than a controlled estimate of the effect attributable to treatment. This is a general interpretation of the design, not a judgment about whether the intervention caused any specific change. No comparison with an untreated group or another therapy is listed.

The safety entries report affected-participant counts and a serious adverse event term, but they do not provide a randomized comparison or establish causality. They should not be interpreted as a complete estimate of risk. Information on event timing, attribution, and deaths is not reported in the registry record.

Overall, the record defines a biological and laboratory-focused research question and documents how the study was structured. It does not provide enough numerical efficacy information to characterize the primary outcome’s observed result. The listed planning illustrations, where available in the accompanying material, are hypothetical planning calculations rather than observed outcomes or evidence of achieved power.

13. Why This Trial Matters Statistically

This study is statistically informative as an example of the distinction between measuring change and estimating a comparative treatment effect. The primary endpoint uses baseline and post-treatment BAL epithelial lining fluid measurements in a single group. That structure can describe within-group change, but without a comparator it cannot distinguish treatment-associated change from other influences over time. This distinction is central when interpreting laboratory outcomes from non-randomized studies.

The endpoint also illustrates why the summary statistic matters. The registry specifies a median change and full range rather than a mean and standard deviation. Those summaries answer different descriptive questions: the median locates the center of the observed changes, while the range records their extremes. Neither alone describes the full distribution or quantifies uncertainty around the median. Since the numerical endpoint result and its analysis count are not reported in the registry record, readers cannot judge the observed spread or precision.

The contrast between overall enrollment and the listed safety denominator also highlights the importance of analysis populations. Enrollment is not automatically equivalent to the number analyzed for every outcome. The primary analysis is labeled per protocol, while the safety group is labeled intent to treat; the record does not explain the participant flow between these populations. Clear denominators and reasons for exclusions are important for assessing how representative an analysis may be.

Finally, multiple outcomes make prespecification and transparent reporting important. The registry lists 12 outcome measures and 5 analyses, but does not report a testing hierarchy or adjustment strategy. This does not show that an inappropriate analysis occurred; it means the record does not allow readers to assess how multiplicity was addressed. Together, these features make careful separation of design, result, and uncertainty essential.

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 most direct limitation for interpretation is that the registry does not report the numerical primary endpoint result. The median change and full range for BAL epithelial lining fluid α1-PI, the primary analysis count, and an uncertainty measure are not reported in the registry record. Without them, the endpoint’s observed magnitude, variability, and precision cannot be assessed.

The study is single-group, non-randomized, and unmasked. There is no listed control group to provide a concurrent contrast, and the design therefore does not isolate change associated with treatment from other changes over time. This is a limitation of what the design can establish, not evidence that a particular source of bias affected the findings. The registry does not describe assessment blinding or additional safeguards.

The primary analysis population is per protocol, but the number included and the criteria for that population are not reported in the registry record. The record reports enrollment of 21 and safety denominators of 13, without a participant flow or explanation of the difference. Completion of the planned regimen, completion of BAL procedures, and handling of protocol deviations are also not reported.

Missing-data methods, the statistical test for the primary endpoint, and any sensitivity analyses are not reported in the registry record. Nor does it describe a multiplicity strategy across the listed outcomes and analyses. These omissions limit assessment of analytical robustness and the confirmatory status of any secondary findings. The efficacy outcomes beyond their names and the primary endpoint definition are not numerically reported in the record summarized for this interpretation.

Safety reporting is limited to the listed affected-participant counts and serious adverse event term. Event timing, attribution, severity details, and deaths are not reported in the registry record. These limits make the safety entries descriptive rather than a complete comparative assessment.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Efficacy and Safety Study of Augmentation Therapy With ARALAST Fraction IV-1 (Human Alpha 1 - Proteinase Inhibitor) — NCT00396006.
• Registry record last updated 2021-05-13; status last verified 2021-04.
• Results first posted 2011-01-04.
• 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

NCT00396006 is a completed Phase 4, non-randomized, unmasked, single-group study of ARALAST Fraction IV-1 augmentation therapy in severe congenital alpha 1-antitrypsin deficiency. The registry lists enrollment of 21 and a regimen of 60 mg/kg/week intravenously for 8 consecutive weeks. The primary endpoint is median change in BAL epithelial lining fluid antigenic α1-PI, measured in μM, from baseline to post-treatment; the analysis population is per protocol.

The study record describes BAL procedures at baseline and after treatment, with minimum participation of 12 weeks. It lists 12 outcome measures and 5 analyses. Numerical results for the primary endpoint, its analysis count, and methods for missing data and multiplicity are not reported in the registry record. The safety entries list 13 at risk and 1 affected for serious adverse events, and 13 at risk and 7 affected for other adverse events. The serious adverse event term Hepatitis A antibody positive is listed as 7.7%.