Aralast alpha1-proteinase Inhibitor Surveillance Study: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Aralast alpha1-proteinase Inhibitor Surveillance Study (NCT00313144), a non-randomized phase 4 study. The primary outcome is HRQoL 'Physical Functioning (PF)' From Baseline to ≤6 Months.

2. Clinical Question

The study asked how health-related quality of life, healthcare resource use, and laboratory measures changed among people with alpha1-antitrypsin deficiency who initiated ARALAST. Its primary outcome concerned physical functioning on the SF-36, comparing the baseline score with a score measured by 6 months. The registry describes additional outcomes related to emergency room visits, hospitalizations, antibiotic use, and steroid pulse courses, as well as safety-related laboratory assessments.

This is a question about change over time in a treated group, not a randomized comparison of treatment against an alternative. The registry record does not report the primary endpoint estimate or its uncertainty, so it does not establish the magnitude or direction of any observed change. It also does not report a comparator-based estimate of what would have happened without treatment. The listed healthcare resource and laboratory assessments provide additional areas of follow-up, but their results are not reported in the registry record.

3. Trial Design

This was a Phase 4, prospective U.S. surveillance study with a single-group, non-randomized, open-label design. The registry records enrollment of 127 and lists the study status as terminated. The recorded study start was 2006-06-09, and primary completion was 2008-12-01. The brief summary describes assessment of health-related quality of life and healthcare resource utilization at baseline and every 6 months thereafter, for 2 years. It also describes a blood-draw subset for antibody assessments and a chemistry panel.

ARALAST was the study intervention. Treatment was to follow the prescribing physician’s instructions based on the prescribing information. Because there was no randomized control group and masking was absent, outcome changes would be observed among people receiving treatment in routine prescribing circumstances rather than estimated from a direct comparison with an assigned alternative. The study can therefore describe observed outcomes over follow-up, but its design alone cannot separate treatment-associated change from other influences such as changes in health over time, concomitant care, or differences in who contributed follow-up measurements.

The brief summary states that up to 120 subjects would be enrolled, while the registry record lists enrollment of 127. The reason for this difference is not reported in the registry record. The reasons for termination and any details of recruitment, follow-up completion, protocol changes, or study conduct are also not reported in the registry record. The record does not report the rationale for the enrollment target or a statistical plan explaining how the study was intended to handle outcome analysis. Its description of a planned assessment schedule should not be read as evidence that every participant completed every scheduled assessment.

There are 24 outcome measures and 6 analyses listed in the record. Those counts describe the scope of registered outcomes and analyses, not the number of statistically significant findings. The primary outcome is a continuous SF-36 physical-functioning score, but the numerical result and details of its analysis are not reported in the registry record.

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: 127 participants enrolled in the study, of these 126 participated in the health related quality of life (HRQoL) and healthcare resource utilization (HCRU) portion, 61 consented to the blood draw portion, and 66 only consented to the Quality of Life portion

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants with baseline and participating during the period from baseline to ≤6 months data for HRQoL

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 HRQoL 'Physical Functioning (PF)' From Baseline to ≤6 Months, measured over Screening to ≤ 6 Months.

The primary endpoint is change in the SF-36 physical-functioning domain score from baseline to ≤6 months. The registry describes the measure as a score on a scale, analyzed as a mean with standard deviation. SF-36 responses are transformed into norm-based scores for each of the 8 health domains. The stated score range is 0 to 100, with higher scores representing better health. The instrument has domain and summary scores rather than one total overall score.

Physical functioning is used to capture a patient-reported aspect of health: how respondents describe their functioning in daily life. It complements measures such as healthcare utilization and laboratory results, which address different dimensions of health and care. A change score is intended to describe how the measured domain differs from baseline over the follow-up interval. It is not, by itself, proof that treatment caused the change. In an uncontrolled study, changes may reflect treatment, the course of the underlying condition, other care, measurement variation, or which participants have data at each time point.

The registry identifies the endpoint population as participants with baseline and participating-period HRQoL data from baseline to ≤6 months. The number who met that description, the mean change, the standard deviation of change, and any confidence interval or test result are not reported in the registry record. Accordingly, the endpoint definition can be described, but its observed result and precision cannot be assessed from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record describes a continuous primary endpoint: an SF-36 physical-functioning score and its change from baseline to ≤6 months. It identifies the summary measure as a mean and the accompanying dispersion measure as a standard deviation. The numerical outcome results and the inferential methods used to analyze them are not reported in the registry record. The explanations below are general statistical context, not a description of unreported methods used by the study.

What does a mean change represent?

For a continuous outcome, a mean summarizes the average value in the observations being analyzed. A mean change summarizes the average difference between a follow-up measurement and baseline for the included participants. It can be useful for describing the overall direction and size of change in the analyzed group. However, the average does not show how much individuals varied, whether changes were similar across participants, or whether a small number of unusual values influenced the group summary.

The standard deviation describes the spread of individual values around a mean. It is not the same as the standard error or a confidence interval. A standard deviation characterizes variation among observations, whereas a confidence interval is used to express uncertainty around an estimated quantity. To judge the precision of an estimated mean change, readers generally need an uncertainty measure, such as a confidence interval, along with the estimate itself. Neither the mean change nor its uncertainty is reported for the primary endpoint in the registry record.

What would a confidence interval tell a reader?

In general, a confidence interval gives a range of values compatible with the observed data and the statistical model used to construct it. Its width reflects precision: a narrower interval indicates greater precision than a wider interval, under the same method and assumptions. It does not give the probability that a particular fixed value is true, and it does not resolve biases caused by study design or missing data. Since no primary endpoint confidence interval is reported in the registry record, the precision of the change estimate cannot be evaluated.

Why does the study design matter?

A single-group study can describe the outcomes observed among participants over time. It does not create the contemporaneous counterfactual comparison that random allocation can support. Without a control group, a change from baseline may coincide with treatment without being attributable to treatment. This is a general limitation, not a claim about the actual source of any particular change in this study. The registry record does not report an adjustment strategy that would address this limitation.

Non-randomized enrollment can also result in a group whose characteristics differ from those of people not enrolled. In general, such differences may affect outcomes or follow-up. Open-label conduct means masking was absent, as recorded in the registry. Patient-reported outcomes can be influenced by respondents’ perceptions and expectations; this is a general consideration and does not establish that such influence occurred. The record does not report procedures intended to reduce measurement or reporting bias.

How should repeated measurements be understood?

The brief summary describes HRQoL and healthcare resource assessments at baseline and every 6 months thereafter, for 2 years. Repeated measurements can show how an outcome varies over follow-up, but the analysis must account for the fact that measurements from the same participant are related. General approaches may model within-person correlation or define a particular follow-up comparison. The registry record does not report which repeated-measures method, if any, was used for the outcomes.

For the primary outcome, the registered comparison is baseline to ≤6 months. The notation identifies a window, rather than an exact visit date for every participant. The record does not report how measurements taken at different times within that window were selected or combined. It also does not state whether the primary analysis used raw change scores, a model adjusted for baseline, or another approach. These choices can affect the estimate and its uncertainty, so they should not be assumed.

Why can variability and skew matter for utilization outcomes?

Healthcare utilization measures often represent counts, such as visits, hospitalizations, or medication courses. In general, count data can be highly variable and may include many low values alongside a small number of high values. A mean can summarize average use, but the distribution and the time participants were observed also matter. If count variation exceeds what a simple statistical model expects, over-dispersion can make conventional standard errors too small; methods suited to over-dispersed counts may then be appropriate. This is general guidance only. The registry record does not report the distributions or analysis methods for its utilization outcomes.

Hospital length of stay is another measure for which a few long stays can influence a mean. A complete interpretation would consider how the outcome was defined, whether zero values were included, the observation period, and the distribution. Those details and the results are not reported in the registry record. The listed outcomes alone do not establish how they were analyzed.

What do the planning illustrations mean?

Sample-size calculations based on an observed effect are planning illustrations. They ask, under stated assumptions, how many participants per arm might be required to detect a chosen fraction of that effect at a specified power and significance level. They are not evidence that the study had that power, and they do not replace the trial’s original sample-size justification. In particular, an observed effect from a study can be imprecise, and planning calculations inherit that uncertainty. The registry record does not report its original sample-size justification. Any listed planning illustration should be read as hypothetical, not as an observed efficacy result or as the study’s prospective design calculation.

The record describes the illustration assumptions as a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect set as a stated fraction of the observed effect. These are assumptions for the planning illustration, not evidence that this single-group surveillance study used a two-arm design. The statistical interpretation of a recalculated comparison, if one is presented elsewhere, would also differ from a sponsor analysis; when a discrepancy is identified, the sponsor’s own analysis takes precedence. No such primary endpoint result or discrepancy is reported in the registry record.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Baseline", "Baseline to ≤6 Months")
n   <- c(106, 106)
m   <- c(31.958, 33.129)
sp  <- c(11.291, 11.527)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Baseline  106  31.958  11.291  29.783  34.133
CARM  Baseline to ≤6 Months  106  33.129  11.527  30.909  35.349

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 24 outcome measures and 6 analyses. That breadth raises a general multiplicity concern: when many outcomes or analyses are examined, the chance of at least one apparently notable result can increase if each is tested separately. Statistical plans may address this through a prespecified hierarchy, adjustment procedures, or a clear distinction between primary and exploratory analyses. The registry record identifies the primary physical-functioning outcome, but does not report a multiplicity strategy, a hierarchy for other outcomes, or how analyses were selected for reporting. It is therefore not possible to determine how multiplicity was handled.

The record describes the primary endpoint population as participants with baseline and participating-period HRQoL data from baseline to ≤6 months. It does not report how many participants had the required data, how many lacked follow-up measurements, or why data were missing. It also does not report whether missing measurements were handled by complete-case analysis, imputation, a repeated-measures model, or another method. These methods have different assumptions. In general, missing-data methods cannot fully correct bias when the chance of missingness depends on unobserved outcomes unless additional assumptions or sensitivity analyses are used. No missing-data assumptions or sensitivity analyses are reported in the registry record.

The analysis populations are not described beyond the endpoint-specific population definition. The registry record does not say whether all enrolled participants, a treated subset, or another defined population contributed to each outcome analysis. It also does not report how deviations from the planned assessment schedule were handled. Without the analysis population sizes, participant flow, and missing-data details, readers cannot assess how representative the analyzed observations were of the enrolled group or how robust the estimates might be to missingness.

12. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: chronic obstructive pulmonary disease (8.7%), pneumonia (4.7%), respiratory failure (3.9%), respiratory tract infection (2.4%), cardiac failure congestive (1.6%).

The registry lists an overall study group with 127 at risk in the serious adverse-event entry and 127 at risk in the other adverse-event entry. It lists 39 affected in the serious entry and 97 affected in the other entry. These are separate adverse-event listings, and the figures should not be added together to infer a unique number of people with any event. The record does not specify in the posted safety summary whether affected counts refer to participants with at least one event or another counting convention.

The listed serious-event terms include chronic obstructive pulmonary disease at 8.7%, pneumonia at 4.7%, respiratory failure at 3.9%, respiratory tract infection at 2.4%, cardiac failure congestive at 1.6%, and chest pain at 1.6%. These term percentages are descriptive registry entries. The record does not provide event-level timing, severity details beyond the serious-event classification, exposure-adjusted rates, or a control group for comparison. It also does not report whether events were judged related to ARALAST. The deaths field is not reported in the registry record.

Consequently, these entries describe reported safety observations in the study group; they do not establish comparative risk or causation. The registry record does not report the detail needed to determine how the figures were constructed or how follow-up duration varied across participants.

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

The study’s registered primary question concerns the change in SF-36 physical functioning from baseline to ≤6 months among participants with the specified HRQoL data. The measure is patient-reported, scored from 0 to 100, and interpreted with higher scores representing better health. These details clarify what the endpoint was intended to capture. They do not reveal what change was observed: the mean change and its uncertainty are not reported in the registry record.

As a result, the record does not establish whether the average physical-functioning score increased, decreased, or remained similar, nor how precisely any estimate was measured. It also does not support a conclusion about whether a change was clinically important. The registry does not report a threshold for meaningful change or the endpoint result needed to assess one.

Even if an observed before-and-after change were available, this single-group, non-randomized study could not by itself show that ARALAST caused it. There is no control group to distinguish treatment-associated change from the course of health over time, other clinical care, or other influences. The design is useful for surveillance and descriptive follow-up, but it is not a randomized estimate of comparative treatment effect.

The safety entries give descriptive counts and selected percentages, not comparative estimates. The registry does not report a control group, treatment attribution for events, or sufficient event detail to infer causation from the listed terms. Nor do the listed healthcare utilization outcomes establish changes in resource use because their numerical results are not reported in the registry record.

In short, the record documents a study aimed at observing patient-reported health, resource use, and safety in people initiating ARALAST, and it includes limited safety figures. It does not report the primary outcome result or the information needed to quantify a comparative effect. Any interpretation should distinguish the study’s aims and outcome definitions from evidence about the outcomes actually observed.

14. Why This Trial Matters Statistically

This study is statistically relevant because it illustrates the difference between defining an outcome and reporting an estimate. The registry gives a detailed description of a patient-reported primary measure, its scoring direction, and its follow-up window. Without the numerical change and a measure of uncertainty, however, readers cannot judge the observed pattern or its precision. Clear endpoint definitions are necessary for interpretation, but they cannot substitute for outcome results.

The design also makes the boundary between surveillance and causal inference especially important. A prospective study can collect information over time in a structured way, and an open-label single-group study can describe experiences among people receiving care. But without randomization or a comparison group, temporal change is not equivalent to a treatment effect. Statistical adjustment, if performed, cannot automatically supply the missing counterfactual, and the registry record does not report an adjustment plan.

The range of registered outcomes—from physical functioning to utilization and laboratory assessment—also highlights why analysis plans matter. Multiple measures can answer different descriptive questions, but readers need to know which were primary, how analyses were conducted, how missing data were handled, and whether multiplicity was addressed. The record identifies a primary endpoint but does not report these statistical details or the endpoint results.

Finally, safety summaries require attention to denominators, event definitions, follow-up, and attribution. The record lists overall affected counts and selected serious-event percentages, but the available information does not support comparison or causal claims. Taken together, the study is a useful example of why registry design details and posted results answer different questions: the former describe what investigators intended to assess; the latter are needed to evaluate what the data show and how certain those findings are.

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 registry record does not report the primary physical-functioning result, its standard deviation, a confidence interval, or a statistical test. It also does not report numerical findings for the listed healthcare resource utilization outcomes or the laboratory assessments. This prevents evaluation of the direction, magnitude, and precision of the main outcome and limits interpretation of the broader study aims.

The single-group, non-randomized, open-label design lacks a direct control comparison. Changes over time therefore cannot be separated from other changes in health or care on the basis of this design alone. Patient-reported outcomes may also be sensitive to expectations or reporting conditions as a general matter, but the registry does not describe measures to reduce those influences.

The record does not report participant flow, completion of scheduled visits, the number included in each analysis, reasons for missing data, or methods used to address missing measurements. It does not describe the statistical model, adjustment variables, multiplicity handling, or the analysis populations beyond the primary endpoint’s data-availability description. The reason for termination and the reason enrollment is recorded as 127 while the brief summary describes enrollment of up to 120 are not reported in the registry record.

The safety summary is limited: the record does not provide event timing, exposure-adjusted rates, treatment-relatedness assessments, or a comparator. The deaths field is not reported. The record also does not report the original sample-size justification. These omissions constrain both statistical and clinical interpretation; they should not be filled by assumptions about how the study may have been conducted.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Aralast alpha1-proteinase Inhibitor Surveillance Study — NCT00313144.
• Registry record last updated 2021-05-26; status last verified 2021-05.
• Results first posted 2011-08-26.
• 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

This Phase 4 surveillance study evaluated ARALAST in people with alpha1-antitrypsin deficiency. It was prospective, non-randomized, open-label, and single-group. The registry records enrollment of 127, study status as terminated, a start date of 2006-06-09, and primary completion on 2008-12-01.

The primary outcome was change in SF-36 physical functioning from baseline to ≤6 months. The registry describes the score range and direction but does not report the primary result or its uncertainty. It also lists healthcare resource outcomes and safety assessments without reporting their numerical results.

The safety summary lists 39 affected in the serious adverse-event entry and 97 affected in the other adverse-event entry, with 127 at risk in each listing, plus percentages for selected serious-event terms. The record does not provide a control comparison or enough detail for causal interpretation. Missing-data methods, multiplicity handling, the original sample-size justification, and the reason for termination are not reported in the registry record.