A Study to Evaluate the Safety and Effect of Escalating Doses of CINRYZE: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate the Safety and Effect of Escalating Doses of CINRYZE (NCT00914966), a na phase 4 study. The primary outcome is Number of Subjects With Adverse Events, Hospitalizations, Thrombotic Events, Treatment-emergent C1 INH Antibodies, Post-baseline Toxicity Grade Increases in Clinical Laboratory Parameters, and Post-dose Vital Signs Changes of Potential Clinical Importance.

2. Clinical Question

These questions address different kinds of evidence. Safety counts describe how often specified events were recorded in the study population. Attack-rate outcomes concern disease episodes over time. Neither type of result, by itself, establishes what would have happened under a different treatment or without treatment. A concurrent control group is not reported, so the record does not offer a randomized comparison that could distinguish changes associated with dose escalation from changes that might have occurred for other reasons.

The registry record identifies the study as Phase 4 and lists its status as completed. It does not report numerical attack-rate results or inferential estimates for the primary question. The available safety counts can be described as observed participant counts at each dose level, but they do not provide a controlled estimate of a treatment effect.

3. Trial Design

This was a Phase 4, single-group study sponsored by Shire, with 20 participants enrolled. The registry lists hereditary angioedema as the condition and identifies the intervention as C1 inhibitor (human). Allocation is listed as not applicable, and masking is listed as none. The study status is completed. Its recorded start date is 2009-08-31 and its primary completion date is 2012-05-24.

The CINRYZE arm description identifies three potential dose steps: 1500 Units, 2000 Units, and 2500 Units. For the 1500-Unit and 2000-Unit steps, it specifies administration by intravenous infusion twice per week for 12 weeks at each dose. The description of the third step does not provide a complete regimen in the registry record, so its schedule should not be inferred from the earlier steps.

A single-group design means that participants are not assigned to separate randomized treatment and control groups. The dose-level counts are therefore not a like-for-like controlled comparison. Participants recorded at risk differ by dose level: 20 at Step 1, 13 at Step 2, and 12 at Step 3. The registry does not describe the reasons for these changing denominators or provide enough detail to establish how participants entered or left each dose step.

The stated objectives were to assess safety and tolerability, assess the effect of an escalating-dose algorithm on hereditary angioedema attack rates, and assess immunogenicity. The primary outcome description focuses on safety measures over 12 to 24 weeks at each dose level. It also states that events reported during the 3 month follow-up period are counted with the dose level at which they occurred.

The registry record does not report a randomized allocation procedure, a masking procedure beyond listing none, or a concurrent control group. It also does not report the rules governing dose escalation, the planned statistical analysis, or a sample-size justification. Those features cannot be reconstructed from the design label or the observed counts.

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.

Step 1: 1500 Units

Reasons for not completing this period:

Step 2: 2000 Units

Reasons for not completing this period:

Step 3: 2500 Units

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 Number of Subjects With Adverse Events, Hospitalizations, Thrombotic Events, Treatment-emergent C1 INH Antibodies, Post-baseline Toxicity Grade Increases in Clinical Laboratory Parameters, and Post-dose Vital Signs Changes of Potential Clinical Importance, measured over 12 to 24 weeks at each dose level.

The primary outcome is a count of participants with one or more specified safety findings: adverse events, hospitalizations, thrombotic events, treatment-emergent C1 INH antibodies, post-baseline increases in toxicity grade for clinical laboratory parameters, and post-dose changes in vital signs judged to be of potential clinical importance. The unit is participants, and the outcome parameter is listed as a number rather than a rate or a time-to-event measure.

The registry gives the timeframe as 12 to 24 weeks at each dose level. It specifies that events reported during the 3 month follow-up period are counted with the dose level at which they occurred. The endpoint therefore organizes safety observations by dose level, while the all-subjects result provides a broader count across the study population.

In general, safety endpoints of this kind are used to describe the occurrence of harms and clinically monitored changes during treatment. Including several kinds of findings can make a safety assessment broader than a count of a single event type. However, a composite-style endpoint can combine events that differ substantially in nature and severity. The overall count should not be interpreted as though every listed event had the same clinical meaning.

The registry does not give detailed thresholds for the laboratory or vital-sign changes, nor does it report a separate numerical result for every component of the primary outcome. The grouped adverse-event counts are not a substitute for component-level results. The stated objective also includes immunogenicity, but detailed antibody findings are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a single-group design, no masking, and allocation as not applicable. These design features shape what statistical conclusions can be drawn. A randomized controlled comparison can help separate treatment-related differences from differences that arise because groups vary by chance or receive different care. In a single-group study, there is no such concurrent comparison. Counts can describe what was recorded among participants, but they cannot directly estimate a difference from a control condition.

What do participant counts represent?

The primary outcome uses participants as its unit and a number as its parameter. A participant count answers how many people met the outcome definition within the specified group and observation period. It is not the same as an event count: one participant may have more than one event, while the participant-level measure may count that person once for a particular outcome. The registry’s aggregate figures do not provide enough detail to determine all event-level patterns or overlaps.

The dose-level results have different numbers at risk: 20 for Step 1, 13 for Step 2, and 12 for Step 3. In general, a denominator is essential for interpreting a count because the same count can represent different proportions in groups of different sizes. The counts can be read with their reported denominators, but no new proportion or cross-dose comparison is needed to describe the registry results. The reason for the differing denominators is not reported in the registry record.

Why does the design limit dose comparisons?

In a nonrandomized, single-group dose-escalation study, later dose-level observations may not be directly comparable with earlier ones. Participants may contribute observations at more than one dose, and the number at risk can change across steps; the registry does not specify participant-level transitions in sufficient detail. Observation duration may also vary within the stated timeframe. In general, comparing raw counts across dose levels without accounting for these features can be misleading. The record does not report an analysis that adjusts for them.

Masking is listed as none. In general, lack of masking can affect the reporting or assessment of outcomes, especially outcomes that involve judgment. The extent of any such effect cannot be determined from the registry record. The listed endpoint includes findings such as laboratory-grade changes and vital-sign changes, but detailed assessment rules are not reported.

What can inferential statistics add?

Inferential analyses use statistical models to quantify uncertainty and, where the design permits, estimate contrasts between conditions. Confidence intervals describe the uncertainty around an estimate under stated assumptions; hypothesis tests assess compatibility with a specified null model. Neither can correct for a lack of a suitable comparison group, and their interpretation depends on the analysis plan and the data structure. The registry lists 0 analyses. Comparative estimates, confidence intervals, and p-values are not reported in the registry record.

The study also lists attack rates as a secondary outcome. Rate analyses generally require a definition of the observation period and a method for handling differences in time at risk. The registry record does not report numerical attack-rate results, the exact analysis method, or how varying observation time was handled. No particular model, distributional assumption, or adjustment method should be attributed to the study.

What does the planning illustration mean?

Sample-size illustrations based on an observed effect are planning exercises, not findings from the trial and not evidence that the trial had a particular probability of detecting an effect. The stated illustration assumes a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect expressed as a fraction of the observed effect. Those assumptions do not describe the single-group design of this study. The illustration is not the trial’s own sample-size justification, and the registry record does not report such a justification. Sample sizes in a planning exercise are not observed power.

More generally, statistical precision depends on the amount and structure of the data, the outcome definition, and the analysis method. A small number of observed participants can leave estimates imprecise, but no precision estimate is available for these results. The registry’s event counts are useful as descriptive observations; they should not be converted into unreported inferential claims.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists two outcome measures, including the primary safety measure and a secondary outcome concerning hereditary angioedema attack rates. It lists 0 analyses. A statistical analysis plan specifying which outcomes were tested, which comparisons were intended, or how results would be selected for reporting is not reported in the registry record.

When a study examines multiple outcomes or makes multiple statistical tests, the chance of at least one apparently unusual result can increase. In general, multiplicity methods define how that issue is handled, for example by adjusting interpretation or by identifying a primary analysis in advance. The record does not report whether any multiplicity adjustment was planned or used. Because inferential results are not reported, no conclusion about such adjustments can be drawn.

Missing-data procedures are also not reported in the registry record. The record gives numbers at risk for each dose level, but does not explain why these numbers differ, whether observations were missing, or how missing measurements were handled. A changing number at risk is not, by itself, evidence of missing outcome data or a particular reason for participant non-observation.

The analysis populations are not described. The registry does not state which participants were included in each outcome analysis, how participants who did not complete a dose step were handled, or whether the analysis followed any prespecified population definition. These details matter because the set of participants used for an analysis can affect both the estimate and its interpretation. No unreported method should be assumed.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cerebral hygroma (8.3%), anemia (7.7%), bile duct stone (7.7%), hereditary angioedema (5.0%).

The serious-event counts are 1 of 20 at Step 1, 1 of 13 at Step 2, and 1 of 12 at Step 3; the all-subjects count is 2 of 20. The registry separately lists other-event counts of 12 of 20, 5 of 13, 6 of 12, and 13 of 20 for those same groups. These figures are participant counts with the reported numbers at risk, not event totals or comparative estimates.

Serious events and other events are distinct reported categories and should not be treated as interchangeable measures of severity. The registry also lists serious-event terms and percentages: Cerebral hygroma (8.3%), Anemia (7.7%), Bile duct stone (7.7%), and Hereditary angioedema (5.0%). The record does not specify enough detail to assign those percentages to a particular dose group or explain their precise denominator. They should therefore be read as listed terms, not as dose-specific risks.

Deaths are not reported in the registry record. The available counts do not establish causation, and the lack of a control group means they cannot show whether the event counts differ from what would occur under another condition. Detailed participant-level timing and overlap among events are not reported.

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

The results establish that the registry records serious and other adverse events among participants at each listed dose level and across all subjects. They also show that the numbers at risk differ by dose level. This is descriptive evidence about events recorded during the study, not a controlled estimate of the effect of CINRYZE on safety outcomes.

The record’s primary outcome covers several domains, including adverse events, hospitalizations, thrombotic events, treatment-emergent C1 INH antibodies, laboratory toxicity-grade increases, and potentially important vital-sign changes. The posted aggregate counts do not give a complete component-by-component account. The listed serious-event terms add some detail, but the registry does not state how the percentages map to dose levels or provide enough information to reconstruct individual event histories.

The study objectives also include attack rates and immunogenicity. Numerical attack-rate results and detailed immunogenicity findings are not reported in the registry record. Therefore, the available figures do not quantify a change in attacks or establish an immunogenicity result. No comparative statistical estimates are reported, and no conclusion about efficacy or a dose-response pattern can be drawn from the safety counts.

In general, a controlled comparison helps estimate how outcomes differ between treatment conditions, while a single-group study mainly describes observations in the group studied. Here, the lack of a separate control group, the unmasked design, and changing numbers at risk limit the interpretation of dose-level contrasts. The counts also do not explain why a participant experienced an event or whether the event was caused by treatment.

The appropriate statistical meaning is therefore bounded: these are registry-reported safety observations from a completed Phase 4, single-group study with 20 enrolled participants. They are not proof that a treatment is beneficial or harmful, and they do not determine how results would compare with another treatment or with no treatment.

13. Why This Trial Matters Statistically

This study illustrates why design and outcome definition matter when reading clinical-trial statistics. A dose-escalation record can report safety observations at several dose levels, but dose-level counts are not automatically a controlled dose comparison. The numbers at risk differ across the steps, and the registry does not report a randomized control group or an adjusted analysis. Treating the step counts as if they came from equivalent parallel groups would overstate what the design can support.

The primary endpoint also demonstrates the distinction between a broad safety measure and its individual components. A single participant count can bring together events, laboratory changes, and vital-sign findings, even though those findings may differ in type and importance. Component-level detail is needed to understand what contributes to an aggregate safety result. The registry’s broad endpoint definition and limited breakdown make that distinction especially important.

The record also makes clear that descriptive results and inferential results answer different questions. Counts describe what was recorded among the participants. A comparative estimate would address how outcomes differ between conditions, with uncertainty quantified under an analysis model. No such estimates are reported. The small enrolled population and absence of a separate comparator further limit the conclusions that can be drawn from the posted results.

Finally, the registry identifies attack rates and immunogenicity as objectives, but numerical results for those outcomes are not reported. A reader should not treat the presence of an outcome in a registry entry as evidence that its results are available or statistically interpretable. This distinction is central to careful evidence appraisal: study objectives, observed descriptive counts, and supported comparative conclusions are not the same thing.

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 central limitation is the single-group design. No separate control group is reported, so the observed counts cannot be interpreted as differences attributable to CINRYZE relative to another condition. Allocation is listed as not applicable, and masking is listed as none. These design features constrain both causal interpretation and the comparability of observations across dose levels.

The study enrolled 20 participants, while the numbers at risk listed by dose level are 20, 13, and 12. The registry does not explain the changes in these denominators, describe participant transitions through the dose steps, or report how incomplete follow-up was handled. Because the dose-level groups may not represent comparable sets of observations, raw counts should not be used to infer a dose trend.

The primary outcome includes multiple safety domains, but the record does not report complete component-level results or detailed event histories. The timeframe is given as 12 to 24 weeks at each dose level, with events during the 3 month follow-up period assigned to the dose level at which they occurred. The record does not provide additional detail about exposure duration, event overlap, or the criteria for the laboratory and vital-sign findings.

Further limitations are the absence of reported attack-rate and immunogenicity results, the absence of inferential analyses, and the lack of a reported statistical analysis plan. The registry does not report missing-data procedures, analysis-population definitions, or the sample-size rationale. The third dose-step regimen is not fully specified in the registry record. Together, these omissions prevent a more complete assessment of the analysis and its uncertainty.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study to Evaluate the Safety and Effect of Escalating Doses of CINRYZE — NCT00914966.
• Registry record last updated 2021-06-23; status last verified 2021-06.
• Results first posted 2013-07-18.
• 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.

18. Record Summary

The registry record describes NCT00914966, a completed Phase 4 study sponsored by Shire, with 20 participants enrolled and hereditary angioedema listed as the condition. It evaluates escalating doses of CINRYZE in subjects with inadequately controlled attacks. The study is single-group, with allocation listed as not applicable and masking listed as none.

The primary outcome concerns participant counts for specified safety findings over 12 to 24 weeks at each dose level. The registry reports serious and other adverse-event counts by dose step and for all subjects. It also lists attack rates as a secondary outcome and immunogenicity as a study objective, but numerical results for these outcomes are not reported in the registry record.

Comparative analyses, confidence intervals, p-values, missing-data procedures, analysis populations, and the sample-size rationale are not reported. The safety counts are descriptive observations and do not establish treatment causation or a dose-response effect.