This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Subcutaneous Treatment With Icatibant for Acute Attacks of Hereditary Angioedema (NCT00097695), a randomized phase 3 study. The primary outcome is Time to Onset of Symptom Relief (TOSR).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00097695 |
| Phase | Phase 3 |
| Condition | Angioedema |
| Allocation | Randomized |
| Design model | Single Group |
| Masking | Double |
| Enrollment | 84 |
| Arms in the primary outcome | 2 |
| Lead sponsor | Shire |
| Results posted | Yes |
2. Clinical Question
Population
Patients with hereditary angioedema who experienced moderate to very severe acute cutaneous and/or abdominal attacks during the controlled phase. The primary endpoint population is described as the intention-to-treat population. The overall registry enrollment was 84, but enrollment is not the same as the number included in this endpoint comparison.
Intervention
Subcutaneous icatibant, a bradykinin antagonist, given for an eligible acute attack. The registry describes randomized patients assigned to icatibant after an eligible first in-study attack.
Comparator
Placebo during the randomized controlled phase. Patients with laryngeal symptoms at baseline were not randomized and received open-label icatibant; they are not part of the randomized icatibant-versus-placebo comparison.
Primary question
Among the patients in the endpoint population, how long after injection did patients first document symptom relief, and how did the time distribution in the randomized icatibant group compare with that in the randomized placebo group? Relief was assessed by the patient using a Visual Analogue Scale.
The clinical question concerns the timing of initial symptom relief, not whether every symptom resolved, how long relief lasted, or whether attacks were prevented. The registry defines the primary symptom according to attack type: abdominal pain for abdominal attacks, or the more severe of skin swelling and skin pain for cutaneous attacks. The listed results concern the controlled phase and the patients experiencing moderate to very severe acute cutaneous and/or abdominal attacks. The registry separately describes nonrandomized laryngeal-attack patients and patients who did not receive treatment during the controlled phase. Those groups do not form the randomized comparison used for the primary result.
3. Trial Design
The registry describes a Phase 3 randomized, double-blind, placebo-controlled, multicenter study of a subcutaneous formulation of icatibant. Its stated purpose was to assess efficacy and safety for acute cutaneous and/or abdominal attacks in patients with hereditary angioedema. The trial is marked completed, with enrollment of 84. The registry lists Shire as the sponsor.
The controlled comparison was not simply a comparison of everyone enrolled. Randomization followed an eligible first in-study attack: one group was randomized to icatibant and another to placebo. In the primary endpoint population, the registry lists 27 patients in the randomized icatibant group and 29 in the randomized placebo group. The endpoint description identifies the population as intention-to-treat patients experiencing moderate to very severe acute cutaneous and/or abdominal attacks.
Other participants were handled differently. Patients with laryngeal symptoms at baseline were not randomized and received open-label icatibant during the controlled phase. The registry also describes eligible patients who had no attack, or an attack not severe enough to merit treatment, while the controlled phase was ongoing; these patients were not treated during that phase and were treated with icatibant during the open-label extension. These pathways should not be folded into the placebo-controlled estimate.
Although the study is described as randomized and double-blind, the registry's analysis model is labeled single group. That label does not alter the explicit treatment-group listings or the reported two-group test, but its meaning for the analysis is not explained in the registry record. Further details about the randomization procedure, allocation concealment, blinding implementation, treatment schedule, and protocol-defined analysis plan are not reported in the registry record. The registry gives the primary endpoint timeframe as 5 days.
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: Patients must have an eligible HAE attack to be randomized.64 patients were in the controlled phase(27icatibant,29 placebo,8subjects with laryngeal attacks were treated with open label icatibant).A total of 72 were treated in the open label phase(20 entered directly into the OLE phase+ 52 from the controlled phase).
The Controlled Phase
| Stage | Randomized -Icatibant | Randomized -Placebo | Controlled Open-label / Laryngeal Attack | Untreated Patients at the Baseline |
|---|---|---|---|---|
| STARTED | 27 | 29 | 8 | 20 |
| COMPLETED | 23 | 26 | 3 | 0 |
| NOT COMPLETED | 4 | 3 | 5 | 20 |
The Open Label Extension (OLE) Phase
| Stage | Randomized -Icatibant | Randomized -Placebo | Controlled Open-label / Laryngeal Attack | Untreated Patients at the Baseline |
|---|---|---|---|---|
| STARTED | 23 | 26 | 3 | 20 |
| COMPLETED | 10 | 11 | 1 | 15 |
| NOT COMPLETED | 13 | 15 | 2 | 5 |
Analysis population for the primary outcome, as defined in the registry: Time to onset of symptom relief - Controlled phase - ITT population (patients experiencing moderate to very severe acute cutaneous and/or abdominal HAE attacks)
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.
| Characteristic | Unit | Randomized -Icatibant | Randomized -Placebo | Controlled Open-label / Laryngeal Attack | Untreated Patients at the Baseline | Total |
|---|---|---|---|---|---|---|
| Participants analysed | 27 | 29 | 8 | 20 | 84 | |
| Age, Continuous | Years | 34.8 (SD 9.81) | 34.9 (SD 11.37) | 47.1 (SD 13.86) | 37.4 (SD 11.48) | 36.6 (SD 11.5) |
| Sex: Female, Male: Female | Participants | 16 | 21 | 5 | 15 | 57 |
| Sex: Female, Male: Male | Participants | 11 | 8 | 3 | 5 | 27 |
6. Primary Endpoint
The registry lists the primary outcome as Time to Onset of Symptom Relief (TOSR), measured over 5 days.
| Element | Registry entry |
|---|---|
| Result type | Median |
| Measure of spread | Inter-Quartile Range |
| Unit | Hours |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is time to onset of symptom relief, measured in hours. It records the time between injection and the first documented onset of relief for the relevant primary attack symptom. The patient assessed symptom intensity using a Visual Analogue Scale, a horizontal 10cm line anchored at no symptoms and the patient's worst symptoms ever experienced. Patients marked the line to indicate their current symptom state at baseline and at predetermined assessment times during treatment.
The symptom used for the endpoint depended on attack type. Abdominal pain was the single primary symptom for abdominal attacks. For cutaneous attacks, the primary symptom was either skin swelling or skin pain, whichever was more severe. The registry defines onset of relief as the first documented symptom improvement, not almost complete relief. Time to almost complete symptom relief is listed as a secondary outcome, as is patient-assessed time to regression, or start of improvement.
Time-to-event endpoints are useful when the question is how soon an event occurs, rather than only whether it occurs by one fixed assessment. A median gives a central point in the observed event-time distribution, while an inter-quartile range describes the middle portion of that distribution. As a general statistical point, time-to-event analysis can also account for participants whose event time is not observed during follow-up, but the handling of such observations is not reported in the registry record. The posted primary result summarizes time to onset of relief over the stated 5 days; it does not, by itself, describe the duration or completeness of relief.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted median time to onset of symptom relief was 2.5 hours in the randomized icatibant group and 4.6 hours in the randomized placebo group. The reported inter-quartile ranges were 1.1 to 6.0 hours and 1.8 to 10.2 hours, respectively. Descriptively, the listed median is shorter in the icatibant group. These summaries do not give a complete picture of each participant's event time, and the inter-quartile ranges describe within-group distributions rather than uncertainty around a treatment effect.
The registry reports a Wilcoxon version of the log-rank test with p = 0.142. This test evaluates evidence of a difference in the time-to-event distributions under its assumptions; the p-value is not the probability that the treatments are equivalent, nor the probability that the null hypothesis is true. A p-value of 0.142 does not provide strong statistical evidence against the null hypothesis under commonly used testing conventions. It does not establish that the groups are the same, and it does not quantify the size or precision of a treatment effect on its own.
No comparative effect estimate or confidence interval is reported for this test. The intervals attached to the group medians are identified in the registry endpoint as inter-quartile ranges, not confidence intervals. It would therefore be incorrect to read them as confidence limits for the difference between groups. The registry also does not report a hazard ratio or another effect measure that would directly characterize the relative timing across the full follow-up period.
The endpoint population lists 27 patients assigned to icatibant and 29 assigned to placebo. These figures are smaller than the overall enrollment of 84 because the primary comparison is restricted to the eligible randomized attack population, rather than all enrolled participants. The registry does not explain all transitions from enrollment to endpoint analysis, nor how incomplete follow-up was handled. Interpretation should remain focused on the reported comparison and should not extend it to the nonrandomized laryngeal-attack group or the open-label extension.
The results are summaries of a patient-reported symptom endpoint. The use of a Visual Analogue Scale makes the measured outcome directly connected to patients' assessments, but it also means the endpoint depends on reported symptom intensity and assessment timing. The registry gives no assessment schedule beyond saying that assessments occurred at predetermined time points. Overall, the posted summaries show a lower median time in the icatibant group, while the reported comparative test does not supply strong evidence of a group difference. Neither observation establishes equivalence or resolves the uncertainty about the size and precision of a comparative effect.
9. Statistical Methods Explained
The primary outcome is a time-to-event measure: the event is the first documented onset of symptom relief after injection. Time is measured in hours, and the registry sets the endpoint timeframe as 5 days. Patients rated symptom intensity using a Visual Analogue Scale, with symptom relief identified from their symptom assessments. The endpoint therefore concerns when relief first appeared, not the amount of symptom improvement at a single final visit.
What does a median time mean?
As a general statistical explanation, the median is the point that divides an ordered set of observed times into two halves. It is a measure of central tendency that is less dependent on unusually long times than a mean can be. The reported median was 2.5 hours for randomized icatibant and 4.6 hours for randomized placebo. Those values summarize each group separately; they are not a direct estimate of the difference between treatment groups.
The registry identifies the spread as an inter-quartile range. In general, an inter-quartile range describes the central half of a distribution, from its lower quartile to its upper quartile. The reported ranges are 1.1 to 6.0 hours for icatibant and 1.8 to 10.2 hours for placebo. These ranges show variation in the observed times within each arm. They are not confidence intervals for the median or for a between-group effect. The registry does not describe the method used to calculate uncertainty around the medians.
How should the reported test be understood?
The registry reports a Wilcoxon version of the log-rank test. In general, log-rank-family tests compare event-time distributions between groups while accounting for the ordering of event times; the Wilcoxon version gives relatively more weight to earlier events than the conventional log-rank test. That description is general and does not establish how every detail of the test was implemented in this trial. The registry does not report the test's exact weighting specification, treatment of ties, censoring rules, or other implementation details.
The reported p-value is 0.142. A p-value measures how incompatible the observed test result is with a specified null model, assuming that model and the test assumptions apply. It is not a measure of clinical importance, does not give the probability that the null hypothesis is true, and does not show the probability that the observed difference arose by chance in a literal sense. A p-value also does not tell how large or precise a treatment effect is. The registry reports no comparative confidence interval or effect estimate alongside this test.
Why does the time-to-event structure matter?
As a general matter, time-to-event methods are designed for outcomes where both whether an event occurs and when it occurs are relevant. A participant may have a documented relief time, or the observation period may end before relief is documented. Statistical methods can use incomplete event-time information through censoring, but the registry record does not report whether censoring occurred or how it was handled. It also does not report the number of events contributing to the analysis. Without those details, readers cannot independently assess how much information contributed to the comparison or how the analysis treated participants without an observed event.
The endpoint relies on patient ratings collected at predetermined time points. In general, when an event is detected between assessments, the recorded onset can depend on the assessment schedule. The registry does not list that schedule, nor does it give information about missing ratings or the rules used to determine a first documented relief time. These are relevant features of a patient-assessed time-to-event measure, but their absence does not justify assuming a particular schedule or data-handling approach.
What is the analysis population?
The registry calls the primary endpoint population the intention-to-treat population and describes it as patients experiencing moderate to very severe acute cutaneous and/or abdominal attacks during the controlled phase. The posted arm counts are 27 for randomized icatibant and 29 for randomized placebo. In general, an intention-to-treat analysis aims to preserve the randomized comparison by analyzing participants according to their assigned group. The registry does not report the detailed operational definition, deviations, or exclusions used to produce these endpoint counts, so the label alone does not resolve how the population was implemented.
Randomized patients with eligible first in-study attacks were assigned to icatibant or placebo. Patients with laryngeal symptoms at baseline were instead treated open label and were not randomized. The separate open-label and untreated-at-baseline groups should not be treated as randomized controls when interpreting the primary test. The record does not report a fuller statistical analysis plan, prespecified test hierarchy, missing-data strategy, or adjustments for multiple outcomes. The listed method and p-value should therefore be read as the reported primary comparison, without assuming details that the registry does not state.
10. Analyses Reported by the Sponsor
| Method | Estimate | 95% CI | P-value |
|---|---|---|---|
| Wilcoxon version of the log-rank test | not reported | 0.142 |
The registry's posted comparison is the Wilcoxon version of the log-rank test, with p = 0.142. It also reports group medians and inter-quartile ranges: 2.5 hours and 1.1 to 6.0 hours for randomized icatibant, and 4.6 hours and 1.8 to 10.2 hours for randomized placebo. These are the reported summaries and inferential result.
No recalculated comparative effect estimate or confidence interval is reported in the registry record for this endpoint. The available figures do not support reconstructing the sponsor's time-to-event test from the group medians and inter-quartile ranges. A test based on individual event-time data cannot generally be reproduced from those summaries alone. The registry record also does not supply the participant-level event times or the details needed to duplicate the analysis.
There is no reported discrepancy between a sponsor analysis and a recalculated result. Accordingly, the posted test remains the basis for describing the comparative evidence. The fact that the icatibant median is lower is a descriptive comparison; it should not be presented as a separately recalculated treatment effect or as proof of a difference. The registry does not report additional details that would allow an independent assessment of the sponsor's analysis choices.
11. Multiplicity, Missing Data and Analysis Populations
The registry lists three outcome measures and three analyses, including the primary endpoint and two secondary outcomes: patient-assessed time to regression, or start of improvement, and time to almost complete symptom relief. The record does not report whether these outcomes were tested in a prespecified order, whether testing was adjusted for multiple comparisons, or whether any outcome was designated as supportive or exploratory. A multiplicity strategy is therefore not reported in the registry record.
As a general statistical point, when several outcomes or analyses are examined, the chance of at least one apparently notable result can increase if each is treated as an independent confirmatory test. Adjustment or a prespecified testing hierarchy can address that issue, but neither should be assumed. The primary test should be interpreted as the reported test, without inferring that the p-value was adjusted or that the secondary outcomes confirm it.
The endpoint population is labeled intention-to-treat, but details of its implementation are not reported in the registry record. The arm counts for the primary endpoint are 27 and 29. The overall enrollment was 84, and some participants followed nonrandomized or open-label pathways. The registry describes those pathways but does not give a complete accounting of the reasons participants were not included in the randomized endpoint comparison.
Missing ratings, withdrawals, loss to follow-up, censoring, and the handling of participants whose relief time was not documented are not reported in the registry record. Nor are the analysis assumptions for those situations. This matters because the primary endpoint is a time-to-event outcome assessed at predetermined times: incomplete observation and assessment timing can affect how event times are represented. Without the missing-data and censoring details, the reported medians and test cannot be independently reconstructed or fully evaluated for sensitivity to those choices.
The registry also does not report a full statistical analysis plan, sample-size justification, interim analyses, or a protocol-defined significance threshold for the primary test. These omissions do not invalidate the posted result, but they limit what can be inferred about planning, testing hierarchy, or the robustness of the analysis. Planning illustrations based on an observed effect, when presented, are hypothetical design calculations and are not observed power or evidence that the original trial was adequately powered.
12. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Controlled Phase- Icatibant (Randomized Subjects ) | 0 | 27 | 0.0% |
| Controlled Phase- Placebo (Randomized Subjects | 0 | 29 | 0.0% |
| Controlled Phase- Icatibant (Subjects w/ Laryngeal Attack) | 1 | 8 | 12.5% |
| Open Label Extension Phase- Icatibant (Previously Randomized) | 3 | 49 | 6.1% |
| Open Label Extension -Icatibant (Subjects w/ Laryngeal Attack) | 0 | 3 | 0.0% |
| Open Label Extension Phase(Untreated Patients at the Baseline) | 0 | 20 | 0.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Controlled Phase- Icatibant (Randomized Subjects ) | 12 of 27 |
| Controlled Phase- Placebo (Randomized Subjects | 19 of 29 |
| Controlled Phase- Icatibant (Subjects w/ Laryngeal Attack) | 6 of 8 |
| Open Label Extension Phase- Icatibant (Previously Randomized) | 39 of 49 |
| Open Label Extension -Icatibant (Subjects w/ Laryngeal Attack) | 3 of 3 |
| Open Label Extension Phase(Untreated Patients at the Baseline) | 17 of 20 |
Most frequent serious adverse event terms
| Event term | Organ system | Controlled Phase- Icatibant (Randomized Subjects ) | Controlled Phase- Placebo (Randomized Subjects | Controlled Phase- Icatibant (Subjects w/ Laryngeal Attack) | Open Label Extension Phase- Icatibant (Previously Randomized) | Open Label Extension -Icatibant (Subjects w/ Laryngeal Attack) | Open Label Extension Phase(Untreated Patients at the Baseline) |
|---|---|---|---|---|---|---|---|
| HAE attack | Congenital, familial and genetic disorders | 0 of 27 | 0 of 29 | 1 of 8 | 1 of 49 | 0 of 3 | 0 of 20 |
| Pancreatitis | Gastrointestinal disorders | 0 of 27 | 0 of 29 | 0 of 8 | 1 of 49 | 0 of 3 | 0 of 20 |
| Chest Pain | General disorders | 0 of 27 | 0 of 29 | 0 of 8 | 1 of 49 | 0 of 3 | 0 of 20 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Controlled Phase- Icatibant (Randomized Subjects ) | Controlled Phase- Placebo (Randomized Subjects | Controlled Phase- Icatibant (Subjects w/ Laryngeal Attack) | Open Label Extension Phase- Icatibant (Previously Randomized) | Open Label Extension -Icatibant (Subjects w/ Laryngeal Attack) | Open Label Extension Phase(Untreated Patients at the Baseline) |
|---|---|---|---|---|---|---|---|
| Hereditary angioedema | Congenital, familial and genetic disorders | 4 of 27 | 5 of 29 | 4 of 8 | 17 of 49 | 1 of 3 | 5 of 20 |
| Infections | Infections and infestations | 4 of 27 | 4 of 29 | 1 of 8 | 20 of 49 | 0 of 3 | 7 of 20 |
| Administration site conditions | General disorders | 3 of 27 | 4 of 29 | 0 of 8 | 11 of 49 | 1 of 3 | 3 of 20 |
| Headache/Migraine | Nervous system disorders | 0 of 27 | 2 of 29 | 2 of 8 | 0 of 49 | 2 of 3 | 1 of 20 |
| Nausea | Gastrointestinal disorders | 0 of 27 | 3 of 29 | 0 of 8 | 2 of 49 | 0 of 3 | 0 of 20 |
| Blood Creatine Phosphokinase Increased | Investigations | 1 of 27 | 0 of 29 | 0 of 8 | 1 of 49 | 1 of 3 | 2 of 20 |
| Dizziness | Investigations | 2 of 27 | 1 of 29 | 0 of 8 | 0 of 49 | 1 of 3 | 0 of 20 |
| Contusion | Injury, poisoning and procedural complications | 0 of 27 | 0 of 29 | 0 of 8 | 3 of 49 | 0 of 3 | 0 of 20 |
| Pruritus | Skin and subcutaneous tissue disorders | 0 of 27 | 2 of 29 | 0 of 8 | 0 of 49 | 0 of 3 | 0 of 20 |
| Nasal Congestion | Respiratory, thoracic and mediastinal disorders | 2 of 27 | 0 of 29 | 0 of 8 | 0 of 49 | 0 of 3 | 0 of 20 |
Serious events with the highest arm-level rate: hae attack (12.5%), pancreatitis (2.0%), chest pain (2.0%).
In the controlled phase, the registry records serious adverse events in 0 of 27 randomized icatibant subjects and 0 of 29 randomized placebo subjects. In the separate controlled-phase laryngeal-attack group treated with icatibant, it records 1 serious adverse event among 8 subjects. The open-label extension groups are also listed separately: 3 among 49 previously randomized subjects, 0 among 3 subjects with laryngeal attack, and 0 among 20 untreated-at-baseline patients. These groups differ in treatment and study phase and should not be combined into a randomized comparison.
The registry lists HAE attack at 12.5% among the top serious adverse event terms, with pancreatitis and chest pain each at 2.0%. The record does not provide enough context in these figures to establish a comparative risk for those specific terms, and they should not be treated as event rates for the randomized arms. The adverse-event listing also includes other adverse events: 12 of 27 in randomized icatibant and 19 of 29 in randomized placebo, with separate counts for the other cohorts.
These are descriptive counts from the registry. Serious adverse event counts do not alone capture all safety dimensions, and a zero recorded count in a group is not proof that an event cannot occur. Death counts are not reported in the registry record. The groups outside the randomized comparison, including open-label participants, cannot support the same direct causal comparison as the blinded randomized arms.
13. What the Result Does, and Does Not, Mean
The posted primary results describe time to first documented symptom relief for patients with eligible moderate to very severe acute cutaneous and/or abdominal hereditary angioedema attacks in the controlled phase. The reported median was 2.5 hours with randomized icatibant and 4.6 hours with randomized placebo. The registered group summaries are accompanied by inter-quartile ranges, and the reported Wilcoxon version of the log-rank test has p = 0.142.
These results do not establish that the two groups are equivalent. A p-value that does not provide strong evidence against a null model is not evidence that the null model is true. The record also does not provide a comparative confidence interval or effect estimate, so the precision of a between-group effect cannot be described from the reported summaries alone. The medians describe the centers of the separate group distributions; they do not capture the full distributions or quantify the uncertainty in a contrast.
The endpoint is initial patient-assessed symptom relief, not almost complete relief, sustained relief, attack prevention, or an overall assessment of every symptom. The record gives no basis for claims beyond this acute-attack endpoint. Its findings should not be extended to the nonrandomized laryngeal-attack cohort, the untreated-at-baseline participants, or the open-label extension as though those groups were part of the placebo-controlled comparison.
General interpretation of a randomized comparison also depends on the integrity of randomization, adherence to the analysis plan, completeness of follow-up, and handling of missing observations. The registry provides limited detail on those matters. The outcome is patient assessed, and the schedule of assessments is not reported in detail. These features limit the degree to which readers can evaluate measurement and analysis choices from the registry record alone.
The clearest conclusion is descriptive: the reported median time was shorter in the randomized icatibant arm, while the reported test did not show strong statistical evidence of a difference. The result neither proves benefit nor establishes no effect. It also does not answer whether the observed difference is clinically important, because a clinical importance threshold is not reported in the registry record.
14. Why This Trial Matters Statistically
This trial illustrates the distinction between a treatment-group summary and an inferential comparison. The medians, 2.5 hours and 4.6 hours, describe each arm separately. The Wilcoxon version of the log-rank test evaluates the time-to-event distributions using more than the two median values. A descriptive contrast and a formal test answer related but different questions, and neither should be substituted for the other.
The design also shows why analysis populations matter. Enrollment was 84, but the primary endpoint comparison includes randomized groups of 27 and 29 patients who experienced qualifying attacks. Some eligible patients were not randomized because they had laryngeal symptoms at baseline; others did not receive treatment during the controlled phase. Treating every enrolled participant as though they contributed to the same randomized comparison would blur important differences in study pathway and eligibility.
The primary outcome is patient-assessed and time-based. Such endpoints can convey when patients first report improvement, rather than only whether an event is present at one final assessment. At the same time, interpretation depends on how symptom ratings were collected and how event times that were not fully observed were handled. The registry gives the general measurement approach but leaves important analytic details unreported.
Finally, a p-value without a comparative effect estimate and confidence interval gives limited information about magnitude and precision. The result is a useful example of why statistical interpretation should consider the endpoint definition, analysis population, test, uncertainty, and missing-data information together. It also demonstrates the limits of what can be concluded from registry-level results when the detailed analysis plan and participant-level data are not available.
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 protocol's detailed statistical analysis plan, the rationale for the chosen test, or the test's exact implementation. It does not provide a comparative effect estimate or confidence interval for the primary endpoint. Consequently, readers cannot quantify the precision of a between-group effect from the reported medians and inter-quartile ranges alone, or reproduce the reported test using the posted summaries.
The time-to-relief endpoint is defined through patient ratings on a Visual Analogue Scale at predetermined time points, but the assessment schedule is not reported. The registry does not report how an onset between assessments was assigned, what rules defined a valid symptom change, or how missing symptom ratings were handled. Censoring and incomplete event-time observations are not described, and the number of documented relief events is not reported.
The primary comparison concerns a selected controlled-phase population: patients with moderate to very severe acute cutaneous and/or abdominal attacks. The overall enrollment of 84 should not be mistaken for the size of that endpoint population. The registry describes several other participant pathways, including nonrandomized laryngeal-attack treatment and open-label follow-up, but does not provide a complete flow accounting of all participants from enrollment through each analysis.
The record identifies a randomized, double-blind, placebo-controlled, multicenter study, yet does not report detailed procedures for allocation concealment, maintenance of masking, or deviations from assigned treatment. It also does not report the primary endpoint's prespecified significance threshold, sample-size justification, interim analysis plan, or approach to multiplicity. These details should not be inferred from the design label or from the reported p-value.
Finally, the safety listings include multiple study phases and groups with different treatment pathways. They are descriptive and do not all represent randomized comparisons. The registry does not provide death counts, and the serious adverse event term percentages are not accompanied by enough detail to interpret them as arm-specific comparative risks.
16. Related Tutorials
17. Related Statistical Calculators
18. Sources
- ClinicalTrials.gov: Subcutaneous Treatment With Icatibant for Acute Attacks of Hereditary Angioedema — NCT00097695.
- Registry record last updated 2021-06-09; status last verified 2021-05.
- Results first posted 2013-12-24.
- 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.
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19. Record Summary
The registry describes a completed Phase 3, randomized, double-blind, placebo-controlled, multicenter study of subcutaneous icatibant for acute hereditary angioedema attacks. Enrollment was 84. The primary endpoint was patient-assessed time to onset of symptom relief, measured in hours over 5 days, in the controlled-phase intention-to-treat population with moderate to very severe acute cutaneous and/or abdominal attacks.
The reported median times were 2.5 hours for randomized icatibant and 4.6 hours for randomized placebo, with inter-quartile ranges of 1.1 to 6.0 hours and 1.8 to 10.2 hours. The registry reports a Wilcoxon version of the log-rank test with p = 0.142. No comparative confidence interval or effect estimate is reported. The record also lists two secondary outcomes, separate nonrandomized and open-label participant groups, and adverse event counts by group. Important details of missing-data handling, multiplicity, and the full analysis plan are not reported in the registry record.