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 (HAE) (NCT00500656), a randomized phase 3 study. The primary outcome is Time to Onset of Symptom Relief..
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00500656 |
| Phase | Phase 3 |
| Condition | Hereditary Angioedema |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Double |
| Enrollment | 85 |
| Arms in the primary outcome | 2 |
| Lead sponsor | Shire |
| Results posted | Yes |
2. Clinical Question
Population
People with hereditary angioedema who experienced an attack during the controlled phase and were eligible for randomization. The registry record reports enrollment of 85 participants; 36 were included in the icatibant outcome group and 38 in the tranexamic acid outcome group. Participants with laryngeal symptoms at baseline were treated with open-label icatibant rather than randomized.
Intervention
Subcutaneous icatibant, described as a single 30 mg injection, alongside oral placebo. The randomized treatment description identifies the placebo capsules as taken orally over 2 days.
Comparator
Oral tranexamic acid, described as 1000 mg per dose, alongside subcutaneous placebo. The registry describes oral dosing over 2 days. The study was double blind and used a parallel-group design.
Primary question
Among randomized participants treated for an attack, how did time to first documented symptom relief compare between icatibant and tranexamic acid? The registry defined the primary endpoint as time to onset of symptom relief and reported medians of 2 hours for icatibant and 12 hours for tranexamic acid. It also reported a hazard ratio of 3.475, with a 95% confidence interval from 1.901 to 6.355 and p < 0.001.
The endpoint focused on the timing of relief rather than the proportion of participants with relief at a fixed time. The question therefore concerns the distribution of time until the specified symptom event was first recorded during the primary outcome timeframe of 2 days. The registry describes the primary symptom according to attack type: abdominal pain for abdominal attacks, and the more severe of skin swelling or skin pain for cutaneous attacks. The trial also listed time to almost complete symptom relief as a secondary outcome, as well as safety, tolerability, and pharmacoeconomics. Numerical results for those other assessments are not reported in the registry record.
3. Trial Design
NCT00500656 was a phase 3, randomized, double-blind, parallel-group, multicentre study. Its official title describes a comparison of a subcutaneous formulation of icatibant with oral tranexamic acid for treatment of hereditary angioedema. The registry lists enrollment of 85 participants and a completed study status. The recorded study dates are 2005-03-01 for start and 2006-07-25 for primary completion.
The randomized comparison used two treatment groups. Participants assigned to icatibant received a single 30 mg subcutaneous injection and oral placebo. Participants assigned to tranexamic acid received oral treatment described as 1000 mg per dose and a subcutaneous placebo. The regimen descriptions specify repeated oral dosing over 2 days. Matching placebos supported masking of the different routes of administration, and the registry identifies the study as double blind.
The primary outcome analysis included 36 participants in the icatibant group and 38 in the tranexamic acid group. These analysis-group counts do not add up to the enrollment total, and the reasons for the difference are not reported in the registry record. The registry also describes participants with laryngeal symptoms at baseline as receiving open-label icatibant rather than being randomized. Eligible participants who did not have an attack during the controlled phase, or whose attack did not merit treatment, were treated with icatibant in an open-label phase. These groups should not be conflated with the randomized comparison.
The registry describes the study as controlled and gives treatment details, but the specific allocation procedure, concealment procedures, site count, and detailed analysis plan are not reported in the registry record. No sample-size justification or interim-analysis plan is 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: 85 patients participated in the study(36 in the icatibant group and 38 in the tranexamic acid group)3 patients with laryngeal symptoms at Baseline.8 Patients were screened and found eligible but did not experience an angioedema attack, or had an attack that was not severe enough to merit treatment while the controlled phase was ongoing
Controlled Phase
| Stage | Randomized Controlled -Icatibant | Randomized Controlled-Tranexamic Acid | Controlled Open-label / Laryngeal Attack | Untreated Patients at the Baseline |
|---|---|---|---|---|
| STARTED | 36 | 38 | 3 | 8 |
| COMPLETED | 26 | 28 | 2 | 0 |
| NOT COMPLETED | 10 | 10 | 1 | 8 |
Open Label Extension (OLE) Phase
| Stage | Randomized Controlled -Icatibant | Randomized Controlled-Tranexamic Acid | Controlled Open-label / Laryngeal Attack | Untreated Patients at the Baseline |
|---|---|---|---|---|
| STARTED | 23 | 21 | 2 | 8 |
| COMPLETED | 16 | 9 | 1 | 6 |
| NOT COMPLETED | 7 | 12 | 1 | 2 |
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 Controlled -Icatibant | Randomized Controlled-Tranexamic Acid | Controlled Open-label / Laryngeal Attack | Untreated Patients at the Baseline | Total |
|---|---|---|---|---|---|---|
| Participants analysed | 36 | 38 | 3 | 8 | 85 | |
| Age, Continuous | years | 40.4 (SD 13.59) | 41.9 (SD 12.36) | 35.0 (SD 11.36) | 40.6 (SD 13.51) | 40.9 (SD 12.8) |
| Sex: Female, Male: Female | Participants | 24 | 23 | 1 | 7 | 55 |
| Sex: Female, Male: Male | Participants | 12 | 15 | 2 | 1 | 30 |
| Region of Enrollment: Austria | Participants | 3 | 4 | 0 | 1 | 8 |
| Region of Enrollment: France | Participants | 3 | 1 | 0 | 2 | 6 |
| Region of Enrollment: Germany | Participants | 13 | 12 | 0 | 0 | 25 |
| Region of Enrollment: Hungary | Participants | 3 | 3 | 0 | 0 | 6 |
| Region of Enrollment: Ireland | Participants | 0 | 1 | 0 | 0 | 1 |
| Region of Enrollment: Israel | Participants | 4 | 4 | 3 | 4 | 15 |
| Region of Enrollment: Italy | Participants | 3 | 5 | 0 | 1 | 9 |
| Region of Enrollment: Lithuania | Participants | 1 | 2 | 0 | 0 | 3 |
| Region of Enrollment: Poland | Participants | 1 | 2 | 0 | 0 | 3 |
| Region of Enrollment: Sweden | Participants | 3 | 2 | 0 | 0 | 5 |
6. Primary Endpoint
The registry lists the primary outcome as Time to Onset of Symptom Relief., measured over 2 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 was time to onset of symptom relief after treatment, measured in hours. The registry defines it as the interval from injection to the first documented onset of relief for the primary symptom associated with the attack. For an abdominal attack, that symptom was abdominal pain. For a cutaneous attack, it was either skin swelling or skin pain, whichever was more severe.
A time-to-event endpoint preserves information about when relief was first documented, rather than reducing the outcome to whether relief occurred by a single chosen time. A median describes the point by which half of the observed event-time distribution lies, subject to the analysis and its handling of censoring. The posted median was 2 hours for icatibant and 12 hours for tranexamic acid. The associated inter-quartile ranges were 1 to 3.5 hours and 3.5 to 25.4 hours, respectively.
As a general statistical point, time-to-event methods can account for participants whose event time is not observed during follow-up, but the registry excerpt does not state how censoring or missing symptom assessments were handled. The primary outcome timeframe was 2 days. The registry also lists time to almost complete symptom relief as a secondary assessment, but numerical results for that outcome are not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted primary outcome results describe shorter observed time to onset of symptom relief in the icatibant group than in the tranexamic acid group. The median was 2 hours among 36 participants in the icatibant outcome group and 12 hours among 38 participants in the tranexamic acid outcome group. The inter-quartile ranges were 1 to 3.5 hours and 3.5 to 25.4 hours, respectively. These summaries describe the recorded event-time distributions; they do not mean that every participant experienced relief at the group median.
The registry reports a hazard ratio of 3.475, with a 95% confidence interval from 1.901 to 6.355, using the Wilcoxon version of the log rank. The registry’s stated test compares the hazard rates under icatibant and tranexamic acid. In general, a hazard ratio contrasts the instantaneous event rates over follow-up, conditional on the analysis framework; it is not a ratio of the two medians. The direction and interpretation of a hazard ratio depend on how the event and group ordering are defined. The posted result is consistent with the registry’s reported median ordering, but the hazard ratio should not be read as saying that relief occurs 3.475 times sooner.
The reported 95% confidence interval excludes 1, and the reported p-value is p < 0.001. In general, a confidence interval expresses the uncertainty of an estimate under the statistical model and sampling assumptions. It does not provide the probability that the true effect lies inside the particular interval. A small p-value indicates that the observed data would be unusual under the specified null model, assuming the analysis assumptions hold; it does not measure clinical importance or remove uncertainty about bias and generalizability.
The record gives no details about the handling of censoring, missing observations, departures from the planned analysis, or adjustment for other factors. It therefore does not allow a full independent assessment of the time-to-event model assumptions. The numerical comparison applies to the randomized outcome groups reported for the controlled phase, not automatically to the open-label participants or every person enrolled. Also, enrollment was 85, whereas the primary outcome group counts were 36 and 38; reasons for this difference are not reported in the registry record.
The registry reports an additional outcome of time to almost complete symptom relief, but its numerical result is not reported in the registry record. It also lists safety, tolerability, and pharmacoeconomics as secondary areas without numerical results in the excerpt. Consequently, the primary time-to-relief result should not be treated as a complete account of all outcomes considered. It describes the posted comparison for one endpoint in this study, with the precision indicated by its interval and the limitations of the registry detail.
9. Statistical Methods Explained
The registry reports a time-to-event endpoint and a Wilcoxon version of the log rank analysis. These methods address when an event occurs, rather than simply comparing average or median values without regard to follow-up time. The event in this study was first documented onset of symptom relief for the attack’s designated primary symptom.
What does the median describe?
The median is the middle of an ordered set of event times, or an estimate of the time at which half the event-time distribution has occurred under the analysis. It offers a direct, interpretable summary of timing. The reported median was 2 hours for icatibant and 12 hours for tranexamic acid. The inter-quartile range describes the middle half of the observed or estimated distribution, depending on the calculation used. The registry reports ranges of 1 to 3.5 hours and 3.5 to 25.4 hours. The exact estimation details are not reported in the registry record.
Comparing medians alone does not describe the full event-time pattern. Two groups can have different distributions even if their medians are close, or similar medians despite differences at other times. The inter-quartile ranges give additional information about spread, but they do not replace an analysis that uses the sequence of event times and any censoring information.
What does the log-rank analysis assess?
In general, the log-rank family of tests compares event experience over follow-up between groups. It uses information from the timing of events and the participants still at risk at each event time. The registry identifies the Wilcoxon version of the log rank and reports a hazard ratio. It does not provide the full test statistic, degrees of freedom, model specification, or the details of how the hazard ratio was estimated. The precise relationship between the reported test and effect estimate therefore cannot be fully reconstructed from the registry record.
The standard log-rank test gives relatively similar emphasis to event times across follow-up. A Wilcoxon-type version generally gives greater emphasis to earlier event times, though the exact weighting depends on the implementation. This is a general description; the registry does not report the weighting formula used in this study. When treatment effects vary over time, different weighting choices can produce different summaries and tests. The registry does not report an assessment of whether proportional hazards or other time-pattern assumptions were examined.
How should the hazard ratio be read?
The posted hazard ratio is 3.475, with a 95% confidence interval from 1.901 to 6.355. The registry states the comparison as the hazard rate under icatibant relative to the hazard rate under tranexamic acid. A hazard is an event rate at a particular time among participants who have not yet experienced the event, as represented in a time-to-event model. It is not a direct measure of the number of hours saved, nor does it give the probability that an individual will experience relief by a particular time.
As a general interpretation, a hazard ratio above 1 for the stated ordering indicates a higher instantaneous rate of the event in the numerator group, if the event definition and model are applied as described. Here the event is symptom relief, and the reported ordering is icatibant relative to tranexamic acid. A single hazard ratio is most straightforward to interpret when the relative event rate is reasonably stable over time. Whether that assumption is appropriate in this trial is not reported in the registry record. The median times and hazard ratio are complementary summaries, not interchangeable quantities.
What do the confidence interval and p-value add?
A confidence interval gives a range of estimates compatible with the data under a specified statistical procedure and its assumptions. The reported 95% interval, 1.901 to 6.355, indicates uncertainty around the hazard-ratio estimate. Its width reflects that the estimate is not known exactly, while its position relative to 1 is relevant to the null hypothesis of equal hazard rates. The registry reports p < 0.001 for the analysis. In general, that p-value measures compatibility with the null model, rather than the size, importance, or certainty of a treatment effect.
The record describes a two-sided null and alternative hypothesis for the hazard-rate ratio. It does not report whether the analysis was adjusted, whether any assumptions were checked, or how missing data were handled. The posted interval and p-value should therefore be interpreted as results of the registry-reported analysis, not as a substitute for the full analysis plan.
Why can over-dispersion matter?
As a general concept, over-dispersion arises when data vary more than a chosen statistical model expects. In count outcomes, for example, a simple model may underestimate variability if observations are more heterogeneous than assumed. That can make standard errors too small and intervals too narrow if the extra variation is ignored. The primary endpoint in this trial is a time-to-event measure, not a count outcome; the registry does not report an over-dispersion analysis, and no such conclusion can be drawn from the posted endpoint summaries.
For time-to-event outcomes, important sources of uncertainty include censoring, differing follow-up, event-time measurement, and whether the model’s assumptions fit the observed data. The registry gives a 2-day primary outcome timeframe but does not report the numbers censored, follow-up distributions, or diagnostic checks. These omissions limit independent evaluation of the method, even though the main estimate, interval, p-value, and group summaries are posted.
10. Analyses Reported by the Sponsor
| Method | Estimate | 95% CI | P-value |
|---|---|---|---|
| The Wilcoxon version of the log rank | Hazard Ratio (HR) 3.475 | 1.901 to 6.355 | < 0.001 |
The registry’s reported result is the sponsor’s stated analysis: a hazard ratio of 3.475, with a 95% confidence interval from 1.901 to 6.355 and p < 0.001, using the Wilcoxon version of the log rank. The registry also reports the group medians and inter-quartile ranges for time to onset of symptom relief. No discrepancy between a sponsor result and a recalculated result is identified in the registry information.
No independent recalculated hazard ratio or recalculated comparison is reported in the registry record. The posted group medians and participant counts alone are not enough to reconstruct a time-to-event analysis, because such an analysis may depend on individual event times, censoring, and the method’s weighting and assumptions. A recalculation based only on summary statistics would not reproduce those details.
Accordingly, the sponsor’s reported analysis is the relevant inferential result in this record. Its interpretation remains conditional on the analysis definition and assumptions, some of which are not described in the registry record. The median summaries offer a separate descriptive view of the endpoint and should not be used to derive a new hazard ratio or p-value.
11. Multiplicity, Missing Data and Analysis Populations
The registry lists the primary endpoint as time to onset of symptom relief and identifies time to almost complete symptom relief as a secondary outcome. It also names safety and tolerability and pharmacoeconomics among secondary assessments. A single primary endpoint helps identify the main planned comparison, but interpreting multiple outcomes can raise a multiplicity concern: the more hypotheses assessed, the greater the chance that at least one result appears unusual by chance if no adjustment or hierarchy is used.
Whether the trial controlled the overall error rate across secondary outcomes, used a prespecified hierarchy, or treated secondary analyses as exploratory is not reported in the registry record. The numerical results for the listed secondary efficacy outcome and the other secondary areas are also not reported in the registry record. The reported p-value for the primary endpoint should therefore be read as the result for that analysis; it does not establish how multiplicity across all planned outcomes was handled.
The registry record does not describe missing-data rules, censoring rules, the number of participants with incomplete symptom assessments, or reasons why the primary outcome groups contain 36 and 38 participants when enrollment is listed as 85. It does not state whether the analysis used an intention-to-treat population, a per-protocol population, or another defined analysis set. These details matter because exclusions or incomplete follow-up can affect which participants contribute information and how precisely the result is estimated.
For a time-to-event endpoint, participants without a recorded event by the end of observation may be censored rather than treated as having no event. In general, valid interpretation depends on appropriate handling of censoring and assumptions about the relationship between censoring and the event process. The registry gives a primary timeframe of 2 days but does not specify the censoring approach or provide enough detail to assess those assumptions. It also does not report sensitivity analyses for missing or censored observations.
These omissions do not negate the posted primary result, but they constrain evaluation of its robustness and the reach of conclusions about the full trial population. The registry record does not report a detailed statistical analysis plan, sample-size justification, or interim-analysis plan.
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 ) | 4 | 36 | 11.1% |
| Controlled Phase- Tranexamic Acid (Randomized Subjects) | 1 | 38 | 2.6% |
| Controlled Phase- Icatibant (Subjects w/ Laryngeal Attack) | 1 | 3 | 33.3% |
| Open Label Extension Phase- Icatibant (Previously Randomized) | 9 | 44 | 20.5% |
| Open Label Extension Phase (Subjects w/ Laryngeal Attack) | 1 | 2 | 50.0% |
| Open Label Extension Phase(Untreated Patients at the Baseline | 0 | 8 | 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 ) | 19 of 36 |
| Controlled Phase- Tranexamic Acid (Randomized Subjects) | 16 of 38 |
| Controlled Phase- Icatibant (Subjects w/ Laryngeal Attack) | 1 of 3 |
| Open Label Extension Phase- Icatibant (Previously Randomized) | 31 of 44 |
| Open Label Extension Phase (Subjects w/ Laryngeal Attack) | 1 of 2 |
| Open Label Extension Phase(Untreated Patients at the Baseline | 4 of 8 |
Most frequent serious adverse event terms
| Event term | Organ system | Controlled Phase- Icatibant (Randomized Subjects ) | Controlled Phase- Tranexamic Acid (Randomized Subjects) | Controlled Phase- Icatibant (Subjects w/ Laryngeal Attack) | Open Label Extension Phase- Icatibant (Previously Randomized) | Open Label Extension Phase (Subjects w/ Laryngeal Attack) | Open Label Extension Phase(Untreated Patients at the Baseline |
|---|---|---|---|---|---|---|---|
| Hereditary Angioedema | Congenital, familial and genetic disorders | 2 of 36 | 0 of 38 | 1 of 3 | 3 of 44 | 1 of 2 | 0 of 8 |
| Gastroenteritis | Infections and infestations | 1 of 36 | 0 of 38 | 0 of 3 | 2 of 44 | 0 of 2 | 0 of 8 |
| Aortic Value Sclerosis | Cardiac disorders | 0 of 36 | 1 of 38 | 0 of 3 | 0 of 44 | 0 of 2 | 0 of 8 |
| Sudden Cardiac Death | General disorders | 0 of 36 | 1 of 38 | 0 of 3 | 0 of 44 | 0 of 2 | 0 of 8 |
| Cholelithiasis | Hepatobiliary disorders | 1 of 36 | 0 of 38 | 0 of 3 | 0 of 44 | 0 of 2 | 0 of 8 |
| Cystitis | Infections and infestations | 1 of 36 | 0 of 38 | 0 of 3 | 0 of 44 | 0 of 2 | 0 of 8 |
| Hypertensive Crisis | Vascular disorders | 1 of 36 | 0 of 38 | 0 of 3 | 0 of 44 | 0 of 2 | 0 of 8 |
| Coronary Artery Disease | Cardiac disorders | 0 of 36 | 0 of 38 | 0 of 3 | 1 of 44 | 0 of 2 | 0 of 8 |
| Head Injury | Injury, poisoning and procedural complications | 0 of 36 | 0 of 38 | 0 of 3 | 1 of 44 | 0 of 2 | 0 of 8 |
| Road Traffic Accident | Injury, poisoning and procedural complications | 0 of 36 | 0 of 38 | 0 of 3 | 1 of 44 | 0 of 2 | 0 of 8 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Controlled Phase- Icatibant (Randomized Subjects ) | Controlled Phase- Tranexamic Acid (Randomized Subjects) | Controlled Phase- Icatibant (Subjects w/ Laryngeal Attack) | Open Label Extension Phase- Icatibant (Previously Randomized) | Open Label Extension Phase (Subjects w/ Laryngeal Attack) | Open Label Extension Phase(Untreated Patients at the Baseline |
|---|---|---|---|---|---|---|---|
| Hereditary Angioedema | Congenital, familial and genetic disorders | 10 of 36 | 6 of 38 | 1 of 3 | 10 of 44 | 1 of 2 | 1 of 8 |
| Nasopharyngitis | Infections and infestations | 2 of 36 | 3 of 38 | 0 of 3 | 4 of 44 | 0 of 2 | 0 of 8 |
| Injury, poisoning and procedual complications | Injury, poisoning and procedural complications | 3 of 36 | 1 of 38 | 0 of 3 | 3 of 44 | 0 of 2 | 0 of 8 |
| Urinary Track Infection | Infections and infestations | 0 of 36 | 0 of 38 | 0 of 3 | 6 of 44 | 0 of 2 | 0 of 8 |
| Musculoskeletal and connective tissue disorders | Musculoskeletal and connective tissue disorders | 2 of 36 | 1 of 38 | 0 of 3 | 3 of 44 | 0 of 2 | 0 of 8 |
| Pharyngitis | Infections and infestations | 0 of 36 | 1 of 38 | 0 of 3 | 3 of 44 | 0 of 2 | 0 of 8 |
| Headache | Nervous system disorders | 2 of 36 | 2 of 38 | 0 of 3 | 0 of 44 | 0 of 2 | 0 of 8 |
| Injection Site Reaction | General disorders | 2 of 36 | 0 of 38 | 0 of 3 | 1 of 44 | 0 of 2 | 0 of 8 |
| Blood and Lymphatic system disorders | Blood and lymphatic system disorders | 0 of 36 | 2 of 38 | 0 of 3 | 1 of 44 | 0 of 2 | 0 of 8 |
| Respiratory Track Infection | Infections and infestations | 0 of 36 | 0 of 38 | 0 of 3 | 1 of 44 | 0 of 2 | 1 of 8 |
Serious events with the highest arm-level rate: hereditary angioedema (50.0%), gastroenteritis (4.5%), cholelithiasis (2.8%), cystitis (2.8%), hypertensive crisis (2.8%).
For the controlled phase, the registry reports serious adverse events in 4 of 36 participants in the icatibant randomized group and 1 of 38 in the tranexamic acid randomized group. It reports other adverse events in 19 of 36 and 16 of 38, respectively. These are counts of participants affected as recorded for those groups; they are not, by themselves, adjusted comparisons or estimates of causal risk.
The adverse-event record also includes separate open-label and laryngeal-attack groups. Those participants were not part of the same randomized comparison and should not be combined with the controlled randomized groups when interpreting the randomized safety counts. The registry lists serious adverse-event terms, including hereditary angioedema, but the term list does not establish that an event was caused by treatment. The causal relationship of the listed events to treatment is not reported in the registry record.
Deaths are not reported in the registry record. The adverse-event summary does not provide enough information to assess event timing, severity beyond the serious classification, duration, recurrence, or exposure-adjusted rates. The counts should therefore be read descriptively, alongside the study’s group definitions and the limits of the registry reporting, rather than as a complete safety profile or as proof of a difference between treatments.
13. What the Result Does, and Does Not, Mean
The primary outcome result describes a difference in the timing of first documented symptom relief between the randomized groups during the controlled phase. The median was 2 hours in the icatibant group and 12 hours in the tranexamic acid group, with inter-quartile ranges of 1 to 3.5 hours and 3.5 to 25.4 hours. The registry-reported hazard ratio was 3.475, with a 95% confidence interval from 1.901 to 6.355 and p < 0.001.
These figures do not mean that every participant followed the group median, nor do they express the number of hours by which a particular person’s symptoms changed. The hazard ratio is a relative event-rate summary under the reported time-to-event analysis; it is not a ratio of median times and does not give an individual probability of relief by a chosen time. The confidence interval communicates statistical uncertainty under the analysis assumptions, while the p-value addresses compatibility with the stated null hypothesis.
The result does not establish how the treatments compare on every outcome. Numerical results for time to almost complete symptom relief, pharmacoeconomics, and the other listed secondary assessments are not reported in the registry record. The safety counts are descriptive and do not determine whether reported events were caused by treatment. Nor do the primary outcome results automatically apply to participants with baseline laryngeal symptoms or those treated in open-label phases, who were not included in the randomized comparison in the same way.
Interpretation is also limited by missing registry detail about analysis populations, censoring, missing data, and statistical assumptions. The enrollment total is 85, while the primary outcome groups contain 36 and 38 participants; the explanation for this difference is not reported in the registry record. Thus, the posted data support a description of the reported randomized comparison, but they do not resolve questions about all enrolled participants, all planned analyses, or performance in populations not represented by that comparison.
14. Why This Trial Matters Statistically
Statistically, this trial illustrates why a clinical outcome’s timing can be informative. Time to onset of symptom relief retains the ordering of events over the observation period, whereas a single fixed-time response measure would discard some of that timing information. The registry reports both medians and a time-to-event analysis, allowing the result to be described in terms of a typical event time and a relative event-rate estimate.
It also illustrates that these summaries answer different questions. The median is a point in the distribution of event times; the hazard ratio describes relative event rates under a time-to-event framework. Neither should be substituted for the other. Their interpretation depends on the endpoint definition, follow-up, censoring, and model assumptions. The registry specifies the symptom-based event and a 2-day timeframe, but does not provide enough analysis detail to assess all those features.
The randomized, double-blind, parallel-group design provides a structured basis for comparing the two assigned regimens. At the same time, exclusions from randomization for baseline laryngeal symptoms and later open-label treatment create distinct populations that must be kept separate from the controlled comparison. The enrollment total and primary outcome analysis counts also differ, with the reason not reported in the registry record.
Finally, the reported confidence interval and p-value show how inferential results complement descriptive summaries. A result can be statistically distinguishable from the null while still requiring careful assessment of precision, assumptions, outcome coverage, and safety reporting. The registry record offers a clear primary endpoint result, but its limited information on multiplicity, missing data, analysis populations, and secondary outcomes leaves important questions unanswered. This is a useful reminder that a numerical result is best understood together with its design and reporting context.
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 provides only limited information for independently assessing the primary analysis. It names the Wilcoxon version of the log rank and reports a hazard ratio, confidence interval, and p-value, but the detailed statistical analysis plan, model specification, and assumption checks are not reported in the registry record. The method used to handle censoring and incomplete symptom assessments is also not reported in the registry record.
The primary outcome groups contain 36 participants assigned to icatibant and 38 assigned to tranexamic acid, while enrollment is listed as 85. The reasons for the difference are not reported in the registry record, nor is the definition of the analysis population. The registry does not say whether the primary analysis was intention-to-treat or based on another population. These gaps make it difficult to assess the effect of exclusions or missing observations.
The study includes participants treated outside the randomized comparison: those with baseline laryngeal symptoms received open-label icatibant, and eligible participants without a sufficiently severe attack during the controlled phase were treated during an open-label phase. Outcomes from those groups cannot be assumed to be directly comparable with outcomes from the randomized groups. The registry does not provide detailed outcome results for those populations in the primary comparison.
Numerical results for the listed secondary endpoint and the other secondary areas are not reported in the registry record. Nor are multiplicity procedures, interim analyses, or a sample-size justification reported in the registry record. Adverse-event counts are posted, but event timing, causal attribution, and further detail needed for a comparative safety assessment are not available in the registry excerpt. These reporting limitations constrain the conclusions that can be drawn beyond the posted primary endpoint summaries.
16. Related Tutorials
17. Related Statistical Calculators
18. Sources
- ClinicalTrials.gov: Subcutaneous Treatment With Icatibant for Acute Attacks of Hereditary Angioedema (HAE) — NCT00500656.
- Registry record last updated 2021-06-09; status last verified 2021-05.
- Results first posted 2014-06-09.
- 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
NCT00500656 is a completed phase 3, randomized, double-blind, parallel-group, multicentre study of subcutaneous icatibant versus oral tranexamic acid for hereditary angioedema. Enrollment was 85. The primary endpoint was time to onset of symptom relief over 2 days, defined by the first documented relief of the attack’s designated primary symptom.
The registry reports median times of 2 hours for 36 participants in the icatibant group and 12 hours for 38 participants in the tranexamic acid group. The respective inter-quartile ranges were 1 to 3.5 hours and 3.5 to 25.4 hours. The reported hazard ratio was 3.475, with a 95% confidence interval from 1.901 to 6.355 and p < 0.001.
Participants with baseline laryngeal symptoms and some participants treated after the controlled phase were managed with open-label icatibant rather than included in the randomized comparison. Detailed reporting on missing data, analysis populations, multiplicity, and secondary outcome results is not reported in the registry record.