Safety and Efficacy Study of CINRYZE for Prevention of Angioedema Attacks in Children Ages 6-11 With Hereditary Angioedema: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy Study of CINRYZE for Prevention of Angioedema Attacks in Children Ages 6-11 With Hereditary Angioedema (NCT02052141), a randomized phase 3 study. The primary outcome is Normalized Number of Angioedema Attacks Per Month in a Treatment Period.

2. Clinical Question

3. Trial Design

This was a Phase 3, multicenter, randomized, single-blind, dose-ranging crossover study of intravenous CINRYZE in children 6 to 11 years of age with HAE. The registry lists 12 participants as enrolled and marks the trial completed. The listed start date is 2014-03-20, and the primary completion date is 2017-05-04. Shire is named as the sponsor.

The two treatment sequences were 500 Units followed by 1000 Units, and 1000 Units followed by 500 Units. Each dose was administered intravenously twice per week for 12 weeks during its treatment period. The official title describes the study as dose-ranging and crossover; the brief summary states the primary objective was to assess relative efficacy of the two dose levels. The registry does not report the duration or handling of any interval between treatment periods, so no washout procedure can be described.

In a crossover design, each participant receives more than one treatment over time. General statistical rationale: comparing treatment periods within the same participant can account for stable differences between participants, while the order of treatments and changes over time may also matter to interpretation. The registry reports paired t-tests for the primary and three posted secondary efficacy comparisons. It does not report enough detail in this record to describe the full crossover model, sequence or period effects, or any adjustment for them.

The primary endpoint was the mean normalized monthly number of angioedema attacks during each treatment period. The Full Analysis Set included participants in the safety set with at least 1 post-baseline primary efficacy assessment. The registry also lists safety, pharmacokinetic, pharmacodynamic, and immunogenicity objectives. Details of the protocol’s original sample-size justification, statistical analysis plan, interim analyses, and handling of missing data are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: A total of 16 participants were screened and of them, 12 were enrolled into the baseline observational period (12 weeks) and were randomized to receive the treatment in sequence A-B and B-A during this crossover study without a washout period.

Intervention Period 1

Intervention Period 2

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set (FAS) included all participants in the safety set who had at least 1 post-baseline primary efficacy assessment.

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.

Population: Safety set included all participants who took at least 1 dose of investigational product.

6. Primary Endpoint

The registry lists the primary outcome as Normalized Number of Angioedema Attacks Per Month in a Treatment Period, measured over From start of treatment up to 12 weeks during each treatment period.

The primary endpoint was the normalized number of angioedema attacks per month in a treatment period, measured from treatment start up to 12 weeks. It expresses attack frequency on a monthly scale, taking account of the number of days a participant took part in a given period. The endpoint is a continuous measure, and the registry reports its mean and standard deviation for each dose group.

The registry defined an attack using participant-reported symptoms or signs, such as swelling or pain at any location, after a report of no swelling or pain on the previous day. Manifestations progressing from one site to another before complete resolution counted as one attack. Worsening before complete resolution, or reappearance without a symptom-free calendar day after apparent resolution, also counted as one attack. Swelling due to trauma and symmetrical nonpainful swelling of the lower extremities were excluded from the attack definition.

General statistical rationale: a normalized monthly frequency allows attack experience to be expressed on a common time scale when participants contribute different numbers of observation days. The mean describes the average frequency in the analysis population, while the standard deviation describes variation among participants. Neither statistic alone describes every participant’s experience. The registry does not report further details about diary completion, adjudication, or missing observations.

7. Results Posted in the Registry

• Treatment B (1000 U CINRYZE): mean 0.70 versus 1.20 on control; difference -0.50 (95% CI -1.65 to 0.65), standardized effect d = -0.35; z-test p = 0.396.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Cumulative Attack-severity Score of Angioedema Attacks Normalized Per Month in a Treatment Period

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Treatment B (1000 U CINRYZE): mean 1.40 versus 2.00 on control; difference -0.60 (95% CI -2.84 to 1.64), standardized effect d = -0.21; z-test p = 0.599.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Treatment B (1000 U CINRYZE) and the control. The interval gives the range of effects that remain compatible with the data.

Cumulative Daily-severity Score of Angioedema Attacks Normalized Per Month in a Treatment Period

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Treatment B (1000 U CINRYZE): mean 2.20 versus 4.10 on control; difference -1.90 (95% CI -5.36 to 1.56), standardized effect d = -0.44; z-test p = 0.281.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Treatment B (1000 U CINRYZE) and the control. The interval gives the range of effects that remain compatible with the data.

Normalized Number of Angioedema Attacks Per Month Requiring Acute Treatment in a Treatment Period

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Treatment B (1000 U CINRYZE): mean 0.40 versus 0.70 on control; difference -0.30 (95% CI -1.41 to 0.81), standardized effect d = -0.22; z-test p = 0.597.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Treatment B (1000 U CINRYZE) and the control. The interval gives the range of effects that remain compatible with the data.

Across the three secondary efficacy outcomes with numerical results, the reported paired estimates are negative for the 1000-Unit period relative to the 500-Unit period. The outcomes cover cumulative attack-severity score, cumulative daily-severity score, and attacks requiring acute treatment. This direction is broadly consistent with the direction of the primary paired estimate, but the secondary findings do not replace or independently establish the primary result.

The secondary paired tests have reported 90% confidence intervals and p-values. The registry does not report a multiplicity adjustment or a prespecified hierarchy for interpreting these outcomes. General statistical explanation: when multiple outcomes are examined, isolated p-values can overstate the strength of evidence if they are interpreted as though each were the only test. This is why secondary results generally carry less weight than a clearly prespecified primary outcome, particularly when the analysis plan and multiplicity handling are not available.

The registry also lists secondary measures for treatment-emergent adverse events, plasma C1 INH antigen concentration, C1 INH functional activity, complement C4, and C1 INH antibodies. Numerical results for those measures are not reported in the registry record. Their absence from the available results prevents a broader synthesis of the listed safety, pharmacokinetic, pharmacodynamic, and immunogenicity objectives. The overall secondary pattern is therefore limited to the three posted efficacy comparisons and should be interpreted cautiously rather than as a complete account of every secondary objective.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Cumulative Attack-severity Score of Angioedema Attacks Normalized Per Month in a Treatment Period
• Cumulative Daily-severity Score of Angioedema Attacks Normalized Per Month in a Treatment Period
• Normalized Number of Angioedema Attacks Per Month Requiring Acute Treatment in a Treatment Period
• Number of Participants With Treatment-emergent Adverse Events (TEAEs) by Dose Group
• Plasma Concentration of C1 Esterase Inhibitor (C1 INH) Antigen
• C1 Esterase Inhibitor (C1 INH) Functional Activity in Plasma
• Plasma Concentration of Complement C4
• Number of Participants With C1 Esterase Inhibitor (C1 INH) Antibodies in Plasma

9. Statistical Interpretation

10. Statistical Methods Explained

Several statistical ideas are needed to read the results carefully: the mean and standard deviation, the paired comparison, a confidence interval, a p-value, and the difference between the registry’s reported analysis and a summary-statistic recalculation. These explanations are general unless they refer explicitly to a registry result.

What the mean and standard deviation describe

The primary outcome is a continuous measure: normalized angioedema attacks per month. The registry reports the mean for each treatment period and a standard deviation. The mean is the arithmetic average of the observations included in the summary. The standard deviation describes how dispersed those observations are around the mean. A larger standard deviation indicates greater variation in the observations; it does not describe uncertainty in the mean in the same way as a confidence interval.

The primary summaries are 1.2 attacks per month in the 500-Unit period and 0.7 in the 1000-Unit period, each with 12 participants listed. Those are descriptive summaries. By themselves they do not account for the crossover pairing, establish a statistically supported difference, or show the range of individual participant responses.

Why pairing matters in a crossover study

General statistical explanation: a paired test analyzes the difference between two measurements from the same participant. It uses the fact that measurements from one person may be more alike than measurements from different people. That within-person association can affect the estimated uncertainty of the mean difference. An analysis that instead treats the two treatment-period summaries as independent groups does not use that association.

The registry reports a paired t-test for the primary comparison. The separate summary-statistic recalculation uses the posted means and standard deviations and is unadjusted; it does not retain the paired information. The record does not report the paired differences or their standard deviation, so the paired test cannot be reproduced from the posted marginal summaries alone. The registry also does not provide details on how the analysis addressed period or sequence effects.

How to read a confidence interval

General statistical explanation: a confidence interval gives a range of values compatible with the data and the specified statistical procedure, under that procedure’s assumptions. A narrower interval indicates greater precision than a wider interval on the same scale. An interval that includes zero for a difference is compatible with no mean difference under the interval’s model; an interval that excludes zero is not. This interpretation does not by itself establish clinical importance or prove that a treatment effect is present.

The registry’s paired primary result is reported with a 90% confidence interval from -0.71 to -0.10. The summary-statistic recalculation has a 95% confidence interval from -1.654 to 0.654. These intervals are not directly comparable as if they were generated by the same analysis: they differ in confidence level and analytical approach. The registry’s reported interval belongs to the paired analysis, while the recalculated interval is based on separate-group summaries.

What a p-value does and does not say

General statistical explanation: a p-value measures how incompatible the observed data are with a specified null hypothesis, assuming the statistical model and its assumptions. It is not the probability that the null hypothesis is true, and it does not measure the size or practical importance of a difference. A smaller p-value is not, by itself, evidence of a more important effect.

The registry reports p = 0.03 for its paired primary analysis. The unadjusted recalculation reports p = 0.396. Because the discrepancy flag is true, the sponsor’s own analysis takes precedence. The difference between the results underlines why the analysis method and the paired structure matter; it is not appropriate to select whichever result appears more persuasive.

Multiplicity and the scope of inference

General statistical explanation: when several outcomes are tested, the chance of obtaining at least one apparently notable result by chance can increase if each test is interpreted separately. A multiplicity strategy can control that issue, but no such strategy is described in the registry record. The primary endpoint is therefore distinct from the multiple secondary assessments, whose results should be interpreted more cautiously when no adjustment is reported.

The registry lists a total of 9 outcome measures and reports 4 analyses in the numerical efficacy information. The primary endpoint and three secondary efficacy outcomes have reported comparisons. Other listed secondary outcomes include treatment-emergent adverse events and measures of C1 INH antigen, C1 INH functional activity, complement C4, and C1 INH antibodies. Results for those outcomes are not reported in the registry record in the information available for this analysis.

Analysis population and missing information

The primary analysis population is defined as the Full Analysis Set: participants in the safety set who had at least 1 post-baseline primary efficacy assessment. The registry does not state how missing outcome days were handled, whether imputation was used, how many participants had complete paired observations, or whether any sensitivity analyses were performed. It also does not report the protocol’s original sample-size assumptions or a detailed analysis plan. Those gaps limit assessment of how well the reported estimate represents all randomized participants and how robust it is to alternative analytic choices.

11. Confidence Intervals and Precision

Precision is about how tightly an estimate is determined by the data and method. A confidence interval communicates uncertainty around an estimated difference; it does not guarantee that the true value lies in the interval or describe the range of effects for individual participants. The width of an interval depends on the amount and variability of information and on the analysis used. General statistical explanation: a larger sample can improve precision, but the gain also depends on outcome variation and the design.

For the primary comparison, the sponsor’s paired analysis reports a 90% confidence interval from -0.71 to -0.10 around a mean difference of -0.4. The posted summary-statistic recalculation reports a 95% confidence interval from -1.654 to 0.654 around a mean difference of -0.5. The recalculated interval includes zero; the sponsor’s reported paired interval does not. This contrast reflects both a different confidence level and a different approach to the crossover data, not simply two versions of the same calculation.

The registry’s 12-participant enrollment indicates that the trial’s evidence base was small. General statistical explanation: with limited observations, estimates can be sensitive to individual data and intervals can remain uncertain, particularly when outcome variability is substantial. The primary group standard deviations are 1.53 and 1.35 attacks per month. The record does not report participant-level values or the variability of paired differences, so the contribution of within-person correlation to the sponsor’s interval cannot be independently assessed.

The secondary paired analyses also have 90% confidence intervals, and their reported widths vary by outcome. Their estimates should be read in the context of the small trial and the absence of a reported multiplicity strategy. Precision is not the same as clinical relevance: the registry record does not provide a threshold for an important difference in monthly attack frequency.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are illustrations based on the observed effect, not a report of the assumptions used to design this trial. For continuous outcomes such as these, the figures are participants per arm, not total events. The listed planning assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Each row considers an effect equal to the stated fraction of the observed effect. The original trial’s own sample-size justification and design assumptions are not reported in the registry record.

The 80% power column represents the illustrative number of participants per arm needed for an 80% chance of detecting the specified effect under those planning assumptions, if the effect and model assumptions were correct. The 90% power column represents the corresponding number per arm for a 90% chance. These are conditional planning quantities, not guarantees about what a future trial would find. They are not observed power.

Rows that plan for a smaller fraction of the observed effect require more participants per arm than rows based on the full observed effect. General statistical explanation: smaller effects are harder to distinguish from random variation, so more information is usually needed to detect them at a chosen significance level and power. These projections also reflect the observed effect, which can be imprecise in a small study. They should not be treated as a validated design recommendation or as evidence that the trial was adequately or inadequately sized.

The calculations are not a reconstruction of the crossover trial’s original design because the stated assumptions describe equal allocation between two arms and normal approximation, while the trial itself used randomized treatment sequences and paired analyses. The registry record does not report an original sample-size calculation that can be compared with these illustrations.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -0.500; pooled standard deviation σ = 1.443.
2. n = 2 × (1.96 + 0.842)² × 1.443² / -0.500² = 130.7, rounded up to 131 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -0.5                      # observed difference in means
sigma <- 1.44280975876933                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(2052141)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 131 (80% power), 175 (90% power)
 75% of observed effect: n per arm = 233 (80% power), 312 (90% power)
 50% of observed effect: n per arm = 523 (80% power), 700 (90% power)
power.t.test: 131.7 
Simulated power at n = 131 per arm: 0.798 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The registry’s primary result is a paired t-test: mean difference -0.4, 90% confidence interval from -0.71 to -0.10, and p = 0.03. The direction is 1000 U CINRYZE compared with 500 U CINRYZE, so the negative estimate corresponds to a lower mean normalized monthly attack frequency during the 1000-Unit treatment period.

The recalculation from the posted group summaries gives a mean difference of -0.5, a 95% confidence interval from -1.654 to 0.654, and an unadjusted p-value of 0.396. It uses the posted group means and standard deviations rather than the within-participant paired differences. The recalculated estimate and the sponsor’s reported estimate therefore differ in both method and inferential result.

The registry record flags a discrepancy. In that circumstance, the sponsor’s own analysis takes precedence over the simple unadjusted recalculation. This does not mean the recalculation is the sponsor’s analysis or that the two results should be combined. It means the reported paired result is the relevant registry analysis, while the independent-summary calculation is a limited check that cannot recover the paired structure. The record does not include enough participant-level detail to resolve the discrepancy further.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary efficacy outcome and multiple secondary outcomes. It does not report a multiplicity adjustment, an outcome hierarchy, or a strategy for controlling the overall false-positive rate across tests. General statistical explanation: testing several hypotheses increases the opportunity for chance findings if each result is judged against the same nominal threshold without accounting for the number of tests. This does not invalidate the reported estimates, but it affects how strongly individual secondary p-values should be interpreted.

The primary endpoint is the normalized number of angioedema attacks per month. The registry reports its comparison using a paired t-test, along with a 90% confidence interval and p = 0.03. Three secondary efficacy outcomes also have paired test results. The record does not explain whether the primary test was the sole confirmatory test, whether secondary outcomes were exploratory, or whether any multiplicity procedure was used. Those details are not reported in the registry record.

The Full Analysis Set included participants in the safety set who had at least 1 post-baseline primary efficacy assessment. The record does not provide a complete account of the safety set definition, the number of participants included in each analysis beyond the posted group summaries, or the number with usable paired observations. It does not describe how missing attack reports, incomplete treatment periods, or missing outcome days were handled. No imputation method or sensitivity analysis for missing data is reported.

Further limitations concern the crossover analysis. The registry identifies a paired t-test but does not describe modeling or adjustment for period, sequence, or carryover effects. It does not report details of randomization implementation, allocation concealment, or the extent of blinding. The protocol’s original sample-size justification, interim analyses, and full statistical analysis plan are also not reported in the registry record. These missing details limit independent assessment of the planned analysis, missing-data assumptions, and the robustness of inference.

16. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports serious adverse events for each dose group. In the 500 U CINRYZE group, 0 of 12 participants at risk had a serious adverse event; in the 1000 U CINRYZE group, 0 of 12 had a serious adverse event. The registry reports 0 deaths in each group. These figures describe the serious-event counts recorded for the treatment periods; they do not establish that the risks are identical or that an event is impossible.

The registry also reports other, non-serious adverse events in 10 of 12 participants in the 500-Unit group and 11 of 12 in the 1000-Unit group. Those figures are distinct from the serious adverse-event counts. The registry record does not provide the serious-event terms, and the list of top serious terms is empty. It does not provide enough detail in the results used to describe event type, duration, relatedness, or treatment-period timing.

General statistical explanation: zero observed serious events in a small group does not precisely estimate the underlying event risk. Safety comparisons therefore require caution, and these counts alone cannot establish comparative safety. The registry lists treatment-emergent adverse events as a secondary outcome, but broader numerical detail for other listed safety outcomes is not reported in the registry record.

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

The posted primary analysis describes a lower mean normalized monthly attack frequency in the 1000-Unit period than in the 500-Unit period, with a paired mean difference of -0.4. Its 90% confidence interval is from -0.71 to -0.10, and its p-value is 0.03. These are the results of the registry’s reported paired t-test in this trial population and analysis set. They do not, on their own, establish a general effect beyond the study or show the experience of every participant.

The separate recalculation from posted summary statistics gives a different result. It is unadjusted and does not preserve the crossover pairing, so it cannot substitute for the reported paired analysis. The registry record flags a discrepancy, and the sponsor’s own analysis takes precedence. The lack of participant-level data and detailed analysis documentation prevents a fuller independent reconciliation.

The trial enrolled 12 participants, and the primary endpoint was measured during treatment periods of up to 12 weeks. These features constrain how broadly the estimates can be applied. The registry record does not report the original sample-size justification, detailed missing-data methods, or a multiplicity strategy. It also does not give a threshold for deciding whether a difference in normalized monthly attack frequency is clinically important. Statistical evidence about a mean difference and clinical importance are separate questions.

The registry’s secondary efficacy results have similar directional estimates in the paired analyses, but multiple secondary comparisons are listed and no multiplicity adjustment is described. Numerical results for several other listed secondary outcomes are not reported in the registry record. The serious adverse-event counts are zero in both groups, but the small groups and limited detail do not allow a precise comparative safety conclusion. Overall, the results should be read as estimates from a small crossover trial with specific reported analyses, not as a complete account of all possible benefits, harms, or outcomes.

18. Why This Trial Matters Statistically

This trial is statistically instructive because its randomized crossover design and its posted summaries require different kinds of analysis. The paired t-test reported by the registry compares treatment periods within participants. A simple calculation from the dose-specific means and standard deviations treats those summaries as separate groups and cannot use the within-participant association. The resulting discrepancy demonstrates why a numerical recalculation is not automatically a reproduction of the study’s analysis.

The record also illustrates the importance of distinguishing descriptive results from inferential ones. Group means summarize average attack frequency, standard deviations describe spread, and the paired estimate and confidence interval address uncertainty under a particular test. No one statistic answers every question. The uncertainty around a mean difference is not the same as variation in individual participants, and a statistically notable result does not by itself establish clinical importance.

Multiplicity and incomplete reporting matter as well. Several secondary outcomes are listed, but the registry record does not describe an adjustment strategy or detailed analysis hierarchy. Some listed secondary outcomes have no numerical results in the record. Without the original sample-size justification, missing-data methods, or full analysis plan, the scope and robustness of the statistical conclusions cannot be completely assessed.

Finally, sample-size planning illustrations based on the observed effect are not evidence about the power achieved in the completed study. They are conditional planning quantities, and smaller target effects require more participants. Keeping that distinction clear prevents retrospective calculations from being mistaken for the trial’s original design rationale or for a measure of the strength of the observed result.

19. 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 describes a small trial with 12 enrolled participants. The primary group summaries each list 12 participants, but the record does not state how many participants contributed complete paired primary observations or whether all randomized participants were included in each analysis. The Full Analysis Set definition excludes participants in the safety set who did not have at least 1 post-baseline primary efficacy assessment; additional exclusions and their reasons are not reported.

The design is crossover, but the registry does not describe the duration or handling of any interval between treatment periods, nor does it report whether period, sequence, or carryover effects were assessed. It names a paired t-test without giving the full statistical model or participant-level paired data. The reported discrepancy between the paired result and the summary-statistic recalculation cannot be independently resolved from the record.

Important analysis details are also absent: the original sample-size justification, interim analyses, missing-data procedures, multiplicity strategy, and detailed statistical analysis plan are not reported in the registry record. The record does not provide a threshold for a clinically important difference in the primary endpoint. Numerical results for several listed secondary outcomes are also not reported, limiting the scope of the overall efficacy and safety assessment.

These limitations do not erase the posted results, but they constrain how independently they can be checked and how broadly they can be interpreted. In particular, the small enrollment and limited reporting make estimates less definitive than a larger, fully documented comparison would allow.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Safety and Efficacy Study of CINRYZE for Prevention of Angioedema Attacks in Children Ages 6-11 With Hereditary Angioedema — NCT02052141.
• Registry record last updated 2021-06-03; status last verified 2021-05.
• Results first posted 2018-08-28.
• 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.

23. Record Summary

NCT02052141 is a completed Phase 3, multicenter, randomized, single-blind, dose-ranging crossover study of intravenous CINRYZE for prevention of angioedema attacks in children 6 to 11 years of age with HAE. The registry lists 12 participants enrolled and two treatment sequences, each using 500 Units and 1000 Units for 12 weeks per treatment period.

The primary endpoint was normalized monthly angioedema attack frequency. The registry reports a paired mean difference of -0.4, a 90% confidence interval from -0.71 to -0.10, and p = 0.03. A summary-statistic recalculation gives a different result and does not preserve pairing; the discrepancy is flagged, and the sponsor’s own analysis takes precedence. The registry does not report several design and analysis details, including the original sample-size justification, missing-data methods, and multiplicity strategy.