A Study of Lanadelumab in Teenagers and Adults to Prevent Acute Attacks of Non-histaminergic Angioedema With Normal C1-Inhibitor (C1-INH): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Lanadelumab in Teenagers and Adults to Prevent Acute Attacks of Non-histaminergic Angioedema With Normal C1-Inhibitor (C1-INH) (NCT04206605), a randomized phase 3 study. The primary outcome is Number of Investigator-Confirmed Angioedema Attacks During the Treatment Period of Day 0 Through Day 182.

2. Clinical Question

The study was designed to evaluate both efficacy and safety. The primary endpoint counted investigator-confirmed attacks during the treatment period, expressed as attacks per month. An attack could involve peripheral, abdominal, or laryngeal angioedema, using the signs and symptoms specified in the registry record.

The clinical question is about a group-level comparison during the study period. It does not by itself determine how an individual participant would respond, whether an observed difference is clinically important, or how results might apply to people outside the enrolled population. The registry record identifies the condition as angioedema and describes the eligible population as teenagers and adults with non-histaminergic angioedema with normal C1-INH. Further eligibility details are not reported in the registry record.

3. Trial Design

This was a Phase 3, multicenter, randomized, placebo-controlled, double-blind, parallel-group study. The registry lists quadruple masking. The trial enrolled 77 participants and is listed as completed. The study start was 2020-05-04, and primary completion was 2022-10-20.

Participants were assigned to placebo or lanadelumab 300 mg. The arm descriptions state that placebo-matching injections were given every two weeks for up to seven months, while lanadelumab was given every two weeks for up to six months. The brief summary describes planned injections over 26 weeks and notes that initial doses were given at the study clinic, with self-injection possible after training. It also describes planned clinic visits. These details describe the registry record; the extent to which each procedure was followed is not reported in the registry record.

The primary endpoint covered Day 0 through Day 182. Its analysis population was the Full Analysis Set, defined as all randomized participants who received any exposure to the investigational product during that period. The arm-level primary results include 27 participants in the placebo group and 50 in the lanadelumab group. The registry record does not report the rationale for this allocation pattern or the original sample-size justification.

The stated secondary outcomes include attack-free status, attack counts by severity, attack counts during the presumed steady-state period, maximum attack severity, and time to first attack. The registry lists 17 outcome measures and 8 analyses. Details of the full protocol, including the planned statistical analysis beyond what is reported for the posted results, 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: Participants with a diagnosis of non-histaminergic angioedema were randomized in a 2:1 ratio to receive lanadelumab or placebo.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set (FAS) included all randomized participants who received any exposure to the investigational product (IP) during the treatment period (Day 0 through Day 182).

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 analysis set (SAS) included all participants who received any exposure to the investigational product.

6. Primary Endpoint

The registry lists the primary outcome as Number of Investigator-Confirmed Angioedema Attacks During the Treatment Period of Day 0 Through Day 182, measured over Day 0 through Day 182.

The primary endpoint is the number of investigator-confirmed angioedema attacks during Day 0 through Day 182, expressed as attacks per month. The registry defines an attack by symptoms or signs consistent with peripheral, abdominal, or laryngeal angioedema. Peripheral symptoms include cutaneous swelling in specified body regions; abdominal symptoms include abdominal pain with or without associated gastrointestinal symptoms; and laryngeal symptoms include specified breathing, speaking, swallowing, throat, or oral signs.

For each participant, the attack rate was calculated by dividing the number of attacks during the specified period by the number of days contributed to that period and multiplying by 28 days. This adjusts the rate for the time each participant contributed, rather than treating every participant’s observation period as necessarily identical. The registry reports the arm-level outcome as a mean and standard deviation.

Attack rate is used to express the frequency of recurrent events over time. In general, this can make a rate easier to compare across participants whose observation time differs. However, a mean rate alone does not show the distribution of attacks among participants: people with no attacks and people with many attacks can contribute to the same group mean. The endpoint also depends on the registry’s attack definition and investigator confirmation. The registry record does not report further details about adjudication procedures or how uncertainty in event classification was handled.

7. Results Posted in the Registry

• Lanadelumab 300 mg: mean 2.17 versus 1.63 on control; difference 0.54 (95% CI -0.23 to 1.31), standardized effect d = 0.29; z-test p = 0.168.

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.

Number of Participants Achieving Attack-Free Status During the Treatment Period of Day 0 Through Day 182

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Lanadelumab 300 mg: 4.0% (2/50) versus 3.7% (1/27) on control; risk difference 0.3 percentage points (95% CI -8.7 to 9.3), risk ratio 1.08 (0.10–11.37); unadjusted two-proportion z-test p = 0.949.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Lanadelumab 300 mg and the control. The interval gives the range of effects that remain compatible with the data.

Number of Investigator-Confirmed Moderate or Severe Angioedema Attacks During the Treatment Period of Day 0 Through Day 182

• 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:
  • Lanadelumab 300 mg: mean 1.45 versus 1.10 on control; difference 0.35 (95% CI -0.25 to 0.95), standardized effect d = 0.23; z-test p = 0.255.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Lanadelumab 300 mg and the control. The interval gives the range of effects that remain compatible with the data.

Number of Investigator-Confirmed Angioedema Attacks During the Presumed Steady State Period of Day 70 Through Day 182

• 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:
  • Lanadelumab 300 mg: mean 2.05 versus 1.37 on control; difference 0.68 (95% CI -0.09 to 1.45), standardized effect d = 0.35; z-test p = 0.085.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Lanadelumab 300 mg and the control. The interval gives the range of effects that remain compatible with the data.

The posted secondary outcomes cover several complementary aspects of angioedema: whether participants were attack-free, counts of all attacks and moderate or severe attacks, attack rates during a presumed steady-state period, maximum attack severity, and time to first attack. Together, these outcomes broaden the description beyond the primary mean attack rate, but they do not replace it. They address different features of the experience measured during treatment.

Across the posted secondary results, estimates do not form a clear pattern that independently resolves the uncertainty in the primary result. The attack-free outcome involves few participants, while the rate outcomes remain variable and their sponsor-reported intervals include a range of comparative values. Secondary measures may be useful context, especially when they address distinct dimensions such as severity or time to an event, but they should be interpreted alongside the endpoint definitions, analysis populations, and uncertainty intervals.

Unadjusted secondary results carry less weight when many outcomes are examined. In general, testing multiple outcomes increases the chance that some findings appear notable through chance alone. A multiplicity adjustment or a prespecified hierarchy can help control that issue, but the registry record does not report whether such procedures were planned or applied to these analyses. The posted secondary p-values should therefore not be treated as if each were the sole, prespecified test.

The registry lists 17 outcome measures and 8 analyses, and 16 secondary outcomes are posted. The record does not report how the sponsor prioritized these measures, whether all were intended for formal hypothesis testing, or how missing outcome data were handled for each one. The secondary results can inform the overall statistical picture, but they do not supply a definitive answer beyond the primary analysis.

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

• Number of Participants Achieving Attack-Free Status During the Treatment Period of Day 0 Through Day 182
• Number of Investigator-Confirmed Moderate or Severe Angioedema Attacks During the Treatment Period of Day 0 Through Day 182
• Number of Investigator-Confirmed Angioedema Attacks During the Presumed Steady State Period of Day 70 Through Day 182
• Number of Participants Achieving Attack-Free Status During the Presumed Steady State Period of Day 70 Through Day 182
• Number of Participants With Maximum Attack Severity During Treatment Period of Day 0 Through Day 182
• Number of Investigator-Confirmed Moderate or Severe Angioedema Attacks During the Presumed Steady State Period of Day 70 Through Day 182
• Number of Participants With Maximum Attack Severity During Presumed Steady State Period of Day 70 Through Day 182
• Time to First Angioedema Attack After Day 0 Through Day 182

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is a continuous rate measure summarized by a mean and standard deviation. The registry’s primary analysis is reported separately as a rate ratio tested using a Chi-squared method. The recalculation is an unadjusted comparison of the posted arm means, with a mean difference and an approximate confidence interval based on the posted summary statistics. These approaches answer related, but not identical, statistical questions.

What does an attack rate represent?

An attack rate expresses recurrent events relative to contributed observation time. In this trial, each participant’s count was divided by the number of days contributed to the specified period and multiplied by 28 days, giving an attacks-per-month scale. In general, accounting for exposure time can be useful when participants contribute different amounts of follow-up. It does not remove all challenges associated with recurrent counts, such as differences in event frequency across participants or possible clustering of attacks within the same person.

The mean rate summarizes the group, but it can be influenced by participants with comparatively high event counts. A standard deviation describes variation among participant-level rates; it is not the same as the uncertainty around the group mean. The registry reports standard deviations of 1.357 for placebo and 2.062 for lanadelumab 300 mg. The recalculation uses the reported arm sizes and standard deviations and does not adjust for other variables.

Why are two comparative measures reported?

The sponsor’s analysis gives a rate ratio, whereas the recalculation gives a mean difference. A rate ratio compares rates on a relative scale; a mean difference compares them on an absolute scale. In general, the relative measure describes proportional separation, while the absolute measure describes the difference in the units of the endpoint. Their estimates and confidence intervals cannot be directly substituted for one another. The sponsor’s reported rate ratio is 1.02, with a 95% confidence interval from 0.71 to 1.47; the recalculated mean difference is 0.54 attacks/month, with a 95% confidence interval from -0.227 to 1.307.

The registry identifies the sponsor’s method as Chi-squared and lists the parameter as Rate Ratio. It does not report the full model specification, including any covariates, distributional assumptions, or details of how over-dispersion was assessed. In general, over-dispersion means that count data vary more than a simple model assumes. If present, it can affect estimated uncertainty and tests, so the model used to analyze recurrent event rates matters. The registry record does not report whether or how over-dispersion was addressed.

What does the recalculation add?

The recalculation is a transparent, unadjusted reading of the posted summary statistics. It compares the two reported means and uses the corresponding standard deviations and group sizes to estimate uncertainty. It is not a reconstruction of the sponsor’s analysis and does not incorporate any unreported adjustment or modeling choices. Its p-value of 0.168 therefore belongs to this simple recalculation, not to the sponsor’s reported rate-ratio analysis.

In general, a p-value describes how compatible the observed data are with a specified null hypothesis under the analysis assumptions. It does not give the probability that a treatment is effective, and it does not measure the magnitude or clinical value of an effect. A confidence interval presents a range of estimates consistent with the data and method at the stated confidence level. Both require attention to the estimand and analysis assumptions.

How should the analysis population be understood?

The primary endpoint population is the Full Analysis Set: randomized participants who received any exposure to the investigational product during Day 0 through Day 182. This definition is stated in the registry record. It does not establish how participants with incomplete outcome data were handled, whether any imputation was used, or whether sensitivity analyses were conducted. Those details are not reported in the registry record.

The arm sizes for this primary endpoint are 27 in the placebo group and 50 in the lanadelumab 300 mg group. Unequal arm sizes can affect the precision of a comparison, particularly when outcomes are variable. In general, the confidence interval reflects both the amount of information and the variation under the chosen method; it should be read alongside the endpoint definition and analysis population rather than as a stand-alone judgment.

11. Confidence Intervals and Precision

The sponsor’s primary estimate is a rate ratio of 1.02, with a 95% confidence interval from 0.71 to 1.47. The interval spans values that would represent different comparative patterns, including values on either side of the no-difference value for a ratio. Its width indicates that the estimate does not pin down a narrow range of possible rate ratios.

The unadjusted recalculation gives a mean difference of 0.54 attacks/month, with a 95% confidence interval from -0.227 to 1.307. This interval includes both negative and positive mean differences. As a result, the recalculation does not precisely establish the direction or magnitude of a mean difference from the posted summary statistics. The interval is expressed on an absolute scale, so it should not be compared numerically with the sponsor’s rate-ratio interval.

In general, a confidence interval is a measure of statistical uncertainty under a particular analysis and its assumptions. It is not a range guaranteed to contain the true value, nor is it a probability statement about the treatment effect after the data are observed. A narrower interval generally indicates greater precision for the estimate on that scale, while a wider interval leaves more uncertainty about its magnitude.

Precision depends on factors including the number of participants, outcome variability, and the analysis method. The primary groups included 27 placebo participants and 50 participants assigned to lanadelumab 300 mg, and the reported standard deviations were 1.357 and 2.062, respectively. The registry record does not report a precision target or a prespecified clinically important difference. Consequently, the confidence intervals can describe statistical uncertainty, but they cannot by themselves determine whether the range of effects is clinically meaningful.

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 illustrations describe hypothetical sample sizes based on the observed effect, not the trial’s original design. For the primary continuous outcome, figures are participants per arm. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect set at the stated fraction of the observed effect. The original design assumptions and sample-size justification are not reported in the registry record.

For the primary endpoint, planning for 100% of the observed effect gives 184 participants per arm for 80% power and 247 participants per arm for 90% power. Planning for 75% of the observed effect gives 327 participants per arm for 80% power and 438 participants per arm for 90% power. Planning for 50% of the observed effect gives 736 participants per arm for 80% power and 985 participants per arm for 90% power.

In plain terms, the 80% power column describes the planned number per arm for a hypothetical study with an 80% chance of detecting the specified effect under the listed assumptions, if that effect is truly present. The 90% power column uses a higher target chance of detection, which generally requires more participants. Smaller effects need more participants to distinguish them from random variation under the same assumptions. These are planning illustrations, not observed power.

The registry’s general planning note says that time-to-event illustrations, when present, give total events; other illustrations give participants per arm. The primary endpoint is not a time-to-event outcome, so its planning figures are participants per arm. These illustrations are sensitive to the observed effect used as their starting point and should not be interpreted as evidence that the trial was designed around that effect.

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 = 0.540; pooled standard deviation σ = 1.848.
2. n = 2 × (1.96 + 0.842)² × 1.848² / 0.540² = 183.9, rounded up to 184 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 <- 0.54                      # observed difference in means
sigma <- 1.84830744195872                     # 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(4206605)
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 = 184 (80% power), 247 (90% power)
 75% of observed effect: n per arm = 327 (80% power), 438 (90% power)
 50% of observed effect: n per arm = 736 (80% power), 985 (90% power)
power.t.test: 184.9 
Simulated power at n = 184 per arm: 0.800 (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 sponsor’s posted primary analysis reports a rate ratio of 1.02, with a 95% confidence interval from 0.71 to 1.47 and p=0.899. It is identified as a superiority analysis using a Chi-squared method. The posted arm summaries, by contrast, give mean rates of 1.63 attacks/month for placebo and 2.17 attacks/month for lanadelumab 300 mg.

The simple recalculation compares those arm means directly. It gives a mean difference of 0.54 attacks/month, a 95% confidence interval from -0.227 to 1.307, and an unadjusted p-value of 0.168. This is not a reproduction of the sponsor’s rate-ratio analysis. It uses a different effect scale and does not apply any unreported modeling choices.

The sponsor’s analysis and the recalculation should therefore be read as distinct summaries, not as competing versions of the same numerical estimate. The rate ratio is the sponsor’s reported analysis; the mean difference is a supplementary unadjusted calculation from the posted summary statistics. The registry record does not report enough analysis detail to reconcile their differing numerical values. The sponsor’s test and interval are the appropriate reference for the sponsor-reported primary analysis, while the recalculation helps describe the arm means on the endpoint’s original scale.

15. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when several outcomes or comparisons are tested. In general, the more tests conducted, the greater the chance that at least one will appear unusual under a no-effect scenario, even when there is no real difference. Approaches such as adjustment for multiple testing or a prespecified testing sequence can address this concern. The registry record lists 17 outcome measures, 8 analyses, and 16 posted secondary outcomes, but it does not report a multiplicity procedure or a hierarchy specifying which tests were confirmatory.

The primary endpoint is identified in the registry, and the sponsor’s reported primary analysis is labeled as a superiority analysis. That information does not establish what multiplicity strategy was used for the full set of endpoints, nor whether secondary analyses were intended as confirmatory or exploratory. Unadjusted secondary p-values should accordingly be read with caution and in the context of the primary result.

The primary population is defined as the Full Analysis Set, consisting of all randomized participants who received any exposure to the investigational product during the treatment period. The record does not report the number excluded from this set, the reasons for any exclusions, or the handling of participants with missing or incomplete outcome data. It also does not report whether imputation, sensitivity analyses, or other missing-data methods were used.

These omissions matter because incomplete follow-up can affect an attack-rate estimate, particularly if the amount or pattern of missing information differs between groups or is related to attacks. The endpoint’s participant-level rate accounts for days contributed, as described in the registry, but that definition alone does not explain how missing outcomes were addressed. The registry record does not report interim analyses, stopping rules, or the full statistical analysis plan, so no conclusions about those procedures can be drawn from the posted information.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: angioedema (12.0%), cellulitis staphylococcal (2.0%), lymphoedema (2.0%).

The registry reports serious adverse events among 1 of 27 participants at risk in the placebo group and 7 of 50 participants at risk in the lanadelumab 300 mg group. The listed number of participants affected by other adverse events was 27 of 27 in the placebo group and 49 of 50 in the lanadelumab group. No deaths were reported in either group.

The serious-event terms listed most often were Angioedema at 12.0%, Cellulitis staphylococcal at 2.0%, and Lymphoedema at 2.0%. These percentages are reported as listed in the registry record; the record does not explain their calculation or give additional context for interpreting the terms.

These figures are descriptive counts, not proof that a treatment caused an event or that a difference between groups is attributable to treatment. Serious adverse events and other adverse events are distinct summaries, and the counts do not convey timing, duration, severity beyond the serious-event classification, or individual clinical circumstances. The registry record does not report further details needed to assess those aspects. The safety figures should be read as the events recorded during this study, rather than as a complete account of risk in other populations or settings.

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

The posted results describe a randomized comparison of lanadelumab 300 mg and placebo for investigator-confirmed angioedema attacks during Day 0 through Day 182. The sponsor’s primary analysis estimates a rate ratio of 1.02, with a 95% confidence interval from 0.71 to 1.47 and p=0.899. The unadjusted recalculation from the arm means gives a difference of 0.54 attacks/month, with a 95% confidence interval from -0.227 to 1.307 and p=0.168.

These results do not establish a precise difference between groups. The intervals cover a range of comparative values, and the recalculated interval includes both negative and positive mean differences. A p-value above a conventional threshold is not proof that there is no difference, just as a point estimate alone does not demonstrate a meaningful effect. The registry record does not report a clinical threshold for interpreting the size of a difference.

The results also do not establish equivalence. An equivalence conclusion requires a prespecified margin and an analysis designed to assess whether the plausible differences fall within that margin; the registry record does not report such a margin or design. Nor do the findings determine an individual participant’s likely outcome. Group summaries describe averages and uncertainty across participants, not certainty for any one person.

Finally, the findings apply to the enrolled trial population, treatment schedules, outcome definition, and follow-up period described in the registry record. They should not be generalized automatically to other populations, dosing schedules, or durations. The statistical results are evidence about this particular randomized comparison, interpreted with the limitations of its reported analyses and incomplete methodological detail.

18. Why This Trial Matters Statistically

This trial matters statistically because it evaluates a recurrent-event outcome rather than a single event measured once. Recurrent attack data require attention to observation time, variability among participants, and the analysis scale. The registry’s participant-level rate calculation accounts for the number of days contributed, while the sponsor’s analysis reports a rate ratio and the simple recalculation compares mean rates. Understanding these distinctions prevents unlike estimates from being treated as though they answer exactly the same question.

The study also illustrates why point estimates need uncertainty intervals. The primary sponsor estimate is close to the no-difference value for a ratio, but its confidence interval is broad enough to include a range of possibilities. The simple mean-difference recalculation likewise has an interval spanning both directions. Neither point estimate alone captures this uncertainty.

Another important feature is the breadth of the secondary outcomes. Attack-free status, attack severity, rates during a later period, and time to first attack address different dimensions of the outcome. Multiple measures can provide context, but they also make prespecification and multiplicity handling important. Those procedures are not reported in the registry record, which limits how strongly the secondary findings can be interpreted as formal tests.

Finally, the registry record makes a useful distinction between the Full Analysis Set definition and the arm-level results, but leaves important analytical details unreported. Information about missing-data handling, model specification, and the original design assumptions would help readers assess robustness and precision more fully. The posted findings can be interpreted, but they do not answer every question required for a comprehensive statistical appraisal.

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.

Several trial-specific limitations constrain interpretation. The primary comparison has unequal arm sizes: 27 participants in the placebo group and 50 in the lanadelumab 300 mg group. The reported standard deviations are 1.357 and 2.062, respectively, indicating variability in participant-level attack rates. The confidence intervals reflect uncertainty under their respective analyses, but the registry record does not report a prespecified precision goal or clinically meaningful difference.

The primary sponsor analysis is reported as a Chi-squared rate-ratio analysis, but the full model specification is not reported in the registry record. Details about covariate adjustment, the distributional assumptions, and any assessment or handling of over-dispersion are not reported. This limits independent reconstruction of the sponsor’s result and assessment of whether the chosen method fits the recurrent-event data.

The registry record also does not report how missing outcome data were handled, whether participants were excluded from the Full Analysis Set, or whether sensitivity analyses were performed. Those details could affect interpretation of rates over the treatment period. Further limitations include the absence of a reported multiplicity strategy for the many listed outcomes and the lack of a reported clinical threshold for interpreting the size of an effect.

The simple recalculation is unadjusted and uses posted summary statistics. It cannot reproduce any adjustments or modeling decisions in the sponsor’s analysis. The registry record does not report the original sample-size justification, interim analyses, or complete statistical plan. These gaps should be kept in mind when assessing the robustness and generalizability of the findings.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: A Study of Lanadelumab in Teenagers and Adults to Prevent Acute Attacks of Non-histaminergic Angioedema With Normal C1-Inhibitor (C1-INH) — NCT04206605.
• Registry record last updated 2023-12-27; status last verified 2023-12.
• Results first posted 2023-12-27.
• 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

NCT04206605 is a completed Phase 3, multicenter, randomized, placebo-controlled, double-blind study of lanadelumab for prevention of acute attacks of non-histaminergic angioedema with normal C1-INH. The registry lists quadruple masking, a parallel-group model, and enrollment of 77 participants.

The primary outcome was investigator-confirmed angioedema attacks per month during Day 0 through Day 182. The sponsor reported a rate ratio of 1.02, with a 95% confidence interval from 0.71 to 1.47 and p=0.899. An unadjusted recalculation of the arm means gives a mean difference of 0.54 attacks/month, with a 95% confidence interval from -0.227 to 1.307.

The posted results leave uncertainty about the comparative attack rate. The registry record does not report the full statistical plan, missing-data methods, or original sample-size justification.