Rilzabrutinib for the Treatment of Chronic Spontaneous Urticaria in Patients Who Remain Symptomatic Despite the Use of H1 Antihistamine: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Rilzabrutinib for the Treatment of Chronic Spontaneous Urticaria in Patients Who Remain Symptomatic Despite the Use of H1 Antihistamine (NCT05107115), a randomized phase 2 study. The primary outcome is Change From Baseline in Weekly Urticaria Activity Score (UAS7) at Week 12.

2. Clinical Question

The registry lists an enrollment of 160 and identifies the study as a randomized, quadruple-masked, parallel-group phase 2 trial. Its brief description says the double-blind treatment phase lasted 12 weeks and was followed by an optional open-label extension. The clinical question therefore has two distinct settings: a placebo-controlled comparison during the initial phase and longer-term follow-up in an extension where treatment was open label. The primary result concerns only the double-blind Week 12 endpoint in the stated omalizumab-naïve population.

3. Trial Design

The registry describes NCT05107115 as a completed phase 2, randomized, quadruple-masked, parallel-group study sponsored by Sanofi. The study began on 2021-11-24, and primary completion was recorded as 2023-07-19. The design included four double-blind groups: placebo TID, rilzabrutinib 400 mg QPM plus placebo, rilzabrutinib 400 mg BID plus placebo, and rilzabrutinib 400 mg TID. The planned double-blind treatment period was 12 weeks.

The target population was male and female participants aged 18 years or older with chronic spontaneous urticaria who remained symptomatic despite H1 antihistamine treatment. The primary outcome record narrows its analysis population to randomized omalizumab-naïve participants with Baseline and Week 12 data, analyzed according to allocated treatment. The primary endpoint was change from Baseline in UAS7 at Week 12.

After the double-blind phase, participants could choose to enter a 40-week open-label extension. The description says extension participants received open-label rilzabrutinib at dose B or dose C, with dose potentially modified according to the 12-week safety and efficacy data. Monitoring was described at Week 14, Week 16, Week 20, and Week 24, followed by Week 36 and Week 52. Because the extension was open label and participants could enter by choice, it is not the same kind of controlled comparison as the initial phase.

The registry does not report the original sample-size justification, the detailed allocation procedure, the masking procedures, or a full prespecified statistical analysis plan. It also does not report the original design assumptions for the primary analysis in the registry record. Those omissions limit what can be inferred about the intended power, analysis choices, and handling of departures from the planned analysis.

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 160 participants were enrolled in the study. Randomization was stratified by region and prior use of omalizumab.

Double-Blind Period (Up to 12 Weeks)

Reasons for not completing this period:

OLE Period (Weeks 13 to 52: 40 Weeks)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Omalizumab-naïve population consisted of all randomized omalizumab-naïve participants. Participants were analyzed according to the study treatment allocated by the randomization. Only participants with data collected at Baseline and Week 12 are reported.

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: The randomized population consisted of all participants from screened population (who signed the informed consent form \[ICF\]) and had been allocated to a randomized study treatment by interactive response technology (IRT), regardless of whether the study treatment was received.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in Weekly Urticaria Activity Score (UAS7) at Week 12, measured over Baseline and Week 12.

The primary endpoint is change from Baseline in UAS7 at Week 12. UAS7 is a weekly composite score built from hive severity and itch severity. Each daily UAS score combines a hive-severity score and an itch-severity score; daily scores are summed across a 7-day period. The total ranges from 0 to 42, with higher scores indicating worse disease. Its components are HSS7, the weekly hive-severity score, and ISS7, the weekly itch-severity score.

Combining itch and hives gives a single measure that reflects two symptoms central to the condition described in the registry. A change score expresses how the measured weekly symptom burden at follow-up compares with the participant’s Baseline. Negative changes in the posted arm summaries indicate lower scores at Week 12 than at Baseline; the endpoint definition makes clear that lower scores correspond to less severe measured symptoms. This description explains the score’s direction, but does not by itself establish the clinical importance of any particular change.

For this outcome, Baseline is defined as the sum of the 7 days of measurements obtained on and prior to the target visit day. The primary analysis reports least-squares means and standard deviations for the change scores. The registry states that only participants with data collected at Baseline and Week 12 are reported. The reason UAS7 was selected as the primary endpoint, and any threshold for a clinically meaningful change, are not reported in the registry record.

7. Results Posted in the Registry

• DB Period: Rilzabrutinib 400 mg QPM + Placebo: mean -9.74 versus -10.14 on control; difference 0.40 (95% CI -0.61 to 1.41), standardized effect d = 0.20; z-test p = 0.437.
• DB Period: Rilzabrutinib 400 mg BID + Placebo: mean -14.24 versus -10.14 on control; difference -4.10 (95% CI -5.16 to -3.04), standardized effect d = -2.00; z-test p = <0.001.
• DB Period: Rilzabrutinib 400 mg TID: mean -16.89 versus -10.14 on control; difference -6.75 (95% CI -7.79 to -5.71), standardized effect d = -3.30; z-test p = <0.001.

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.

Change From Baseline in Weekly Urticaria Activity Score at Week 4

• 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 errors.
• Result:
  • DB Period: Rilzabrutinib 400 mg QPM + Placebo: mean -9.14 versus -7.06 on control; difference -2.08 (95% CI -6.77 to 2.61), standardized effect d = -0.21; z-test p = 0.384.
  • DB Period: Rilzabrutinib 400 mg BID + Placebo: mean -12.89 versus -7.06 on control; difference -5.83 (95% CI -10.61 to -1.05), standardized effect d = -0.58; z-test p = 0.017.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between DB Period: Rilzabrutinib 400 mg QPM + Placebo and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for DB Period: Rilzabrutinib 400 mg BID + Placebo than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Change From Baseline in Weekly Hives Severity Score (HSS7) at Week 12

• 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 errors.
• Result:
  • DB Period: Rilzabrutinib 400 mg QPM + Placebo: mean -4.49 versus -4.40 on control; difference -0.09 (95% CI -3.00 to 2.82), standardized effect d = -0.02; z-test p = 0.952.
  • DB Period: Rilzabrutinib 400 mg BID + Placebo: mean -6.52 versus -4.40 on control; difference -2.12 (95% CI -5.07 to 0.83), standardized effect d = -0.37; z-test p = 0.159.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between DB Period: Rilzabrutinib 400 mg QPM + Placebo and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between DB Period: Rilzabrutinib 400 mg BID + Placebo and the control. The interval gives the range of effects that remain compatible with the data.

Percentage of Participants With Weekly Urticaria Activity Score Less Than or Equal to (≤)6 at Week 12

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • DB Period: Rilzabrutinib 400 mg QPM + Placebo: 5.4% (2/37) versus 11.1% (4/36) on control; risk difference -5.7 percentage points (95% CI -18.3 to 6.9), risk ratio 0.49 (0.09–2.49); unadjusted two-proportion z-test p = 0.375.
  • DB Period: Rilzabrutinib 400 mg BID + Placebo: 20.0% (7/35) versus 11.1% (4/36) on control; risk difference 8.9 percentage points (95% CI -7.9 to 25.7), risk ratio 1.80 (0.58–5.61); unadjusted two-proportion z-test p = 0.301.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between DB Period: Rilzabrutinib 400 mg QPM + Placebo and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between DB Period: Rilzabrutinib 400 mg BID + Placebo and the control. The interval gives the range of effects that remain compatible with the data.

The posted secondary results give additional views of symptom change and a binary symptom threshold. Across these outcome types, the arm summaries generally show more negative mean changes in the higher-frequency rilzabrutinib regimens than in placebo, while the QPM regimen is closer to the placebo summary. The proportions reaching UAS7 at most 6 also vary across arms. These outcomes add context to the primary UAS7 comparison, but they do not replace it: they use different time points, score components, or definitions of response.

The primary outcome and secondary measures are related because they draw on the same underlying urticaria activity and symptom measures. The Week 4 measure is an earlier assessment of UAS7 change; HSS7 focuses on hive severity rather than the combined UAS7 score; and the threshold outcome classifies participants according to a specified Week 12 score. Similar patterns across related outcomes can be informative, but the outcomes are not interchangeable and may have different amounts of missing data or variability.

Unadjusted secondary results carry less weight as confirmatory evidence when several outcomes and comparisons are considered. Testing multiple hypotheses raises the chance that at least one result will appear notable by chance. The registry record does not report whether secondary tests were adjusted for multiplicity, whether a hierarchical testing strategy was used, or whether the secondary outcomes were intended to support formal claims. They should therefore be read as descriptive or exploratory unless the registry record reports otherwise.

The registry lists additional secondary outcomes, including UAS7 equal to 0, adverse events, and plasma concentration, but numerical results for those outcomes are not reported in the registry record. That limits a complete assessment of consistency across all registered measures. The secondary findings are best considered alongside the sponsor-reported primary analysis and its uncertainty, rather than as separate proof of efficacy.

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

• Change From Baseline in Weekly Urticaria Activity Score at Week 4
• Change From Baseline in Weekly Hives Severity Score (HSS7) at Week 12
• Percentage of Participants With Weekly Urticaria Activity Score Less Than or Equal to (≤)6 at Week 12
• Percentage of Participants With Weekly Urticaria Activity Score Equal to 0 at Week 12
• Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs), Treatment-Emergent Adverse Events of Special Interest (AESIs), and Withdrawals Due to Treatment-Emergent Adverse Events
• Plasma Concentration of Rilzabrutinib

9. Statistical Interpretation

10. Statistical Methods Explained

What does a mean change represent?

A mean change summarizes the average difference between a participant’s score at the defined follow-up and Baseline within an arm. Here, the endpoint is UAS7 change at Week 12, and the registered result parameter is a least-squares mean. Least-squares means are model-based group summaries; their precise interpretation depends on the analysis model and any terms included in it. The registry reports that the sponsor used ANCOVA for the primary comparisons, but the covariates and full model specification are not reported in the registry record.

The arm summaries list the number of participants contributing to each outcome, a mean change, and a measure of dispersion. The primary outcome lists standard deviation as the dispersion measure. A standard deviation describes variability among individual observations around the group mean; it is not the uncertainty of the group mean itself. The posted primary comparison also gives sponsor-reported LS mean differences and confidence intervals, which provide information about uncertainty in the between-group estimates.

How should ANCOVA be understood?

ANCOVA is a regression-based method for comparing group outcomes while accounting for covariates included in the model. In a clinical trial, this can produce adjusted comparisons rather than a simple difference between the two arm means. The registry identifies ANCOVA as the sponsor’s method and reports LS mean differences. It does not identify the covariates, model diagnostics, or other modeling details. Those details should not be inferred from the method label alone.

The registry’s sponsor-reported comparisons are therefore the appropriate basis for discussing the planned model results. The separate recalculated comparisons use posted summary statistics and represent simple unadjusted approximations. They do not reproduce the sponsor’s ANCOVA. Their confidence intervals and p-values can differ because a summary-statistic calculation does not account for the full fitted model or its adjustments. In this trial the discrepancy is flagged, so the sponsor’s analysis takes precedence.

What do the confidence intervals and p-values convey?

A confidence interval describes a range of estimates compatible with the data under the assumptions of the analysis procedure. A wider interval indicates less precision; an interval spanning zero is compatible with both negative and positive differences at the stated confidence level. For a difference in change scores, zero corresponds to no between-group difference in mean change. The sponsor reports 95% confidence intervals for each primary comparison.

A p-value measures how unusual the observed data, or data more extreme, would be under a specified null hypothesis and the statistical model. It does not measure the probability that the null hypothesis is true, and it does not communicate the clinical importance of the estimate. The sponsor-reported p-values are attached to ANCOVA comparisons. The recalculated p-values are unadjusted and approximate; they should not be substituted for the sponsor’s results.

Why can recalculation differ from a trial analysis?

Recalculation from arm means and dispersion measures can provide a transparent, simple comparison, but it discards information available to a trial’s full analysis. It may not match the adjustment set, analysis population details, or variance calculations used by the sponsor. In addition, the registry reports least-squares means and dispersion, while the recalculation approximates standard deviations for comparisons. The recalculated intervals are consequently not the sponsor’s model-based intervals. When the record identifies a discrepancy, the reported trial analysis is the primary reference.

What is the role of the secondary outcomes?

Secondary outcomes provide additional descriptions of symptoms and response at other time points or using other measures. The posted results include Week 4 UAS7 change, Week 12 HSS7 change, and the proportion with UAS7 at most 6 at Week 12. The registry also lists other outcomes, including UAS7 equal to 0, adverse-event summaries, and plasma concentration. Numerical results for outcomes not included in the posted secondary summaries are not reported in the registry record.

Results across several outcomes can help describe whether observed patterns are consistent, but testing many comparisons creates a multiplicity issue: even if no real differences exist, a collection of tests can produce some small p-values by chance. The registry record does not report a multiplicity adjustment or a testing hierarchy. Therefore unadjusted secondary comparisons are best treated as exploratory evidence, rather than as independent confirmation of the primary result.

Why does over-dispersion matter in general?

For binary outcomes, a binomial model assumes a particular relationship between the event probability and the variability in observed counts. If outcomes vary more than that model assumes, the data are over-dispersed relative to the model. In general, ignoring over-dispersion can make standard errors too small and intervals too narrow. The registry does not report whether over-dispersion was assessed or which inferential model was used for the posted binary secondary outcome. This is a general statistical consideration, not a finding about this trial.

For continuous outcomes, variation among participants also matters: a mean difference estimated with more variability is typically less precise than the same difference estimated with less variability. The posted arm summaries and confidence intervals convey part of this uncertainty, but the full analytic assumptions and diagnostic information are not reported in the registry record.

11. Confidence Intervals and Precision

The sponsor’s 95% confidence intervals show how precisely the primary between-group differences were estimated under the reported ANCOVA. For 400 mg QPM plus placebo versus placebo, the LS mean difference was 0.40, and the interval extended from -5.08 to 5.89. This interval includes zero and allows a range of differences in either direction. For 400 mg BID plus placebo, the reported estimate was -4.09, with an interval from -9.59 to 1.40, which also includes zero. For 400 mg TID, the estimate was -6.75, and the interval from -12.23 to -1.26 is entirely below zero.

These intervals are not statements that a particular percentage of individual participants had scores within the interval. They concern uncertainty about the estimated group difference under the analysis. Nor do they indicate whether a difference is clinically important: the registry record does not report a threshold for meaningful change. The more the interval spans plausible values in both directions, the less decisive the estimate is about the direction and size of the comparison.

The sponsor-reported intervals differ from the recalculated intervals based on posted summary statistics. For example, the sponsor’s reported BID interval includes zero, while the unadjusted recalculated interval does not. This is a material difference in inference, not a reason to combine the two approaches. The recalculation is an approximate, unadjusted check; the sponsor’s ANCOVA is the reported trial analysis and takes precedence because the record flags a discrepancy.

Precision also depends on who contributes data. The primary outcome specifies that only participants with Baseline and Week 12 measurements are reported. The registry record does not provide a complete account of missing outcome data or the assumptions used to address it. Thus, the intervals describe uncertainty in the analyzed data under the reported method, and do not resolve possible uncertainty arising from missing measurements or departures from the analysis population.

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

The 80% power column gives the illustrative number of participants per arm for a design with an 80% chance of detecting the specified effect under those planning assumptions, if that effect and the model assumptions were correct. The 90% power column gives the corresponding illustration for a 90% chance. Power is a property of a planned study under assumptions; it is not a measure of the probability that a result is true.

Rows planning for 100%, 75%, or 50% of the observed effect show how the illustration changes if the effect a future study aims to detect is smaller than the observed estimate. Smaller effects need more participants to distinguish them from random variation with the same stated power and assumptions. In the posted comparisons, very small observed effects can yield especially large planning figures, while large observed effects can yield very small figures. Such extreme estimates should not be treated as reliable design recommendations without independent justification of the target effect and suitable planning assumptions.

These calculations are not observed power. They are hypothetical planning illustrations computed from the observed effect and stated assumptions; they do not show the actual power of this completed trial or validate its original design.

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 = 0.400; pooled standard deviation σ = 2.026.
2. n = 2 × (1.96 + 0.842)² × 2.026² / 0.400² = 402.7, rounded up to 403 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 <- 0.4                      # observed difference in means
sigma <- 2.02598741358381                     # 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(5107115)
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 = 403 (80% power), 540 (90% power)
 75% of observed effect: n per arm = 716 (80% power), 959 (90% power)
 50% of observed effect: n per arm = 1,611 (80% power), 2,157 (90% power)
power.t.test: 403.7 
Simulated power at n = 403 per arm: 0.802 (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 reports sponsor ANCOVA results for all three primary comparisons. The reported LS mean differences were 0.40 for QPM plus placebo, -4.09 for BID plus placebo, and -6.75 for TID, each compared with placebo. Their corresponding 95% confidence intervals and p-values are reported with the primary outcome. Those model-based results are the trial’s own reported analyses.

Separate recalculations use the posted arm summaries to form simple unadjusted comparisons. They are useful as a transparent check of the direction and approximate magnitude, but they do not reproduce the ANCOVA model. In particular, the recalculated BID interval excludes zero whereas the sponsor’s reported interval includes zero; the p-values also differ. The TID estimate is similar in magnitude, but its recalculated uncertainty differs from the sponsor’s reported interval. The QPM recalculation likewise does not match the sponsor’s confidence interval or p-value.

The registry flags a discrepancy between the sponsor’s analysis and the recalculation. Accordingly, the sponsor’s own ANCOVA takes precedence for interpretation of the trial’s reported inferential results. The recalculations should not be described as corrected sponsor findings, nor should the unadjusted p-values be used to override the reported analysis. The full model specification and reasons for the discrepancy are not reported in the registry record.

15. Multiplicity, Missing Data and Analysis Populations

The study has multiple treatment-versus-placebo comparisons and several registered secondary outcomes. Each additional comparison creates another opportunity for a result to appear statistically notable by chance. Multiplicity procedures can control that risk, for example by adjusting tests or defining a testing sequence. The registry record does not report a multiplicity adjustment, a hierarchy among the treatment arms, or how confirmatory claims were to be controlled. The sponsor-reported p-values should therefore be understood as reported for individual comparisons, without assuming that they were adjusted for all comparisons.

The record identifies ANCOVA for the primary comparisons but does not provide the complete model specification, covariates, missing-data assumptions, or sensitivity analyses. The primary population definition says that only participants with data at Baseline and Week 12 are reported. It does not explain the amount or pattern of missing data, why measurements were unavailable, or whether any imputation or other missing-data method was used. Those details are not reported in the registry record.

The results also distinguish the omalizumab-naïve primary population from the full randomized study population. The outcome description states that the analyzed participants were randomized omalizumab-naïve participants, analyzed according to allocated treatment, with Baseline and Week 12 data. The registry does not give further detail about how that population was defined operationally or how participants lacking endpoint data were handled. This limits assessment of whether the primary estimate represents all randomized participants.

There is a further interpretive distinction between the double-blind randomized phase and the optional open-label extension. The extension was not a blinded placebo comparison, and entry was optional. Its treatment and follow-up data should not be treated as equivalent to the randomized primary comparison. The registry record does not report an inferential plan for comparing extension groups or integrating extension findings with the primary endpoint.

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: joint dislocation (11.1%), ligament rupture (11.1%), peritonsillar abscess (2.5%), urticaria (2.4%), iatrogenic injury (2.4%).

During the double-blind period, the registry lists serious adverse events in 1 of 40 participants at risk in the placebo group, 0 of 38 in the QPM plus placebo group, 0 of 41 in the BID plus placebo group, and 2 of 41 in the TID group. These are counts within the registry’s stated groups and risk denominators. They describe recorded serious adverse events, not a causal comparison between treatments.

The registry lists 14 participants with other adverse events among 40 at risk for placebo, 20 among 38 for QPM plus placebo, 26 among 41 for BID plus placebo, and 25 among 41 for TID. No deaths are listed in these double-blind groups. In the open-label extension, serious adverse events were recorded for 1 of 9 participants in the BID group and 4 of 128 in the TID group; other adverse events were recorded for 7 of 9 and 59 of 128, respectively. No deaths are listed for those extension groups.

The extension counts come from an open-label period with different group sizes and selected participants, so they should not be read as direct randomized comparisons with the double-blind groups. The registry also lists serious-event terms and percentages, but these summaries do not provide event timing, participant-level context, or a comparative safety analysis. The counts alone cannot establish whether an event was caused by a study treatment.

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

The primary endpoint summarizes change in a weekly measure of hives and itch. The posted group means show decreases from Baseline across placebo and all three rilzabrutinib groups. The sponsor’s ANCOVA estimates suggest different between-group patterns across the three regimens: the QPM and BID confidence intervals include zero, while the TID interval is below zero. These statements describe the recorded outcomes and their statistical uncertainty, not a recommendation about care.

A statistically distinguishable estimate does not automatically establish that the magnitude matters to patients. The registry record does not report a clinically meaningful difference threshold, so the practical importance of the estimated score differences cannot be determined from the statistical result alone. Conversely, a confidence interval that includes zero does not prove that the groups are identical; it indicates that the estimated difference is uncertain under the reported analysis.

The primary analysis applies to the specified omalizumab-naïve participants with Baseline and Week 12 data, not automatically to every participant enrolled or to all people with chronic spontaneous urticaria. The randomized double-blind period lasted 12 weeks, and the optional extension was open label. The primary outcome therefore does not establish what would happen over the extension period or in populations not represented by the analyzed group.

The discrepancy between the sponsor’s ANCOVA and the summary-statistic recalculation matters. The recalculation is unadjusted and approximate, and the sponsor’s reported analysis takes precedence. The registry record does not include sufficient model detail to independently reproduce the ANCOVA or fully resolve the difference.

Finally, the registry record is not a complete clinical interpretation. It does not report the original sample-size rationale, multiplicity plan, detailed missing-data methods, or a clinical-importance threshold. The results should be read as estimates from a specific trial analysis, with these limits kept in view.

18. Why This Trial Matters Statistically

This trial is statistically informative because it compares three rilzabrutinib dosing regimens with a placebo group in a randomized, double-blind phase. The parallel design provides a structured basis for comparing Week 12 symptom-score changes, and the primary outcome combines itch and hive severity into a weekly measure. The sponsor reports an ANCOVA estimate and confidence interval for each active regimen versus placebo, allowing readers to consider both estimated direction and uncertainty rather than relying only on a single significance label.

The record also illustrates why the analysis method matters. A direct calculation from group summaries is not equivalent to the sponsor’s ANCOVA, and the difference is consequential for the BID comparison. Reporting the model-based result and the approximate recalculation side by side makes clear that a seemingly simple mean comparison may not reproduce a trial’s adjusted analysis. The registry’s discrepancy flag is therefore important context for statistical interpretation.

The outcome set offers complementary perspectives: a primary composite score, an earlier UAS7 assessment, hive severity, and a response threshold. These measures can help describe consistency, but their multiplicity and incomplete adjustment details mean secondary findings need cautious interpretation. Similarly, the optional open-label extension contributes follow-up safety and treatment exposure information but does not preserve the controlled comparison of the initial phase.

Finally, the registry record shows the value of distinguishing statistical evidence from clinical importance. Confidence intervals describe precision around estimates, while the record does not supply a clinically meaningful threshold or the full analysis plan. Readers can assess what the reported data estimate while recognizing which questions remain unanswered.

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 primary endpoint analysis is restricted to omalizumab-naïve randomized participants with both Baseline and Week 12 data. The registry record does not describe the extent or pattern of missing data, or how missing measurements were addressed beyond reporting participants with both time points. This makes it difficult to judge the effect of missing outcomes on the estimates.

The sponsor’s ANCOVA is identified, but its covariates and full model specification are not reported. The summary-statistic recalculation does not reproduce that model, and the record flags a discrepancy. Although the sponsor’s results take precedence, the available record does not explain the discrepancy or permit a full independent replication of the reported analysis.

The registry record does not report the multiplicity strategy for the three primary comparisons and the several registered secondary outcomes. It also does not report a clinically meaningful difference threshold. These omissions limit interpretation of both the evidence across multiple comparisons and the practical significance of the estimated score differences.

Only some registered secondary outcomes have numerical results in the posted summaries. Other listed outcomes, including UAS7 equal to 0, adverse-event summaries, and plasma concentration, do not have numerical results reported in the registry record. Consequently, the complete pattern across registered measures cannot be evaluated from these data.

The open-label extension was optional and did not provide the same randomized, blinded comparison as the initial period. Its groups also have different risk denominators. Extension results should therefore be considered separately from the primary placebo-controlled comparison. The registry record does not report a detailed statistical plan for extension analyses.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Rilzabrutinib for the Treatment of Chronic Spontaneous Urticaria in Patients Who Remain Symptomatic Despite the Use of H1 Antihistamine — NCT05107115.
• Registry record last updated 2026-08-06; status last verified 2025-04.
• Results first posted 2026-08-06.
• 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

NCT05107115 is a completed, randomized, quadruple-masked, parallel-group phase 2 study of rilzabrutinib for adults with chronic spontaneous urticaria who remained symptomatic despite H1 antihistamine treatment. The double-blind phase compared three oral rilzabrutinib regimens with matching placebo over 12 weeks. The primary endpoint was change from Baseline in UAS7 at Week 12 in the stated omalizumab-naïve population with both time-point measurements.

The sponsor-reported ANCOVA found a 95% confidence interval crossing zero for QPM and BID comparisons, while the TID comparison’s interval was below zero. The registry flags a discrepancy with unadjusted summary-statistic recalculations, so the sponsor’s analysis takes precedence. The record also describes an optional 40-week open-label extension. Original sample-size assumptions, detailed missing-data methods, multiplicity handling, and a clinically meaningful threshold are not reported in the registry record.