Cold Urticaria Treatment With Xolair: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Cold Urticaria Treatment With Xolair (NCT01580592), a randomized phase 2 study. The primary outcome is Change in Critical Temperature Thresholds (CTT) From Baseline to Day 70 After Treatment With Omalizumab Compared to Placebo.

2. Clinical Question

The trial asked whether omalizumab was associated with a change in cold-trigger threshold in people with antihistamine-resistant cold contact urticaria. The primary outcome was the change in critical temperature threshold from baseline to day 70, assessed using TempTest® and reported as a mean change in degrees Celsius. The registry lists two omalizumab doses, 150 mg and 300 mg, and a placebo group.

The registry describes the study as randomized, double blind, and parallel design. These design features frame the intended comparison, but the posted outcome data alone do not establish how randomization was implemented or whether masking remained intact. Nor do they establish the clinical importance of a given threshold change. The results should therefore be read as registry-recorded group summaries and analyses, with attention to the limitations and discrepancies described in the statistical interpretation.

3. Trial Design

This completed phase 2 study is registered as NCT01580592, with the title Cold Urticaria Treatment With Xolair. Its official title describes a two-center, double-blind, placebo-controlled study in parallel design assessing 150 mg and 300 mg omalizumab in subjects with antihistamine-resistant cold contact urticaria. The registry lists randomized allocation and double masking. Total enrollment was 31.

The registry lists three groups: omalizumab 150 mg, omalizumab 300 mg, and placebo. For the primary outcome, the reported group sizes were 10, 9, and 12 participants, respectively. The study start is listed as 2012-04, primary completion as 2014-12, and status as completed. The sponsor is Charite University, Berlin, Germany.

The primary outcome was the change in critical temperature threshold from baseline to day 70. The registry description says TempTest® was used to assess critical temperature thresholds in degrees Celsius, with the primary efficacy outcome described as change in trigger thresholds from baseline to week ten. Day 70 and week ten are both used in the registry record to describe the assessment timing.

The record lists one secondary outcome concerning participants with abnormal physical examinations, laboratory assessments, vital signs, and adverse events. Although the record indicates two outcome measures and four analyses, fuller details about the analysis populations, model specification, handling of missing observations, and procedures for multiple testing are not reported in the registry record. The original sample-size justification and design assumptions are also not reported in the registry record. The posted planning illustrations are based on the observed effect and should not be taken as the trial’s original design rationale.

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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: female and male

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: Intention-to-treat

6. Primary Endpoint

The registry lists the primary outcome as Change in Critical Temperature Thresholds (CTT) From Baseline to Day 70 After Treatment With Omalizumab Compared to Placebo, measured over day 70.

The primary endpoint is the change in critical temperature threshold from baseline to day 70, assessed with TempTest® and measured in degrees Celsius. The registry describes the outcome as a mean change in trigger threshold. A threshold represents the temperature at which the cold stimulus triggers a response under the assessment procedure; recording a change allows the outcome to reflect movement from each participant’s baseline measurement rather than only a value at follow-up.

The posted group summaries report mean changes of -10.6 for omalizumab 150 mg, -10.4 for omalizumab 300 mg, and -0.3 for placebo. The associated standard deviations are 7.6, 9.4, and 3.9, respectively. These are group-level summaries, not individual participant results. The registry does not provide the underlying individual measurements or confidence intervals for the group means.

In general, a continuous endpoint such as a temperature threshold can preserve more detail than reducing observations to a simple event/no-event classification. A mean summarizes the group’s average change, while a standard deviation describes how spread out individual changes are around that mean. Neither statistic alone describes the full distribution. The clinical meaning of a negative change depends on the endpoint’s direction and measurement conventions, and the registry record does not give enough detail to translate these values into a specific patient-level interpretation. The result is therefore best read as a measured change in threshold, not as a direct measure of symptom relief or quality of life.

7. Results Posted in the Registry

• Omalizumab 150mg: mean -10.60 versus -0.30 on control; difference -10.30 (95% CI -15.50 to -5.10), standardized effect d = -1.76; z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: it is a mean change in critical temperature threshold. The posted group summaries pair each mean with a standard deviation and a group size. In general, a mean gives a compact description of the group’s average measured change. A standard deviation describes the spread of individual measurements around that average; it is not the uncertainty of the mean and should not be read as a confidence interval.

What does the recalculated comparison estimate?

The recalculated comparison is an unadjusted difference between the mean change in the omalizumab 150 mg group and the mean change in the placebo group. Its estimate is -10.3. In general, a difference between group means expresses how far apart the two group averages are on the outcome scale. The negative sign reflects the ordering used in the calculation: the 150 mg group mean minus the placebo group mean. It does not, on its own, establish whether that direction is beneficial, because the registry record does not explain the clinical interpretation of positive versus negative threshold change.

The recalculation uses the posted sample sizes, means, and standard deviations. It is described as unadjusted because it does not incorporate baseline covariates or other model adjustments. The registry does not provide participant-level records, so the recalculation cannot reproduce analyses that may have used additional variables or different data-handling choices. It should be understood as a simple analysis of the posted summaries, not as a reconstruction of every aspect of the trial analysis.

What do the confidence interval and p-value add?

The recalculated 95% confidence interval runs from -15.5 to -5.098. In general, a confidence interval expresses the range of estimates reasonably compatible with the data and the statistical assumptions used for the calculation. Its width conveys precision: a narrower interval indicates greater precision than a wider interval on the same scale. A confidence interval is not a guarantee that the true effect lies within its limits, and it does not cover uncertainty about design choices, measurement, or missing data.

The recalculated p-value is p < 0.001. In general, a p-value describes how unusual results at least as incompatible with a specified null hypothesis would be if that hypothesis and the analysis assumptions held. It is not the probability that the null hypothesis is true, nor a measure of clinical importance. The recalculated p-value and interval summarize the same unadjusted contrast from different perspectives: the p-value gives a tail-area measure under a null model, while the interval gives a range of estimates.

Why does variability matter?

The posted standard deviations are not identical across groups. In general, variability affects the uncertainty of a difference in means: more spread in participant outcomes can make the group comparison less precise, while more observations can help estimate a mean more precisely. The recalculation uses a pooled standard deviation of 5.862 and reports a standardized difference of -1.757. A standardized difference expresses the mean contrast relative to a measure of outcome spread, rather than in degrees Celsius. Such a measure can help describe magnitude on a scale independent of the original measurement units, but it does not substitute for interpreting the outcome in its clinical context.

In general, pooling variability relies on assumptions about how the groups’ outcome variances relate. The registry does not report a detailed variance model for the sponsor’s analysis. The recalculation’s reported standard errors for the placebo and 150 mg group means are 1.126 and 2.403. Standard errors describe the estimated sampling uncertainty of a statistic, rather than the spread of participant measurements. They are used in constructing the comparison’s uncertainty estimate, but they do not capture every source of uncertainty in a clinical trial.

What is not specified about the analysis?

The record lists ANOVA for two sponsor-reported analyses, but does not provide a complete statistical analysis plan or enough detail to determine precisely how those analyses were specified. The original sample-size justification, any interim analyses, analysis-population definitions, and approach to missing primary outcome data are not reported in the registry record. Nor are details about any baseline adjustment, multiplicity correction, or sensitivity analyses reported in the registry record. These omissions matter because analysis choices can affect estimates, uncertainty, and the interpretation of multiple comparisons.

The registry’s reported analysis values do not align straightforwardly with the posted group means, including a sign difference for the 300 mg entry. The registry record does not explain whether this reflects a different contrast, a sign convention, or another reporting issue. The recalculation therefore offers a clearly described, simple contrast for 150 mg versus placebo, while the sponsor’s own analysis remains the primary reported analysis in light of the discrepancy. Neither analysis alone answers questions the record does not address, such as how missing measurements were handled or how a clinically meaningful change was defined.

General statistical interpretation should keep the measurement scale, variation, design, and analysis method in view together. A group mean difference can be estimated precisely yet still be difficult to interpret clinically if the scale’s direction or meaningful-change threshold is unclear. Conversely, a numerical contrast is only one component of evidence: study conduct, representativeness, outcome assessment, and transparent analysis details also shape how registry results should be read.

10. Confidence Intervals and Precision

The recalculated mean difference for omalizumab 150 mg versus placebo is -10.3, with a 95% confidence interval from -15.5 to -5.098. This interval describes uncertainty around the unadjusted contrast based on the posted group summaries and the assumptions of the recalculation. Its limits are both negative, so the range of values compatible with that calculation does not include zero. That statistical feature does not establish clinical importance or resolve the discrepancy with the sponsor-reported analysis.

In general, a confidence interval gives more information than a point estimate alone because it indicates a range of plausible values under the model. The interval’s width reflects sampling precision in the calculation: a wider interval indicates less precision than a narrower interval on the same scale. Precision is affected by outcome variability and sample size. The standard deviations for the groups were 7.6 for omalizumab 150 mg and 3.9 for placebo, with 10 and 12 participants, respectively. The relatively small group sizes mean the estimates are based on limited numbers of observations, although the confidence interval itself should be interpreted using its stated calculation rather than by a general impression of sample size.

The confidence interval is not a range for individual participants’ changes, and it does not show where most individual outcomes fell. It also does not incorporate uncertainty from unreported analytic decisions, such as missing-data handling or any adjustments used in the sponsor’s analysis. The registry does not report a confidence interval for the sponsor’s analyses or for the group mean changes.

No recalculated confidence interval is listed for the 300 mg-versus-placebo contrast. The registry’s sponsor-reported entries do not include confidence limits. Therefore, precision cannot be compared across all three groups using a consistent set of between-group intervals. The recalculated interval should be read as one unadjusted estimate with uncertainty, not as a complete account of the trial’s inferential results.

11. 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 participants per arm, not total events. They are illustrations based on the observed 150 mg-versus-placebo effect, not a record of the trial’s original design calculation. The original sample-size assumptions are not reported in the registry record.

The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set as a stated fraction of the observed effect. For planning for 100% of the observed effect, the illustration gives 6 participants per arm for 80% power and 7 participants per arm for 90% power. For planning for 75% of the observed effect, it gives 10 participants per arm for 80% power and 13 participants per arm for 90% power. For planning for 50% of the observed effect, it gives 21 participants per arm for 80% power and 28 participants per arm for 90% power.

In general, power is the probability of detecting an effect of a specified size under the assumptions of a planning calculation, if that effect is present. The 80% power column represents a planning target with an 80% chance of detecting the specified effect under those assumptions; the 90% column represents a higher target. Detecting a smaller effect generally requires more participants, which is why the figures rise as the assumed effect becomes a smaller fraction of the observed effect. These are planning illustrations, not observed power.

The calculations use equal allocation for a two-arm comparison, while the trial’s reported outcome group sizes were 10, 12, and 9 across its three arms. The illustrative values do not describe the full three-arm design, do not establish what the investigators planned, and do not correct for other design or analysis considerations that are not reported in the registry record.

12. 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 = -10.300; pooled standard deviation σ = 5.862.
2. n = 2 × (1.96 + 0.842)² × 5.862² / -10.300² = 5.1, rounded up to 6 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 <- -10.3                      # observed difference in means
sigma <- 5.86152710477398                     # 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(1580592)
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 = 6 (80% power), 7 (90% power)
 75% of observed effect: n per arm = 10 (80% power), 13 (90% power)
 50% of observed effect: n per arm = 21 (80% power), 28 (90% power)
power.t.test: 6.2 
Simulated power at n = 6 per arm: 0.787 (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.

13. Analyses Reported by the Sponsor

The registry’s sponsor-reported analyses are listed separately from the recalculated 150 mg-versus-placebo contrast. The sponsor entries identify ANOVA for the 150 mg group, with a reported value of -10.6 and p = 0.001, and for the 300 mg group, with a reported value of 10.4 and p = 0.01. The placebo entry is 0.3, with no method or p-value listed. Confidence intervals are not reported for these entries.

The posted group means are -10.6 for 150 mg, -10.4 for 300 mg, and -0.3 for placebo. The registry record does not explain how the reported analysis values relate to those means. In particular, the sponsor entry for 300 mg has a different sign from the posted group mean. It is not possible to determine from the record whether the entries use a different contrast, a sign convention, or another reporting approach.

The recalculated estimate of -10.3, with a 95% confidence interval from -15.5 to -5.098 and p < 0.001, is a simple unadjusted comparison of the posted 150 mg and placebo summaries. The record flags a discrepancy between that calculation and the sponsor’s analysis. For that reason, the sponsor’s own analysis takes precedence. The recalculation can illustrate what follows from the posted summary statistics, but it should not be presented as a correction to or replacement for the sponsor’s analysis.

14. Multiplicity, Missing Data and Analysis Populations

The trial has three groups and the registry lists four analyses, but the record does not provide a full analysis plan explaining which comparisons were prespecified or how the analyses relate to one another. The posted recalculation is for the 150 mg group versus placebo only. A corresponding recalculated comparison for 300 mg versus placebo is not listed. The sponsor-reported entries are presented by group, rather than as a clearly documented set of pairwise treatment-versus-placebo contrasts.

When several outcomes, treatment groups, time points, or statistical comparisons are examined, the chance of at least one apparently unusual result can increase. In general, multiplicity procedures are methods for controlling or describing that issue. Whether any such procedures were used for this trial is not reported in the registry record. The registry does not state whether the p-values were adjusted, whether the primary comparison was selected in advance, or whether any analyses were exploratory. Accordingly, the listed p-values should not be treated as if the record had established a particular multiplicity strategy.

The registry record also does not report the analysis populations, such as whether results were based on all randomized participants or a subset. It does not explain whether participants without a day 70 assessment were included, how missing outcome values were handled, or whether any imputation or sensitivity analyses were performed. The number of participants contributing to the reported outcome is listed by group, but the record does not provide enough information to determine whether those counts reflect everyone randomized or only participants with available endpoint data.

These details affect interpretation. Missingness can matter when participants with unobserved outcomes differ from those with observed outcomes. Analysis populations can matter when exclusions occur after randomization. In general, prespecification and transparent reporting help readers distinguish a planned primary analysis from additional analyses. The original statistical plan, interim analyses, missing-data methods, and multiplicity adjustments are not reported in the registry record, so conclusions about those aspects cannot be drawn from the posted results.

15. Safety Results

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

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 10 participants at risk in the omalizumab 150 mg group, 9 in the omalizumab 300 mg group, and 12 in the placebo group. The number affected by serious adverse events is listed as 0 in each group. No serious adverse event terms are listed. The registry does not give death counts in the posted safety summary.

These figures describe the serious-event counts recorded for the groups during the reporting period covered by the registry entry. They do not establish that no serious events could occur, and the small group sizes limit how much can be inferred about uncommon events. In general, an absence of recorded events in a limited sample does not demonstrate an absence of risk. The record does not provide further detail about the event definitions, observation duration for safety, or the completeness of adverse-event ascertainment.

The registry separately lists other adverse events affecting 4 participants in the 150 mg group, 4 in the 300 mg group, and 5 in the placebo group. These entries are distinct from the serious adverse event counts; the record does not provide event terms in the safety summary. The safety figures should be read as reported counts, not as a comprehensive comparison of safety profiles or as evidence that one group is safer than another.

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

The posted primary outcome data show mean changes in critical temperature threshold of -10.6 for the omalizumab 150 mg group, -10.4 for the 300 mg group, and -0.3 for placebo at day 70. The registry reports standard deviations of 7.6, 9.4, and 3.9, respectively. These values describe group averages and variability on the measured threshold scale. They do not directly describe the experience of every participant.

The recalculated unadjusted comparison of 150 mg with placebo is -10.3, with a 95% confidence interval from -15.5 to -5.098 and p < 0.001. This is one summary-statistic-based contrast, and the registry record flags a discrepancy with the sponsor’s analysis. The sponsor-reported analysis takes precedence in light of that discrepancy. The reported sponsor values also lack confidence intervals and are not fully explained in relation to the posted group means.

The numbers do not, on their own, establish the clinical importance of a threshold change. The record does not define a threshold for a clinically meaningful difference or explain the clinical interpretation of the sign of change. Nor do these results establish effects on symptoms, quality of life, or other outcomes. The registry’s background description discusses urticaria and treatment context, but background information is not a substitute for measured trial results.

The results also do not establish that the two omalizumab doses differ from one another. The group means are close numerically, but a direct statistical comparison between doses is not reported in the registry record. Without a clearly specified contrast and its uncertainty, the group summaries should not be used to infer equivalence or a dose-response pattern. Similarly, the available serious adverse event counts do not establish comparative safety.

In general, interpretation of a randomized trial depends on more than the direction or size of a point estimate. It also depends on the outcome’s meaning, the precision of estimates, the analysis plan, missing data, study conduct, and how results were reported. Several of these details are not reported in the registry record. The posted findings are therefore best understood as descriptive group changes plus a recalculated comparison whose relationship to the sponsor analysis is uncertain, rather than as a complete account of efficacy or safety.

17. Why This Trial Matters Statistically

This trial illustrates why registry results need to be read at both the outcome and analysis levels. The primary endpoint is a continuous measure, so the record includes group means and standard deviations rather than only event counts. That format allows readers to see both average change and variability, while still requiring care about what the scale means and how results compare between groups.

The comparison also demonstrates the importance of distinguishing a group’s change from a treatment-versus-control contrast. A mean change within one group is not itself the estimated difference between that group and placebo. The recalculated 150 mg comparison makes this distinction explicit, but it is an unadjusted calculation and does not reproduce every aspect of the sponsor’s analysis. The sign discrepancy in the registry’s 300 mg entry shows why analysis labels, direction conventions, and explanations matter.

Confidence intervals contribute information about precision that point estimates and p-values alone do not provide. Yet precision is only one part of interpretation. The record’s small group sizes, lack of a reported confidence interval for sponsor analyses, and absence of detailed information on missing data and analysis populations constrain what can be concluded. The planning illustrations also emphasize that sample-size requirements depend on the effect size a study aims to detect; they are not evidence of the power actually achieved.

For biostatisticians and clinical researchers, the record underscores the value of transparent reporting of prespecified comparisons, analysis methods, multiplicity decisions, missing-data handling, and clinically interpretable outcome definitions. When those details are absent, readers should distinguish clearly between what is directly reported, what can be recalculated from summary statistics, and what remains unresolved. This discipline helps prevent a numerical result from being given more meaning than the record supports.

18. 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 posted outcome groups are small: 10 participants in the omalizumab 150 mg group, 9 in the 300 mg group, and 12 in placebo. Estimates based on limited group sizes may be sensitive to individual observations, and the registry does not provide participant-level results to examine that sensitivity. The record also does not report baseline threshold values or the distribution of individual changes.

The primary outcome is described as change in critical temperature threshold, but the record does not define a clinically meaningful change or explain the clinical meaning of the negative direction. The registry uses both day 70 and week ten to describe assessment timing. The posted group summaries provide standard deviations, but sponsor-reported confidence intervals are absent. The available recalculated confidence interval concerns only the 150 mg versus placebo comparison.

A discrepancy is flagged between the recalculated comparison and the sponsor’s reported results. The 300 mg sponsor entry’s sign differs from the posted 300 mg mean change, and the registry does not explain the relationship between those quantities. The sponsor’s own analysis takes precedence, but its full specification and uncertainty estimates are not reported in the registry record.

Other important trial details are not reported in the registry record, including the original sample-size justification, analysis populations, missing-data handling, multiplicity procedures, interim analyses, and detailed model specification. The registry describes a two-center study, but does not provide center-specific results or information that would allow assessment of differences between centers. The posted safety counts are limited and lack event-term detail. These limitations leave uncertainty about the robustness, generalizability, and clinical interpretation of the reported results.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Cold Urticaria Treatment With Xolair — NCT01580592.
• Registry record last updated 2017-04-07; status last verified 2017-02.
• Results first posted 2016-02-15.
• 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.

22. Record Summary

NCT01580592 is a completed randomized, double-blind, parallel-group phase 2 study of omalizumab 150 mg, omalizumab 300 mg, and placebo in antihistamine-resistant cold contact urticaria. Total enrollment was 31. The registry lists the study start as 2012-04 and primary completion as 2014-12; the sponsor is Charite University, Berlin, Germany.

The primary outcome was mean change in critical temperature threshold from baseline to day 70, assessed using TempTest® in degrees Celsius. Posted mean changes were -10.6, -10.4, and -0.3 for the 150 mg, 300 mg, and placebo groups, respectively. A recalculated unadjusted comparison of 150 mg with placebo was -10.3, with a 95% confidence interval from -15.5 to -5.098 and p < 0.001. The registry flags a discrepancy with the sponsor analysis, which takes precedence. Important details about the analysis plan, missing data, and multiplicity are not reported in the registry record.