A Safety and Efficacy Study of Ciclesonide Nasal Aerosol in Subjects 6-11 Years With Perennial Allergic Rhinitis (PAR).: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Safety and Efficacy Study of Ciclesonide Nasal Aerosol in Subjects 6-11 Years With Perennial Allergic Rhinitis (PAR). (NCT01451541), a randomized phase 3 study. The primary outcome is The Change From Baseline in Average Daily Subject-reported AM and PM Reflective Total Nasal Symptom Scores (rTNSS) Averaged Weekly Over the First 6 Weeks of the Double-blind Treatment..

2. Clinical Question

The rTNSS combines subject ratings of runny nose, sneezing, itchy nose, and nasal congestion. Each symptom is rated on a scale from 0 to 3, with higher scores indicating more severe symptoms; the summed score ranges from 0-12. Reflective ratings concern symptoms over the previous 12-hour interval. The endpoint is a change score, calculated in the registry as the six-week treatment average minus baseline, so a more negative change represents a greater reduction in the recorded symptom score.

The question is about a difference between groups in an average score over a specified period. It is not a direct measure of every symptom experience, nor does the registry record establish how a score difference should be interpreted as meaningful to an individual. The comparison is also limited to the stated age group, diagnosis, treatment period, and reported endpoint.

3. Trial Design

The registry describes NCT01451541 as a Phase 3, randomized, quadruple-masked, parallel-group study with placebo control. The official title identifies a 12-week study of safety and efficacy in subjects aged 6-11 years with perennial allergic rhinitis. The brief summary describes ciclesonide nasal aerosol administered once daily and identifies male and premenarchal female subjects. Enrollment is listed as 848, and the registry status is completed.

Three groups are listed: placebo, ciclesonide nasal aerosol 37 mcg, and ciclesonide nasal aerosol 74 mcg. The active-arm descriptions specify one actuation per nostril once daily, producing the stated total dose. The registry does not describe a placebo-arm dosing procedure in the record. Random allocation and parallel groups mean that participants were assigned to a study group and the groups were followed as separate arms; the registry record does not report the allocation sequence or the exact allocation ratio.

The listed study start is 2011-10, and primary completion is 2012-12. The posted primary endpoint concerns change from baseline in average daily subject-reported morning and evening reflective TNSS averaged weekly over the first 6 weeks of double-blind treatment. The study also lists outcomes concerning instantaneous nasal symptom scores, quality of life, the 12-week symptom period, time to maximal effect, and adverse events.

Quadruple masking is the registry’s stated masking designation. The identities of the masked parties and the practical masking procedures are not reported in the registry record. The original sample-size rationale, planned allocation ratio, and detailed protocol procedures are also not reported in the registry record. The enrollment figure should therefore be read as a registry enrollment entry, not as the analysis count for the primary endpoint.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Intent to Treat (ITT) population: All randomized subjects who received at least one dose of double blind study medication.Subjects with either missing baseline data or postdose data, or both and were not included in the analysis.

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.

6. Primary Endpoint

The registry lists the primary outcome as The Change From Baseline in Average Daily Subject-reported AM and PM Reflective Total Nasal Symptom Scores (rTNSS) Averaged Weekly Over the First 6 Weeks of the Double-blind Treatment., measured over Weeks 0-6.

The primary endpoint is the change from baseline in average daily subject-reported morning and evening reflective Total Nasal Symptom Scores, averaged weekly over the first 6 weeks of double-blind treatment. The score adds ratings for runny nose, sneezing, itchy nose, and nasal congestion. Each symptom is assessed from 0 to 3, and the combined score ranges from 0-12; higher values indicate more severe recorded symptoms. Reflective ratings ask subjects to consider the preceding 12-hour interval.

The registry defines change as the six-week treatment average minus baseline. This makes the sign important: a negative change means the average recorded score was lower than baseline, and a more negative group mean indicates a larger mean reduction. The endpoint is useful for comparing groups because it summarizes repeated symptom ratings over a defined period rather than relying on one rating at one moment. The comparison with placebo helps distinguish changes observed in the active groups from changes observed in the control group during the same study period.

The reported arm values are least-squares means with standard errors. These are model-based group summaries, rather than raw individual observations. The registry record does not report all details of the model used to obtain these estimates, the handling of all missing observations, or a threshold defining a clinically important difference. Statistical separation between group estimates therefore does not, by itself, establish how noticeable or important a difference would be to participants.

7. Results Posted in the Registry

• Ciclesonide Nasal Aerosol 37mcg: mean -2.10 versus -1.51 on control; difference -0.59 (95% CI -0.95 to -0.23), standardized effect d = -0.27; z-test p = 0.001.
• Ciclesonide Nasal Aerosol 74 mcg: mean -1.98 versus -1.51 on control; difference -0.47 (95% CI -0.83 to -0.11), standardized effect d = -0.22; z-test p = 0.011.

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 Average Daily Subject-reported AM and PM Instantaneous Total Nasal Symptom Scores (iTNSS) Averaged Weekly Over the First 6 Weeks of Double-blind Treatment

• 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:
  • Ciclesonide Nasal Aerosol 37mcg: mean -1.77 versus -1.29 on control; difference -0.48 (95% CI -0.82 to -0.14), standardized effect d = -0.24; z-test p = 0.005.
  • Ciclesonide Nasal Aerosol 74 mcg: mean -1.72 versus -1.29 on control; difference -0.43 (95% CI -0.77 to -0.09), standardized effect d = -0.21; z-test p = 0.013.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Ciclesonide Nasal Aerosol 37mcg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Ciclesonide Nasal Aerosol 74 mcg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Change From Baseline in the Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) Overall Score at the End of the First 6 Weeks of Double-blind Treatment

• 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:
  • Ciclesonide Nasal Aerosol 37mcg: mean -0.51 versus -0.39 on control; difference -0.12 (95% CI -0.26 to 0.02), standardized effect d = -0.15; z-test p = 0.090.
  • Ciclesonide Nasal Aerosol 74 mcg: mean -0.30 versus -0.39 on control; difference 0.09 (95% CI -0.05 to 0.23), standardized effect d = 0.11; z-test p = 0.221.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Ciclesonide Nasal Aerosol 37mcg 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 Ciclesonide Nasal Aerosol 74 mcg and the control. The interval gives the range of effects that remain compatible with the data.

Change From Baseline in Daily Average Subject-reported AM and PM rTNSS Averaged Weekly Over the 12-week Double-blind Treatment Period

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Ciclesonide Nasal Aerosol 37mcg: mean -2.60 versus -1.92 on control; difference -0.68 (95% CI -1.05 to -0.31), standardized effect d = -0.30; z-test p = <0.001.
  • Ciclesonide Nasal Aerosol 74 mcg: mean -2.47 versus -1.92 on control; difference -0.55 (95% CI -0.92 to -0.18), standardized effect d = -0.24; z-test p = 0.004.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Ciclesonide Nasal Aerosol 37mcg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Ciclesonide Nasal Aerosol 74 mcg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry lists secondary outcomes that broaden the assessment beyond reflective symptom scores averaged over the first 6 weeks. They include instantaneous nasal symptom scores, a pediatric rhinoconjunctivitis quality-of-life measure, symptom scores over the 12-week treatment period, time to maximal effect, and adverse-event outcomes. These measures are related to the primary question but are not interchangeable: they use different score definitions, time windows, or kinds of outcomes.

In the posted secondary summaries with arm-level results, the symptom-score comparisons generally point toward greater reductions in the active groups than in placebo, while the quality-of-life comparisons do not show a similarly consistent pattern between the two active doses. This broad description is not a substitute for the endpoint-specific estimates and uncertainty. It also does not establish that a difference on one measure implies the same difference on another.

The symptom outcomes lend context to the primary rTNSS result because they assess related nasal symptoms across alternative rating formats or longer follow-up. The quality-of-life outcome asks a distinct question about reported impact. A result on one endpoint does not automatically validate another, especially when the underlying scales and assessment windows differ.

Secondary findings generally carry less weight than a prespecified primary result when many outcomes are examined. Each additional test creates another opportunity for a chance finding, and the registry does not report an adjustment plan for the secondary comparisons. The sponsor’s reported Bonferroni-based gatekeeping method is attached to the primary comparisons in the posted results; the registry does not describe how that procedure applies to the full secondary-outcome family. Unadjusted secondary p-values, where shown in recalculated summaries, should therefore be treated as exploratory evidence rather than a definitive set of confirmatory tests.

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

• Change From Baseline in Average Daily Subject-reported AM and PM Instantaneous Total Nasal Symptom Scores (iTNSS) Averaged Weekly Over the First 6 Weeks of Double-blind Treatment
• Change From Baseline in the Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) Overall Score at the End of the First 6 Weeks of Double-blind Treatment
• Change From Baseline in Daily Average Subject-reported AM and PM rTNSS Averaged Weekly Over the 12-week Double-blind Treatment Period
• Change From Baseline in Daily Average Subject-reported AM and PM iTNSS Averaged Weekly Over the 12-week Double-blind Treatment Period
• Change From Baseline in Daily Average Subject-reported AM iTNSS Averaged Over the First 6 Weeks of Double-blind Treatment
• Change From Baseline in Daily PRQLQ Overall Score at the End of the 12-week Double-blind Treatment Period
• Time to Maximal Effect [Time to >= 90% Maximum Difference From Placebo in LS Means (Days)]
• Number of Subjects Experiencing AEs, SAEs, and Discontinuations Due to AEs

9. Statistical Interpretation

10. Statistical Methods Explained

What does a least-squares mean represent? A least-squares mean is a model-based estimate of a group average. It can differ from a simple arithmetic average because it is estimated through a statistical model. The registry identifies the primary arm results as least-squares means and reports a standard error for each. The model specification and covariates are not reported in the registry record, so the estimates cannot be independently reconstructed from the information available.

What does a change score represent? A change score compares a follow-up measure with a baseline measure. Here, the registry defines the calculation as the six-week treatment average minus baseline. For this scale, lower scores correspond to less severe recorded symptoms, so negative changes indicate reductions from baseline. Comparing change scores between randomized groups is intended to describe whether the average change differed between groups over the stated period. It does not show how much each individual changed.

What is the difference estimate? The recalculated comparison is an unadjusted mean difference formed from the posted arm-level summary statistics. For the primary endpoint, the recalculated differences are -0.59 for 37 mcg versus placebo and -0.47 for 74 mcg versus placebo. These point estimates describe the separation between the group summaries under the stated comparison direction. They are not adjusted for the sponsor’s gatekeeping procedure. As a general statistical point, an unadjusted comparison does not account for the additional error risk that can arise when several hypotheses are tested.

What do the p-values say? A p-value describes how incompatible the observed data are with a specified null hypothesis, under the assumptions of the analysis. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of a difference. The primary comparisons have recalculated unadjusted p-values of 0.001 and 0.011. The sponsor’s reported adjusted p-values are both <0.05 using a Bonferroni-based gatekeeping method. The registry record does not report the full testing sequence or the exact adjustment calculations, so those details should not be inferred from the method label alone.

Why distinguish adjusted from unadjusted results? Testing multiple comparisons can increase the chance of obtaining at least one apparently persuasive result by chance. Adjustment procedures seek to control that risk across a defined family of hypotheses. A gatekeeping approach generally conditions later tests on earlier tests, while a Bonferroni-based procedure uses a conservative adjustment principle. This is general statistical context; the exact sequence, family of endpoints, and decision rules used for this trial are not reported in the registry record. The reported adjusted analysis is therefore the relevant sponsor result, while the unadjusted recalculation is a supplementary summary-based check.

What role do standard errors play? A standard error describes the statistical uncertainty in an estimated mean, under the model and its assumptions. It is not the spread of individual scores. The arm standard errors are 0.13, 0.13, and 0.131 for placebo, 37 mcg, and 74 mcg, respectively. In general, estimates with smaller standard errors are more precise, all else equal. The standard errors alone do not reveal the full distribution of individual scores or the appropriateness of the model.

Why are the recalculated intervals approximate? The recalculated comparisons use posted summary statistics, and the pooled standard deviations are marked as approximate. This approach can provide an indicative unadjusted interval around a mean difference, but it does not reproduce the trial’s fitted model, adjusted tests, or any unreported covariance structure. The registry’s sponsor results do not include confidence limits in the reported analyses. When the discrepancy flag is true, the sponsor’s own analysis takes precedence over a simple summary-based recalculation.

What does over-dispersion mean in general? For count outcomes, over-dispersion means that observed variability exceeds what a basic count model expects. It can make standard errors too small if ignored. That concept is not central to this continuous rTNSS endpoint, and no over-dispersion assessment for this trial is reported in the registry record. It is included only as general statistical context, not as a claim about the analysis used.

What is the analysis population? The primary outcome description calls the population ITT, and defines it as randomized subjects who received at least one dose of double-blind medication. It also states that subjects missing baseline data or postdose data, or both, were not included in the analysis. This is the record’s stated definition; it should not be silently equated with every possible use of the term intention-to-treat. The detailed methods for handling missing follow-up values among included subjects are not reported in the registry record.

Why do randomized comparisons matter? Randomization is intended to make treatment groups comparable on average at assignment, including with respect to factors that may be known or unknown. This is a general principle, not proof that every factor was balanced in this study. The registry record does not provide baseline characteristic tables in the registry record. The interpretation remains tied to the trial’s assigned groups and the outcomes actually analyzed.

11. Confidence Intervals and Precision

The arm estimates include standard errors, which indicate uncertainty in the estimated group means. The posted primary standard errors are 0.13 for placebo, 0.13 for 37 mcg, and 0.131 for 74 mcg. A standard error is not a range containing most individual participants’ scores; it describes uncertainty about an estimated mean under the analysis model.

The recalculated mean differences are -0.59 for 37 mcg versus placebo and -0.47 for 74 mcg versus placebo. Their approximate confidence intervals are based on the posted summary statistics, not on the sponsor’s reported adjusted analysis. They are therefore best read as unadjusted precision estimates for the recalculations. A confidence interval expresses a range of values compatible with the data under the interval method and its assumptions. It does not assign a probability to the true value after the interval has been observed, nor does it establish clinical importance.

The sponsor’s reported analyses give LS-mean differences of 0.59 and 0.47 and adjusted p-values of <0.05, but confidence limits are not reported in the registry record. The positive reported differences and negative recalculated differences reflect an unspecified comparison direction in the sponsor result; the registry summary does not provide enough detail to reconcile the signs. Given the stated discrepancy, the sponsor’s analysis takes precedence.

Precision is distinct from statistical significance. A small p-value does not, on its own, convey the range of plausible effect sizes or whether an observed difference matters to participants. The registry record does not report a clinical-importance threshold for this scale. It also does not report the full model or the confidence intervals for the sponsor’s adjusted comparisons. Consequently, the recalculated intervals should not be used as if they were the trial’s prespecified, adjusted intervals.

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 illustrations are planning calculations based on the observed effect, not the trial’s original design rationale. For these comparisons, the figures are participants per arm. The calculation assumptions listed in the registry summary are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each planning scenario uses the stated fraction of the observed effect as the effect to detect. The original trial’s sample-size assumptions and justification are not reported in the registry record.

The 80% power column gives an illustrative number of participants per arm for a design that would have an 80% probability of detecting the specified effect under the stated assumptions, if that effect and the assumptions were correct. The 90% power column gives the corresponding illustration for a 90% probability. These are prospective design concepts, not guarantees: actual results can differ because the true effect, variability, missingness, and analysis conditions may not match the planning assumptions.

Rows describing 100% of the observed effect use the observed effect estimate as the planning target. Rows describing 75% or 50% use smaller target effects. Smaller effects are harder to distinguish from random variation, so the illustrations require more participants per arm as the target effect becomes smaller. The curves and figures should be read as sensitivity illustrations around the observed estimates, not as estimates of what the trial would have found under another sample size.

This is not observed power. Observed power calculated from the effect estimate after a study is complete does not add useful information beyond the estimated effect and its uncertainty. These planning figures are most useful for understanding how design requirements change when the target effect is smaller or when a higher power target is selected.

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 = -0.590; pooled standard deviation σ = 2.171.
2. n = 2 × (1.96 + 0.842)² × 2.171² / -0.590² = 212.6, rounded up to 213 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 <- -0.59                      # observed difference in means
sigma <- 2.17144209947374                     # 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(1451541)
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 = 213 (80% power), 285 (90% power)
 75% of observed effect: n per arm = 379 (80% power), 507 (90% power)
 50% of observed effect: n per arm = 851 (80% power), 1,139 (90% power)
power.t.test: 213.6 
Simulated power at n = 213 per arm: 0.797 (20000 replicates)

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

14. Analyses Reported by the Sponsor

The registry’s sponsor-reported primary comparisons use a Bonferroni-based gatekeeping method and identify LS Means with adjusted p-values. The reported differences are 0.59 for placebo versus 37 mcg and 0.47 for placebo versus 74 mcg, with adjusted p-values of <0.05 for both. The registry does not provide confidence limits for these reported analyses.

The separate recalculations use arm-level means and standard errors to form simple unadjusted comparisons. They give differences of -0.59 and -0.47 under a treatment-minus-placebo direction, with unadjusted p-values of 0.001 and 0.011. The apparent sign contrast is consistent with a difference in comparison direction, but the registry does not specify the direction used in the sponsor’s reported values. The registry also flags a discrepancy, so the recalculated estimates should not be treated as replacements for the sponsor’s analysis.

The sponsor’s adjusted analysis is the primary inferential result to use when describing the trial. The recalculation can serve as a rough check on the magnitude suggested by the arm summaries, but it does not reproduce the sponsor’s model or multiplicity adjustment. Details of the model, testing order, and adjusted confidence intervals are not reported in the registry record.

15. Multiplicity, Missing Data and Analysis Populations

The registry reports a Bonferroni-based gatekeeping method for the two sponsor-reported primary comparisons. Both adjusted p-values are listed as <0.05. This indicates that the record presents the primary comparisons as adjusted rather than as two isolated unadjusted tests. However, the exact test order, the hypotheses included in the gatekeeping sequence, and the decision rules are not reported in the registry record. The reported adjustment should be acknowledged without assuming details that the record does not give.

The simple recalculations report unadjusted p-values. They do not implement the sponsor’s gatekeeping method and should not be interpreted as multiplicity-adjusted evidence. The registry lists numerous secondary outcomes, but a multiplicity strategy covering those outcomes is not reported in the registry record. Consequently, isolated secondary p-values have less confirmatory weight, particularly when many measures or time windows are considered.

The primary population description states that randomized subjects who received at least one dose of double-blind medication were included, but subjects with missing baseline data or postdose data, or both, were excluded from the analysis. That definition is narrower than an unrestricted analysis of all randomized subjects. The detailed missing-data method for other incomplete observations, including any imputation, model-based handling, or sensitivity analysis, is not reported in the registry record.

Missingness can affect interpretation if the likelihood of having an observed outcome differs between groups or relates to the outcome itself. This is a general statistical concern, not a claim that such a pattern occurred in this study. The registry summary does not provide enough information to assess the extent, reasons, or consequences of missing endpoint data beyond the stated population exclusion.

Other statistical-plan details, including the full model specification and the trial’s original sample-size justification, are not reported in the registry record. These omissions make it difficult to reproduce the sponsor’s analysis or assess every prespecified decision. They do not negate the posted result, but they limit independent verification and argue for keeping the interpretation close to the analyses and populations explicitly described.

16. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: appendicitis (0.4%), herpes zoster (0.4%), neutropenia (0.4%), influenza (0.4%), pneumonia viral (0.4%).

The serious adverse event summaries report 1 event in the placebo group, 1 in the 37 mcg group, and 2 in the 74 mcg group. The corresponding numbers at risk are 283, 282, and 281. These are registry counts, not rates calculated for a common follow-up duration or adjusted comparisons. The record does not provide a statistical comparison of serious adverse events between groups in the registry record.

The listed serious-event terms each have a reported frequency of 0.4%: appendicitis, herpes zoster, neutropenia, influenza, and viral pneumonia. The record does not specify in the summarized details how these terms are distributed among the groups, so they should not be assigned to a particular arm. Death counts are not reported in the registry record.

Serious adverse events are only one part of the safety picture. The registry also reports other adverse-event counts of 83 for placebo, 95 for 37 mcg, and 85 for 74 mcg, with the listed at-risk counts noted above. These figures do not establish causality or permit a reliable comparison of event risk on their own. Interpreting safety requires attention to event definitions, exposure duration, event severity, and the full clinical context; those details are not all reported in the registry record.

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

The posted primary summaries describe average reductions in rTNSS in all three groups over the first 6 weeks, with more negative least-squares mean changes in the two ciclesonide groups than in placebo. The sponsor’s reported adjusted comparisons list differences of 0.59 and 0.47 and adjusted p-values of <0.05. The simple recalculations point in the same broad direction when expressed as treatment-minus-placebo differences, but differ in sign because the sponsor comparison direction is not specified. Since the record flags a discrepancy, the sponsor’s analysis takes precedence.

These findings describe group-level scores for the defined population and period. They do not show that every participant had a reduction, nor do they quantify the chance that an individual will have a particular result. The registry record does not report a threshold for a clinically important rTNSS difference, so statistical evidence should not be equated with a judgment about practical importance.

The results also do not settle questions beyond the registered comparisons. They do not establish what would occur in people outside the stated age range or diagnosis, over periods other than those assessed, or under circumstances not represented by this study. The summary does not report all analysis details needed to reproduce the sponsor’s model or fully assess missing data.

Safety counts should be read as descriptive event summaries. They are not proof that an event was caused by study medication, and the small number of serious events does not establish the absence of risk. The registry record reports no death counts in the registry record. Overall, the most defensible reading stays with the measured outcomes, the stated comparisons, and the limits of the registry-level detail.

18. Why This Trial Matters Statistically

This trial illustrates why statistical interpretation involves more than comparing the sizes of group means. The primary endpoint is a repeated subject-reported symptom measure reduced to an average change over a defined period. Understanding its direction and scale is essential: lower rTNSS values represent less severe recorded symptoms, and the registry defines a more negative change as a greater reduction.

The record also makes the distinction between sponsor-reported inference and a summary-based recalculation concrete. The sponsor reports adjusted p-values using a Bonferroni-based gatekeeping method, while the recalculated comparisons are unadjusted. Even where their broad direction is compatible, they answer different statistical questions and should not be presented as equivalent analyses. The discrepancy flag makes that distinction especially important.

The trial further shows why precision, statistical significance, and practical importance should be considered separately. A p-value summarizes evidence under assumptions; a confidence interval expresses uncertainty about an estimate; neither alone establishes whether a score difference matters to participants. The registry does not provide a clinical-importance threshold or sponsor confidence limits for the primary comparisons.

Finally, the listed secondary measures and adverse-event counts demonstrate the value of reading outcomes in context. Different scales and time windows can yield different patterns, and multiple testing can make isolated secondary findings less persuasive. Transparent details about analysis populations, missing data, model specification, and multiplicity help readers judge how firmly a conclusion is supported. Several of those details are not reported in the registry record, so careful qualification is part of sound statistical interpretation.

19. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record does not report the original sample-size justification or the trial’s detailed design assumptions. The planning illustrations based on observed effects cannot fill that gap. The allocation sequence and allocation ratio are not reported, and the record does not identify which parties were masked under the quadruple-masking designation or describe the masking procedures.

The primary population description excludes subjects without baseline data or postdose data, or both, despite using the label ITT. The handling of other missing observations, reasons for missingness, and any sensitivity analyses are not reported in the registry record. This limits assessment of how incomplete outcome data may have affected the estimates.

The sponsor’s reported primary analysis has no confidence limits in the registry summary, and the full model specification and gatekeeping sequence are not reported. Summary-based recalculated intervals are approximate and unadjusted; they cannot reproduce the sponsor’s analysis. The record flags a discrepancy, so the sponsor’s analysis takes precedence.

The registry does not report a clinically important difference threshold for rTNSS. Nor do the summarized details provide individual-level outcome distributions, so group means cannot describe the range of participant experiences. The secondary results are not accompanied by a reported multiplicity plan for the full set of outcomes. Safety event counts are descriptive, and the reported serious-event terms are not assigned to specific groups in the summarized details. These limitations call for a narrow interpretation rather than extrapolation beyond the endpoints and comparisons described.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: A Safety and Efficacy Study of Ciclesonide Nasal Aerosol in Subjects 6-11 Years With Perennial Allergic Rhinitis (PAR). — NCT01451541.
• Registry record last updated 2014-05-06; status last verified 2014-04.
• Results first posted 2014-05-06.
• 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

NCT01451541 is a completed Phase 3 randomized, quadruple-masked, parallel-group, placebo-controlled study in subjects aged 6-11 years with perennial allergic rhinitis. It compared once-daily ciclesonide nasal aerosol at 37 mcg and 74 mcg with placebo over a 12-week study period.

The primary outcome was change from baseline in average daily morning and evening reflective TNSS over the first 6 weeks. The sponsor-reported primary comparisons used a Bonferroni-based gatekeeping method and listed adjusted p-values of <0.05. Summary-based unadjusted recalculations are also available, but the registry flags a discrepancy, so the sponsor’s analysis takes precedence.

The record lists symptom, quality-of-life, time-to-effect, and safety outcomes. Details of the full statistical model, missing-data handling, original sample-size justification, and complete multiplicity plan are not reported in the registry record.