A Safety, Efficacy and Tolerability Study in Pediatric Subjects With Asthma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Safety, Efficacy and Tolerability Study in Pediatric Subjects With Asthma (NCT00809757), a randomized phase 3 study. The primary outcome is Change From Baseline to Visit 4 in the Mean Daily Composite Score Based on the Pediatric Asthma Caregiver Assessments (PACA).

2. Clinical Question

The score combines caregiver-assessed asthma symptoms across five domains: nocturnal awakenings due to wheeze and cough, daytime wheeze, daytime cough, shortness of breath, and an asthma symptom score. The scale ranges from 0, meaning no symptoms, to 19, meaning severe symptoms. The primary outcome uses the mean of daily scores in the week before Visit 4, compared with baseline.

The central statistical issue is the contrast between change in each active-treatment group and change in the placebo group. Changes within each group alone do not answer that comparative question. The posted results give mean changes and mean differences, with confidence intervals that convey uncertainty around the estimated between-group contrasts.

3. Trial Design

The registry record describes a randomized, triple-masked, parallel-group phase 3 trial in participants with asthma aged birth to <48 months. Enrollment was 197. The listed groups were levalbuterol MDI, levalbuterol UDV, and placebo. The record identifies Sumitomo Pharma America, Inc. as the sponsor, gives a start date of 2008-12, and a primary completion date of 2013-06. The trial status is completed.

Randomization means assignment to study groups was intended to occur by chance; triple masking means the registry labels the study as masked at three levels, but it does not identify those levels. The allocation ratio and the detailed randomization and masking procedures are not reported in the registry record. The parallel model indicates that the groups were compared as separate arms rather than as a crossover sequence.

The intervention descriptions identify levalbuterol MDI, levalbuterol UDV TID, and placebo. The arm descriptions list 90 ug levalbuterol (2 actuations) for the MDI group and 0.31 ug levalbuterol UDV TID for the UDV group. The record does not report the original design assumptions, the planned sample-size justification, or the detailed statistical analysis plan. Those omissions mean the calculated planning illustrations should not be treated as the basis for the trial’s original enrollment target.

The primary outcome was a continuous symptom score measured at baseline and Visit 4 (Week 4). The primary analysis population is labelled Intent-to-Treat, but its stated inclusion rule requires non-missing data at baseline and Week 4 and excludes participants who discontinued before Week 4. That rule describes the analyzed data set more narrowly than an analysis that retains every randomized participant regardless of whether the endpoint was observed.

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: Intent-to-Treat Population. Only those subjects who had non-missing data at Week 4 and at Baseline were included. Subjects who discontinued from the study prior to Week 4 are not included in this 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.

Population: One subject was randomized but not dosed in the Levalbuterol UDV arm.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline to Visit 4 in the Mean Daily Composite Score Based on the Pediatric Asthma Caregiver Assessments (PACA), measured over Baseline, Visit 4 (Week 4).

The primary endpoint is change from baseline to Visit 4 (Week 4) in the mean daily composite score based on the Pediatric Asthma Caregiver Assessment (PACA). It summarizes five symptom domains: nocturnal awakenings due to wheeze and cough, daytime wheeze, daytime cough, shortness of breath, and an asthma symptom score. The possible score ranges from 0, no symptoms, to 19, severe symptoms. The Visit 4 value is the average of daily composite scores in the week before that visit.

A continuous score retains information about the degree of symptom burden rather than reducing the outcome to a yes-or-no category. Change from baseline focuses the comparison on how the score shifted during the study, while comparing those changes across randomized groups helps distinguish group differences from changes shared over time. In this measure, a negative change represents a lower score than at baseline. That direction is descriptive; the relevant treatment comparison is the difference in average change between a levalbuterol group and placebo.

The measure was caregiver-assessed, so it captures symptoms recorded by caregivers rather than an objective physiological measurement. Peak expiratory flow appears among the secondary outcomes, but it is not the primary endpoint. Whether the primary score was selected based on a prespecified clinical threshold or a particular expected treatment effect is not reported in the registry record.

7. Results Posted in the Registry

• Levalbuterol MDI: mean -0.67 versus -1.21 on control; difference 0.54 (95% CI -0.32 to 1.40), standardized effect d = 0.22; z-test p = 0.220.
• Levalbuterol UDV: mean -0.52 versus -1.21 on control; difference 0.69 (95% CI -0.33 to 1.71), standardized effect d = 0.25; z-test p = 0.184.

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 to Visit 3 in Mean Daily Composite Score Based on the Pediatric Asthma Caregiver Assessment

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Levalbuterol MDI: mean -0.28 versus -0.83 on control; difference 0.55 (95% CI -0.39 to 1.49), standardized effect d = 0.20; z-test p = 0.250.
  • Levalbuterol UDV: mean -0.22 versus -0.83 on control; difference 0.61 (95% CI -0.36 to 1.58), standardized effect d = 0.22; z-test p = 0.219.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Levalbuterol MDI 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 Levalbuterol UDV and the control. The interval gives the range of effects that remain compatible with the data.

Change From Baseline to Visit 2 to Visit 3 in the Mean Daily Composite Score Based on the Pediatric Asthma Caregiver Assessment

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Levalbuterol MDI: mean -0.25 versus -0.82 on control; difference 0.57 (95% CI -0.19 to 1.33), standardized effect d = 0.25; z-test p = 0.142.
  • Levalbuterol UDV: mean -0.15 versus -0.82 on control; difference 0.67 (95% CI -0.11 to 1.45), standardized effect d = 0.30; z-test p = 0.092.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Levalbuterol MDI 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 Levalbuterol UDV and the control. The interval gives the range of effects that remain compatible with the data.

Change From Baseline to Visit 3 to Visit 4 in the Mean Daily Composite Score Based on the Pediatric Asthma Caregiver Assessment

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Levalbuterol MDI: mean -0.40 versus -1.08 on control; difference 0.68 (95% CI -0.15 to 1.51), standardized effect d = 0.29; z-test p = 0.109.
  • Levalbuterol UDV: mean -0.52 versus -1.08 on control; difference 0.56 (95% CI -0.30 to 1.42), standardized effect d = 0.23; z-test p = 0.200.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Levalbuterol MDI 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 Levalbuterol UDV and the control. The interval gives the range of effects that remain compatible with the data.

The posted secondary outcomes cover additional time windows for the caregiver-assessed composite score, symptom scores from the Pediatric Asthma Questionnaire, and in-clinic peak expiratory flow. Across the posted caregiver composite-score comparisons, group mean changes are negative, while the recalculated active-treatment-minus-placebo contrasts are positive. The pattern is broadly similar to the primary comparison in direction: average score declines occurred in each group, and the estimated declines were not greater in the active groups than in placebo. The intervals for the posted recalculated comparisons include zero, so the secondary estimates also leave uncertainty about the between-group differences.

These additional outcomes provide context across time points and measures, but they do not replace the designated primary endpoint. A similar pattern across secondary measures can be informative descriptively, yet it does not by itself resolve uncertainty in the primary comparison. The registry lists 26 outcome measures and 25 secondary outcomes posted, creating multiple opportunities for apparent differences to arise by chance when results are considered separately.

The recalculated secondary p-values are unadjusted. Without a reported multiplicity strategy, they should be treated as exploratory evidence rather than as a collection of independent confirmatory tests. The record does not report a prespecified hierarchy among the secondary outcomes, a family-wise error control method, or another adjustment for multiple comparisons. For that reason, the overall pattern is more useful as context than as a basis for selecting a single favorable secondary finding. The secondary results should be interpreted together with their estimates, intervals, outcome definitions, and the primary analysis rather than as separate definitive conclusions.

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

• Change From Baseline to Visit 3 in Mean Daily Composite Score Based on the Pediatric Asthma Caregiver Assessment
• Change From Baseline to Visit 2 to Visit 3 in the Mean Daily Composite Score Based on the Pediatric Asthma Caregiver Assessment
• Change From Baseline to Visit 3 to Visit 4 in the Mean Daily Composite Score Based on the Pediatric Asthma Caregiver Assessment
• Change From Baseline to Visit 3 in the Mean Daily Composite Score Based on the Daytime and Nighttime Asthma Symptom Scores as Measured by the Pediatric Asthma Questionnaire (PAQ)
• Change From Baseline to Visit 4 in the Mean Daily Composite Score Based on the Daytime and Nighttime Asthma Symptom Scores as Measured by Pediatric Asthma Questionnaire
• Change From Baseline to Visit 2 to Visit 3 in the Mean Daily Composite Score Based on the Daytime and Nighttime Asthma Symptom Scores as Measured by the Pediatric Asthma Questionnaire
• Change From Baseline to Visit 3 to Visit 4 in the Mean Daily Composite Score Based on the Daytime and Nighttime Asthma Symptom Score as Measured by the Pediatric Asthma Questionnaire
• Change From Baseline in In-Clinic Peak Expiratory Flow to Postdose Timepoints at Visit 2

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous, so the registry reports group means and standard deviations, and the recalculation compares means. A mean describes the average score change among participants with analyzed data. A standard deviation describes how spread out individual changes are around that group mean; it is not the uncertainty around the mean itself. The group sizes matter when estimating uncertainty because a mean based on more observations is generally more precise than one based on fewer observations, all else being equal.

What does the mean difference represent?

The recalculated contrast is active treatment minus placebo. For MDI, the estimated mean difference is 0.54; for UDV, it is 0.69. These contrasts compare average changes, not the final symptom scores alone. The mean changes were negative in all three groups. Since lower scores indicate fewer reported symptoms on the scale, a negative change means that the average score was lower at follow-up than at baseline. The positive contrast estimates indicate that the active-group change was less negative than the placebo-group change in these observed data.

The registry reports the contrasts in the opposite direction, placebo minus active treatment. This is why its estimates are -0.54 and -0.69 rather than positive values. A contrast’s sign depends on the order of subtraction. Reversing the order reverses the signs of the estimate and its confidence limits, without changing the comparison being described. The registry labels its analyses “Mean Difference (Final Values),” while the recalculations compare the posted changes from baseline.

What does a confidence interval add?

A confidence interval gives a range of values that are compatible with the observed data under the method used. It communicates estimation uncertainty: a narrower interval indicates greater precision, while a wider interval leaves more possible values for the underlying contrast. For the primary outcome, each reported or recalculated interval spans zero. Zero corresponds to no mean difference between the groups. Because the intervals extend to both negative and positive values, they do not establish which group has the greater average change. A confidence interval is not a guarantee that the true value lies within its particular limits, and it is not a measure of clinical importance.

How should the p-values be read?

The p-values in the recalculated comparisons are unadjusted: 0.22 for MDI and 0.184 for UDV. A p-value describes how unusual data at least as incompatible with a specified null comparison would be under the model used, if that null comparison were true. It is not the probability that the null is true, nor does it describe the size of an effect. The registry’s reported analyses have no p-value listed, and the specific analysis method is not reported in the registry record. The recalculated p-values should not be mistaken for sponsor-reported tests.

Why do dispersion and assumptions matter?

The posted standard deviations show variation in the score changes within each group. More variation makes it harder to estimate a group mean difference precisely when sample sizes remain the same. The recalculation uses pooled standard deviations for its standardized effect summaries and planning illustrations. A standardized effect expresses a mean difference relative to the scale of variation; it is not a second clinical outcome and does not determine whether a difference matters clinically. The registry does not report the statistical model or adjustment procedures used for its own primary analysis.

The sample-size planning illustration uses a two-sided significance level of 0.05, equal allocation between the two compared arms, and a normal approximation. It considers effects set to a stated fraction of the observed effect. Those are assumptions for the planning illustration, not confirmed features of the trial’s original design. The record does not report whether the original analysis used a normal approximation, whether it adjusted for baseline scores, or whether it used any covariates.

These comparisons are unadjusted recalculations from the posted summary statistics. They do not reproduce a model-based analysis if the sponsor’s method included additional features that are not described in the record. Nor can summary means and standard deviations address individual trajectories, missing-data patterns, or potential differences in the participants who completed Week 4. The registry’s own reported estimates remain the relevant sponsor analyses; the recalculations offer a transparent, simple comparison based on the posted summaries.

11. Confidence Intervals and Precision

The Week 4 mean-difference confidence intervals are wide enough to include zero for both active comparisons. The MDI-versus-placebo recalculation is 0.54, with a 95% confidence interval from -0.323 to 1.403. The UDV-versus-placebo recalculation is 0.69, with a 95% confidence interval from -0.327 to 1.707. The intervals allow for possible contrasts in either direction, including no difference. They therefore do not provide a precise estimate of the direction of the between-group contrast.

The registry reports the same comparisons with placebo minus active treatment as the contrast: -0.54, with a 95% confidence interval from -1.412 to 0.342, for MDI, and -0.69, with a 95% confidence interval from -1.714 to 0.335, for UDV. The signs differ because the contrast is reversed. The confidence intervals still include zero. The registry does not report p-values for these sponsor analyses.

Confidence intervals describe statistical precision, not whether the estimated differences are important in practice. The record does not state a threshold for a meaningful change in PACA score, so the interval limits cannot be classified against such a threshold. The scale’s range and score direction give context, but they do not supply that missing criterion.

Precision is also shaped by which participants entered the primary analysis. The reported group sizes are 62, 59, and 54, and the primary population excludes participants without both baseline and Week 4 data. The record does not provide a missing-data sensitivity analysis or enough information to assess whether the analyzed participants differ systematically from those excluded. Consequently, the intervals describe uncertainty for the stated analyzed data and method, not every possible source of uncertainty in the trial.

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 display is a planning illustration for a continuous outcome, so its entries are participants per arm, not total events. It presents estimates for planning around 80% power and 90% power. In plain terms, 80% power is the chance, under the stated assumptions and if the specified effect is the true effect, of detecting an effect with the planned test; 90% power represents a higher chance under those same assumptions. Neither column is a statement about what the completed trial achieved.

The calculation assumes a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. It uses the observed effect as a reference and considers planning for 100%, 75%, or 50% of that observed effect. Smaller effects require more participants to detect under the same assumptions. For example, the primary MDI comparison lists 320 participants per arm for planning around 100% of the observed effect at 80% power and 568 per arm for planning around 75% of the observed effect at 80% power. The planning values are not the trial’s original target or the number enrolled.

The original design assumptions and sample-size justification are not reported in the registry record. These figures are planning illustrations based on the posted outcome summaries, not observed power. The curve should be read as a visual representation of how the planning requirement changes as the effect being targeted changes, subject to the same assumptions.

13. How the Sample Size Is Derived

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

Formula

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

Worked calculation for this trial

1. Observed difference Δ = 0.540; pooled standard deviation σ = 2.435.
2. n = 2 × (1.96 + 0.842)² × 2.435² / 0.540² = 319.3, rounded up to 320 participants per arm for 80% power.

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

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 0.54                      # observed difference in means
sigma <- 2.43538555952223                     # 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(809757)
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 = 320 (80% power), 428 (90% power)
 75% of observed effect: n per arm = 568 (80% power), 760 (90% power)
 50% of observed effect: n per arm = 1,278 (80% power), 1,710 (90% power)
power.t.test: 320.3 
Simulated power at n = 320 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 three mean-difference analyses for the primary outcome: placebo versus MDI, placebo versus UDV, and MDI versus UDV. The sponsor-reported contrast for placebo versus MDI is -0.54, with a 95% confidence interval from -1.412 to 0.342. For placebo versus UDV it is -0.69, with a 95% confidence interval from -1.714 to 0.335. The MDI-versus-UDV contrast is -0.15, with a 95% confidence interval from -1.080 to 0.771. Each interval includes zero. The registry does not list p-values or the specific analysis method for these results.

The recalculated comparisons use active treatment minus placebo and therefore show estimates of 0.54 for MDI and 0.69 for UDV, with confidence intervals from -0.323 to 1.403 and -0.327 to 1.707, respectively. The estimates have the opposite signs because the order of subtraction is reversed. The intervals are not identical: the recalculation is a simple unadjusted comparison of posted summary statistics, whereas the sponsor’s specific method is not reported in the registry record. The sponsor estimates and intervals should be treated as the reported trial analyses; the recalculations are supplementary, not replacements for that analysis.

15. Multiplicity, Missing Data and Analysis Populations

The registry identifies a primary outcome and lists multiple secondary outcomes. It states that there are 26 outcome measures, with 25 secondary outcomes posted. The primary outcome compares change in the PACA composite score from baseline to Visit 4. The registry also reports additional time windows for caregiver-assessed scores, Pediatric Asthma Questionnaire scores, and peak expiratory flow. The detailed statistical analysis plan is not reported in the registry record.

When several outcomes or comparisons are tested, the chance of obtaining one or more apparently notable results by chance can increase. Statistical approaches can address this issue by defining a hierarchy, adjusting significance thresholds, or otherwise controlling error across a family of comparisons. Whether any such strategy was planned or used is not reported in the registry record. The recalculated p-values are unadjusted, and the sponsor-reported primary analyses have no p-values listed. Therefore, the posted results do not establish how multiplicity was handled in the trial’s own analysis.

The primary population is labelled Intent-to-Treat, but the stated rule includes only participants with non-missing baseline and Week 4 observations and excludes those who discontinued before Week 4. The record does not report an imputation method, a model for incomplete outcomes, or a sensitivity analysis exploring alternative assumptions about missing data. It also does not provide enough information to assess whether missingness was related to symptom changes or treatment group.

The registry reports group sizes for the primary outcome, but a full account of participant flow and reasons for missing Week 4 data is not included in the outcome description. The original sample-size assumptions, the analysis model, any baseline adjustment, and any interim analyses are not reported in the registry record. These gaps limit assessment of prespecification, multiplicity, and the robustness of the results to analytic choices. They do not change the numerical estimates, but they affect how confidently the reported analysis can be placed within its full planned statistical context.

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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: asthma (3.2%), pneumonia (1.6%), urinary tract infection (1.6%), metapneumovirus infection (1.5%), hypoxia (1.5%).

The registry lists serious adverse events among 68 participants at risk in the placebo group, 65 in the levalbuterol MDI group, and 63 in the levalbuterol UDV group. The reported numbers affected were 0, 1, and 3, respectively. These are counts of participants affected, not a comparison adjusted for differences in exposure or follow-up. The record also lists other adverse events affecting 28, 31, and 27 participants in those groups, respectively.

The listed serious-event terms include asthma at 3.2%, pneumonia at 1.6%, urinary tract infection at 1.6%, metapneumovirus infection at 1.5%, hypoxia at 1.5%, and status asthmaticus at 1.5%. These percentages are reported as serious-event terms and should not be interpreted as group-specific rates because the record does not assign those percentages to treatment groups in the posted summary. The death counts are not reported in the registry record; that is different from a report of zero deaths.

These safety counts are descriptive. They do not establish that a group’s risk was higher or lower, and the record does not provide a statistical comparison for serious adverse events. The counts should be considered with the at-risk group sizes and the trial’s broader safety information, which is not fully detailed in this summary.

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

The primary outcome describes average change in a caregiver-assessed symptom composite over the study interval. Negative mean changes occurred in all three groups. The between-group estimates compare those changes, and their confidence intervals include zero. These results leave uncertainty about the direction and size of the differences between each levalbuterol group and placebo.

They do not establish that the groups are equivalent. Demonstrating equivalence or non-inferiority requires an appropriate prespecified margin and a design and analysis directed at that question; such a margin and plan are not reported in the registry record. Nor do the results establish that a difference is clinically important. The record does not identify a threshold for a meaningful change in the PACA score.

The outcome is based on caregiver assessments, and the analyzed primary population excludes participants without baseline and Week 4 data and those who discontinued before Week 4. The result therefore describes the analyzed observations under that rule. It does not, by itself, resolve the effect that might have been observed under a different missing-data approach or among all randomized participants.

The secondary outcomes add descriptive information about other measures and time windows, but their unadjusted analyses carry additional uncertainty because many outcomes were posted. The serious adverse-event counts are also descriptive and do not provide a formal comparative risk estimate. Taken together, the registry results support a careful reading of estimates and uncertainty rather than a categorical claim about treatment benefit, lack of benefit, or safety. No medical advice follows from these statistical summaries.

18. Why This Trial Matters Statistically

This trial illustrates why within-group change and between-group comparison answer different questions. The mean score declined in each arm, but the randomized comparison concerns whether the average change differed between an active group and placebo. Looking only at a decline within one group would not distinguish a treatment-group difference from changes that also occurred under placebo.

It also shows why effect estimates and confidence intervals belong together. A point estimate gives a direction and scale for the observed contrast, while the interval indicates how uncertain that estimate remains. Here, the primary comparison intervals include zero and span values on both sides of it. That uncertainty matters more than treating a single p-value as a verdict.

The endpoint and analysis population also shape interpretation. PACA is a caregiver-assessed composite with a defined score range and multiple symptom domains. The primary analysis requires baseline and Week 4 data, so its group summaries do not include every enrolled participant. Clear attention to the population analyzed is essential when interpreting any apparent difference.

Finally, the registry contains numerous secondary outcomes, but the multiplicity plan is not reported. This is a common statistical challenge: a broad outcome set can provide useful context while also increasing the risk of over-reading isolated results. The example underscores the value of prespecified analysis details, transparent missing-data methods, and conclusions calibrated to the precision of the estimates.

19. Limitations

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

Several trial-specific features limit how far the posted results can be interpreted. The primary analysis uses only participants with non-missing baseline and Week 4 data and excludes those who discontinued before Week 4. Although the population is labelled Intent-to-Treat, that stated rule is a complete-observation analysis for the endpoint. The registry does not report an imputation method, a missing-data sensitivity analysis, or reasons for missing observations, so the impact of exclusions cannot be assessed from this record.

The primary outcome is a caregiver-assessed composite rather than a single physiological measurement. Its five domains and scale range are described, but the record does not state a threshold for a clinically meaningful change. The results therefore describe score changes without establishing how large a change would matter to families or clinicians.

The record gives the trial’s randomized, triple-masked, parallel design, but not the allocation ratio, detailed masking procedures, original sample-size justification, or complete analysis plan. It does not report the statistical method used for the sponsor analyses. This prevents a full assessment of model choices, baseline adjustment, multiplicity control, or whether the reported approach followed a prespecified plan.

There are multiple posted secondary outcomes, and the multiplicity strategy is not reported. Their unadjusted results should not be treated as independent confirmatory evidence. Finally, the listed serious-event terms and participant counts are descriptive; the summary does not supply a comparative safety analysis, and death counts are not reported in the registry record.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: A Safety, Efficacy and Tolerability Study in Pediatric Subjects With Asthma — NCT00809757.
• Registry record last updated 2014-07-28; status last verified 2014-07.
• Results first posted 2014-07-28.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

23. Record Summary

The completed phase 3 trial enrolled 197 participants with asthma aged birth to <48 months and compared levalbuterol MDI, levalbuterol UDV, and placebo in a randomized, triple-masked, parallel-group design. Its primary outcome was change from baseline to Week 4 in a caregiver-assessed daily composite symptom score.

Mean scores declined in all groups. The recalculated Week 4 differences between each levalbuterol group and placebo had confidence intervals that included zero; the registry-reported contrasts, expressed in the opposite direction, also had intervals including zero. The primary analysis excluded participants without baseline and Week 4 data and those who discontinued before Week 4. The original analysis plan, sample-size justification, multiplicity strategy, and missing-data methods are not reported in the registry record.

The posted secondary outcomes and adverse-event counts add descriptive context, but they do not remove the uncertainty in the primary comparison or establish a definitive comparative conclusion.