Safety and Efficacy of Pimecrolimus Cream 1% in Atopic Disease Modification: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Pimecrolimus Cream 1% in Atopic Disease Modification (NCT00124709), a randomized phase 4 study. The primary outcome is Atopic Dermatitis (AD) Disease Control Over 36 Months.

2. Clinical Question

3. Trial Design

The registry describes a randomized, parallel-group, double-blind, vehicle-controlled Phase 4 study of pimecrolimus cream 1% for atopic dermatitis. The listed study arms are pimecrolimus and a control treatment identified in the study description as conventional corticosteroid-based treatment. The planned allocation ratio was 1:1. The registry lists 1091 enrolled participants and gives the study status as terminated. The reason for termination is not reported in the registry record.

The study plan had two phases. The first was a 3-year double-blind phase comparing pimecrolimus long-term management with conventional corticosteroid-based treatment. The primary outcome was assessed over 36 months during this phase. The plan then called for a 2 to 3-year open-label phase in which all patients would receive pimecrolimus. The study description says asthma incidence at age 6 would be compared at the end of that phase. The registry record does not report an asthma-incidence result in the posted results, and the planned later-phase comparison should not be treated as an observed result.

The reported primary outcome analysis included 530 participants in the pimecrolimus group and 523 in the control group. Its stated analysis population required randomization, dispensing of study medication, and at least one post-baseline efficacy measurement. The registry does not report why the outcome-analysis counts differ from the enrollment figure, nor does it provide enough information to infer how participants without a reported primary outcome were handled. The registry lists an ANCOVA analysis for the primary comparison, but the covariates and detailed model specification are not reported in the registry record.

The record gives a start date of 2003-10 and a primary completion date of 2008-01. These dates do not establish that every planned phase or assessment was completed. The record lists seven outcome measures and one analysis, but it does not report the original sample-size justification, the trial’s full statistical analysis plan, or whether interim analyses were planned or conducted.

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: all randomized patients who were dispensed study medication and had at least one post baseline efficacy measurement.

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 Atopic Dermatitis (AD) Disease Control Over 36 Months, measured over 36 months.

The primary endpoint was the mean proportion of disease-free days at Step 2 or less during the 36-month double-blind phase. For each patient, the denominator was the total number of days in the study; the measure therefore describes the share of observed study days meeting the disease-control definition. The registry identifies the endpoint as a continuous outcome summarized by a mean and standard deviation.

A proportion of disease-free days captures disease control across time rather than at a single visit. That can be useful when the research question concerns how much of the follow-up period participants spend within a specified disease state. It also means interpretation depends on the endpoint definition, the time counted in the denominator, and the availability of observations over follow-up. The registry defines the disease state as Step 2 or less, but does not give further operational detail about how disease status was assessed or how missing days were treated.

The registered primary endpoint addresses disease control during the double-blind comparison. It does not by itself answer the separate planned question about asthma incidence during the later open-label phase. The available record therefore supports interpretation of the disease-free-days comparison, not a conclusion about that later outcome.

7. Results Posted in the Registry

• Pimecrolimus (Elidel) Treatment Group: mean 0.44 versus 0.43 on control; difference 0.01 (95% CI -0.03 to 0.04), standardized effect d = 0.02; z-test p = 0.751.

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.

Atopic Dermatitis (AD) Remission Time

• 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:
  • Pimecrolimus (Elidel) Treatment Group: mean 105.95 versus 117.11 on control; difference -11.15 (95% CI -28.57 to 6.26), standardized effect d = -0.08; z-test p = 0.209.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Pimecrolimus (Elidel) Treatment Group and the control. The interval gives the range of effects that remain compatible with the data.

The registry names several secondary areas, including long-term safety, allergic conditions, medication use, remission time, and patient or caregiver quality of life. The numeric secondary comparison available in the posted results concerns remission time during the 36-month double-blind phase. Its confidence interval includes zero, so it does not provide a clear additional signal that changes the interpretation of the primary disease-control result. Numeric results for the other listed secondary outcomes are not reported in the registry record.

This means the secondary evidence cannot be treated as a uniform set of findings pointing in one direction. The record identifies five secondary outcomes, but does not provide a complete set of numeric estimates and uncertainty measures for those outcomes. The planned asthma comparison at age 6 belongs to the later open-label phase and is not reported as an outcome result in the posted results. It should not be folded into a summary of observed secondary findings.

Secondary results generally carry less weight than a prespecified primary result when several outcomes are examined. Looking at many outcomes creates more opportunities for apparently noteworthy findings to arise by chance. Interpretation is stronger when a statistical plan specifies how such multiplicity will be handled, but that plan is not reported in the registry record. The record also does not report multiplicity-adjusted secondary analyses. Accordingly, any isolated secondary finding would need cautious interpretation, and the absence of numeric results for most listed secondary outcomes prevents a complete assessment of the overall pattern.

The available secondary information is therefore supplementary. It does not overturn the primary result, and it does not establish effects on the other listed outcomes or on asthma incidence.

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

• Long Term Safety in Infants and Young Children
• Incidence of Allergic Rhinitis, Allergic Conjunctivitis and Food Allergies
• Corticosteroid and Pimecrolimus Drug Use
• Atopic Dermatitis (AD) Remission Time
• Patient/Caregiver Quality of Life

9. Statistical Interpretation

10. Statistical Methods Explained

The primary measure is continuous: it is the mean proportion of disease-free days, with a standard deviation describing variability among participants. The posted group summaries permit a simple unadjusted comparison of means. The registry also reports an ANCOVA analysis of final values. These are different statistical approaches: the re-calculation uses the posted group summaries without adjustment, whereas ANCOVA models the outcome while accounting for covariates included in the model. Which covariates were used, and the details of the model specification, are not reported in the registry record.

What does a mean difference represent?

A mean difference expresses the contrast between the group averages on the outcome’s measurement scale. For this endpoint, the scale is the proportion of study days that were disease-free at Step 2 or less. A value near zero indicates that the observed group averages are close. The sign indicates which group’s observed mean is higher, but the estimate alone does not show how precisely the contrast is known. That is why the confidence interval and the analysis method also matter.

Why consider an ANCOVA result as well as a simple comparison?

ANCOVA is a regression-based method that compares outcomes while accounting for specified covariates. In a randomized study, adjustment may be used to improve precision or account for baseline information, but the exact purpose and covariates cannot be determined without the model details. The registry identifies the reported method as ANCOVA and labels the result as a mean difference in final values. It does not report the covariates or enough details to reconstruct that analysis. The re-calculated comparison is therefore useful as a transparent, unadjusted check, not as a substitute for the sponsor’s analysis.

How should the confidence interval be read?

A confidence interval expresses statistical uncertainty around an estimate under the assumptions of the analysis. A wider interval indicates less precision; an interval that includes zero is compatible with no mean difference as well as with effects in either direction. For the posted primary comparison, the unadjusted interval includes zero, and the reported ANCOVA interval also crosses zero. These intervals do not prove that the true difference is zero. They show that the data do not pin down a single direction and magnitude with high precision.

What does the p-value add?

A p-value describes how compatible the observed data are with a specified null model, assuming that model and the analysis assumptions are appropriate. It is not the probability that the null hypothesis is true, nor does it measure the clinical importance of an effect. The unadjusted primary p-value is not close to a conventional significance threshold. This is consistent with the confidence interval spanning zero. Statistical significance and clinical importance are distinct questions; the registry does not provide a threshold for a clinically important difference on this endpoint.

Why does dispersion matter?

The standard deviation describes how spread out individual observations are around the group mean. When participants vary substantially, a small difference in group means can be difficult to distinguish from sampling variability. The primary outcome has substantial reported dispersion relative to the closeness of the observed means. This general statistical point helps explain why precision depends not only on the size of an estimated contrast, but also on variability and the amount of information available. It does not imply that the observed group means are unrepresentative or that a different analysis would necessarily reach a different conclusion.

What can the secondary analysis add?

The registry also reports a continuous secondary outcome for atopic dermatitis remission time during the 36-month double-blind phase. Its posted comparison is an unadjusted re-calculation from summary statistics; no sponsor-reported analysis is listed for that secondary measure. The confidence interval includes zero. Other secondary outcomes are named in the registry, but their numeric results are not reported in the registry record. The evidence available for secondary outcomes is consequently more limited than the primary comparison and should not be treated as a complete account of all planned secondary findings.

What analysis details remain unknown?

The record does not report the original sample-size assumptions, a complete statistical analysis plan, the handling of missing outcome days, or details of any interim analyses. The primary analysis population is defined in the registry, but that definition does not explain how missing observations were handled after entry into the population. Nor does the record say whether any sensitivity analyses were conducted. These omissions limit how fully an independent reader can assess the model assumptions and robustness of the posted findings.

11. Confidence Intervals and Precision

The primary comparison has limited precision for distinguishing a small difference from no difference. The unadjusted confidence interval extends to both sides of zero, so the posted data are compatible with a modest difference favoring either group as well as with little or no difference. The sponsor-reported 95% confidence interval also crosses zero. The two intervals thus share the key interpretive feature, even though one comes from an ANCOVA analysis and the other from an unadjusted re-calculation.

Confidence intervals should be read as ranges of values compatible with the data under the specified analysis, not as guarantees about the true effect. Their width reflects uncertainty, and an interval spanning zero means that the direction of the difference is not established by that analysis. It does not mean that the treatment effects are proven identical. The registry does not report a threshold defining what size of difference in disease-free days would be clinically important, so the interval cannot be classified against such a threshold from the record alone.

The primary outcome counts are 530 in the pimecrolimus group and 523 in the control group, while the record lists 1091 enrolled participants. These figures refer to different reported populations or stages of the record; the reason for the difference is not reported in the registry record. The stated primary analysis population requires dispensing and at least one post-baseline efficacy measurement, which limits the scope of the primary result to participants meeting that definition.

Precision is also affected by participant-level variability and by the way repeated disease status was converted into a proportion over study days. The registry gives standard deviations but does not report how missing days contributed to each participant’s proportion. That missing-data detail matters when judging whether all participants’ observations are comparable. The displayed interval is therefore best interpreted as uncertainty under the reported analysis, not as a complete account of every 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 figures are planning illustrations based on the observed effect, not the trial’s original design assumptions. The original design assumptions are not reported in the registry record. For this continuous-outcome illustration, the figures are participants per arm, not total events. The calculation assumes a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It considers the stated fractions of the observed effect: 100%, 75%, and 50%.

The 80% power column gives the illustrative number of participants per arm for a design with an 80% chance of detecting the specified effect under the calculation’s assumptions, if that effect is the true one. The 90% power column uses a higher target chance of detecting it and therefore calls for more participants per arm. These power targets describe hypothetical future study planning; they are not probabilities that the current study’s result is correct.

The rows show that planning to detect a smaller fraction of the observed effect requires more participants per arm. This is a general feature of statistical design: when the target difference is smaller relative to variability, more information is needed to distinguish it from random variation. The observed primary difference is very small, so the illustration produces large participant requirements, especially when planning around a smaller fraction of that observed effect.

These figures are not observed power. They are not a retrospective measure of whether the trial was adequately designed, and they do not explain why the trial was terminated. They should be read only as planning illustrations under the listed assumptions, rather than as the trial’s original sample-size calculation.

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 = 0.006; pooled standard deviation σ = 0.296.
2. n = 2 × (1.96 + 0.842)² × 0.296² / 0.006² = 40,884.2, rounded up to 40,885 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 <- 0.00580000000000003                      # observed difference in means
sigma <- 0.295996811443276                     # 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(124709)
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 = 40,885 (80% power), 54,733 (90% power)
 75% of observed effect: n per arm = 72,684 (80% power), 97,302 (90% power)
 50% of observed effect: n per arm = 163,537 (80% power), 218,930 (90% power)
power.t.test: 40885.2 
Simulated power at n = 40,885 per arm: 0.800 (20000 replicates)

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

14. Analyses Reported by the Sponsor

The registry reports the sponsor’s primary analysis as an ANCOVA comparison of final values. Its confidence interval crosses zero, and the reported estimate is close to zero. The separate recalculation compares the posted group means without adjustment; it also gives a mean difference close to zero and an interval that crosses zero. The two approaches therefore lead to the same broad statistical reading: neither indicates a clear between-group difference in the posted primary outcome.

The sponsor’s analysis should be distinguished from the recalculation. ANCOVA can account for covariates in a model, while the simple recalculation uses only the posted summary statistics. The registry does not identify the ANCOVA covariates or provide enough detail to reproduce the model. The recalculation is consequently a check on the broad direction and scale of the result, not a replication of the sponsor’s analysis.

The record does not flag a discrepancy between these analyses. That does not make their estimates interchangeable: they arise from different methods and may rely on different information. The sponsor-reported analysis is the trial’s own reported inferential analysis, while the unadjusted comparison helps readers understand what the posted group summaries show.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome and seven outcome measures overall, as well as several secondary outcome areas. When a study assesses multiple outcomes or makes multiple comparisons, the chance of at least one apparently unusual result can increase. A prespecified multiplicity strategy can address this issue, for example by specifying how inference will be distributed across outcomes. Such a strategy is not reported in the registry record. The record also does not report whether the posted secondary analyses were adjusted for multiplicity.

The primary analysis population is defined as all randomized patients who were dispensed study medication and had at least one post-baseline efficacy measurement. This definition is narrower than randomization alone. It is important to retain that distinction when interpreting the primary result: the outcome summaries describe the stated analysis population, not necessarily every participant enrolled or randomized. The record does not report why the primary outcome group counts differ from the enrollment figure.

Missing-data handling is not reported in the registry record. For an endpoint based on the proportion of disease-free days, the treatment of days without a recorded disease assessment could affect the resulting participant-level proportions. The record does not state whether missing days were excluded, imputed, carried forward, or handled by another rule. It also does not report sensitivity analyses to assess the influence of missing data.

The record identifies ANCOVA for the sponsor-reported primary analysis, but the covariates, model details, and assumptions are not reported. A complete statistical analysis plan is not reported in the registry record. Neither the sample-size justification nor any interim-analysis plans or results are reported. These gaps limit independent assessment of the full analytic choices, particularly for secondary outcomes and missing observations. They do not negate the posted estimates, but they constrain how confidently the methods can be reconstructed.

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: asthma (1.3%), pneumonia (1.1%), dehydration (0.9%), gastroenteritis rotavirus (0.7%), bronchial hyper-reactivity (0.6%).

The safety record lists 543 participants at risk for serious adverse events in the pimecrolimus group, with 42 affected, and 544 at risk in the control group, with 37 affected. For other adverse events, it lists the same at-risk counts by group, with 482 affected in the pimecrolimus group and 467 in the control group. These are registry counts and should be read as descriptive summaries, not as proof that treatment caused or prevented an event.

The registry lists asthma, pneumonia, dehydration, gastroenteritis rotavirus, bronchial hyper-reactivity, and status asthmaticus among the most frequent serious adverse-event terms, with the corresponding percentages recorded in the safety results. The summary does not assign those listed terms to a specific treatment group, so they cannot be used from this record alone to compare groups for each event. Deaths are not reported in the registry record.

Safety counts do not by themselves show timing, severity beyond the serious-event classification, duration, recurrence, or a causal relationship to treatment. The record also does not provide a complete event-by-event treatment comparison in the summary. These figures describe what the registry reports; they are not a standalone assessment of comparative safety.

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

The primary result is a comparison of mean disease-free days during the double-blind phase among participants meeting the registry’s defined analysis-population criteria. The observed group means are close, the unadjusted contrast is small, and both the re-calculated and sponsor-reported confidence intervals cross zero. The posted analysis therefore does not establish a clear difference between the treatment groups on this endpoint.

That conclusion is not the same as showing that the treatments are equivalent. A failure to establish a difference can reflect a small true difference, substantial variability, limited precision, or a combination of factors. The registry does not define an equivalence margin or a clinically important difference for the proportion of disease-free days. Without such a margin and an analysis designed for equivalence or non-inferiority, the near-zero estimate cannot be interpreted as proof of equivalence.

The result is specific to the outcome, analysis population, and period described in the record. It concerns disease control during the planned 36-month double-blind phase, not every aspect of atopic dermatitis, long-term safety, or the later open-label phase. The registry’s planned asthma-incidence comparison at age 6 is not accompanied by a posted result in the available results.

The secondary remission-time comparison does not establish a clear difference, and numeric findings for the other listed secondary outcomes are not reported in the registry record. Safety information is descriptive and does not by itself support causal claims. The record also leaves important methods details, including missing-data handling and multiplicity procedures, unreported.

In short, the posted information supports a cautious description: the recorded primary estimates are close to zero and uncertain in direction, with no clear between-group difference demonstrated. It does not establish that no difference exists, does not answer all planned research questions, and does not provide a basis for medical advice.

18. Why This Trial Matters Statistically

This trial raises a useful statistical distinction between a small observed estimate and a precise conclusion. The primary group means are close, but an estimate near zero is not by itself enough to demonstrate that two treatments have the same effect. The confidence interval is essential because it shows that the result remains compatible with differences in either direction. Readers should therefore avoid treating a non-significant comparison as a proof of no effect.

The record also illustrates why a registry’s planned questions and posted results need to be kept separate. The double-blind phase focused on disease control, while the later open-label phase was intended to address asthma incidence at age 6. The posted primary result speaks to the former; it does not answer the latter. A clear description of which phase and endpoint a result concerns prevents one outcome from being mistaken for another.

Methodological transparency matters as well. The registry reports an ANCOVA analysis and supplies group summaries that allow an unadjusted recalculation, but it does not report the full model specification, missing-data rules, multiplicity strategy, or original sample-size rationale. These details affect how readers assess precision, robustness, and the scope of inference. The planning illustrations further show how sample-size requirements depend on the effect a future study aims to detect and on the planning assumptions, rather than serving as a retrospective verdict on this trial.

Together, these features make the record a practical example of interpreting effect estimates, uncertainty, analysis populations, and incomplete reporting without overstating what the evidence establishes.

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 gives a limited account of the methods needed for a full independent assessment. It identifies ANCOVA as the sponsor’s primary analysis but does not report its covariates or complete model specification. The original sample-size assumptions, statistical analysis plan, interim-analysis information, and multiplicity procedures are not reported in the registry record.

The primary analysis population excludes randomized participants who were not dispensed study medication or did not have a post-baseline efficacy measurement, according to the stated definition. The record does not explain the difference between enrollment and the primary outcome counts, nor does it report the reasons for participants not appearing in the outcome summaries. Missing-data handling for the disease-free-days endpoint is also not reported. Because the endpoint is based on days over follow-up, the treatment of unobserved days is relevant to interpretation.

The study status is terminated, but the reason for termination is not reported in the registry record. Although the design description includes an open-label phase and a planned asthma-incidence comparison, the available results do not report that comparison. The record does not establish how much of the planned follow-up occurred or whether the planned later-phase assessment was completed.

Numeric results are also limited for the secondary outcomes. The registry lists several secondary areas, but the numeric remission-time comparison is the only secondary comparison detailed in the posted results; other numeric results are not reported in the registry record. The serious adverse-event terms are listed without a treatment-group attribution in the summary, and deaths are not reported. These limitations restrict conclusions about later outcomes, secondary patterns, and event-specific safety comparisons.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Safety and Efficacy of Pimecrolimus Cream 1% in Atopic Disease Modification — NCT00124709.
• Registry record last updated 2011-03-23; status last verified 2011-02.
• Results first posted 2011-03-23.
• 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

NCT00124709 is a randomized, parallel-group, double-blind Phase 4 study of pimecrolimus cream 1% versus conventional corticosteroid-based treatment for atopic dermatitis. The registry lists 1091 enrolled participants and a terminated status. The reason for termination is not reported in the registry record.

The primary outcome was the mean proportion of disease-free days at Step 2 or less over 36 months in the double-blind phase. The unadjusted recalculation and the sponsor-reported ANCOVA analysis both show estimates close to zero with confidence intervals crossing zero. The record also lists a secondary remission-time comparison, descriptive safety counts, and other planned outcomes, but numeric results for most secondary outcomes are not reported in the registry record. The planned later open-label asthma-incidence comparison is not reported among the posted results.