Efficacy and Safety Study of FP MDPI Compared With FS MDPI in Adolescent and Adult Patients With Persistent Asthma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety Study of FP MDPI Compared With FS MDPI in Adolescent and Adult Patients With Persistent Asthma (NCT02141854), a randomized phase 3 study. The primary outcome is Standardized Baseline-Adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Effect Curve From Time Zero to 12 Hours PostDose (FEV1 AUEC0-12) at Week 12.

2. Clinical Question

3. Trial Design

This was a Phase 3, randomized, triple-masked, parallel-group study. Its title describes a 12-week, double-blind, placebo-controlled study; the registry record separately classifies masking as triple. It lists asthma as the condition and records enrollment of 882. Enrollment is the study-level figure and should not be read as the number contributing to every endpoint: the primary endpoint was measured in a subset of patients who performed serial spirometry at baseline and Week 12.

The study compared FS MDPI at 200 / 12.5 mcg and 100 / 12.5 mcg with Fp MDPI at 200 mcg and 100 mcg, as well as placebo MDPI. The arm descriptions specify one inhalation twice a day for 12 weeks. The FS dose descriptions give total daily doses of 400 mcg of fluticasone propionate and 25 mcg of salmeterol for the 200 / 12.5 mcg arm, and 200 mcg of fluticasone propionate and 25 mcg of salmeterol for the 100 / 12.5 mcg arm. The two Fp arms had total daily doses of 400 mcg and 200 mcg, respectively. Placebo was also taken twice daily.

The registry record lists study start as 2014-06, primary completion as 2015-09, and status as completed. The sponsor is Teva Branded Pharmaceutical Products R&D, Inc. The record does not report the original sample-size justification, details of randomization or masking procedures, or a full statistical analysis plan. Those omissions limit what can be concluded about the design rationale and analysis decisions beyond the information recorded for the outcomes.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: A total of 1661 patients with persistent asthma were screened and 882 patients enrolled. 154 patients were not randomized, most commonly (76 patients) because of not meeting randomization criteria.

Run-In Period (Pre-assignment)

Reasons for not completing this period:

Treatment Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: A subset of patients who performed postdose serial spirometry at the baseline visit and week 12.

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: Randomized participants

6. Primary Endpoint

The registry lists the primary outcome as Standardized Baseline-Adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Effect Curve From Time Zero to 12 Hours PostDose (FEV1 AUEC0-12) at Week 12, measured over Day 1 (predose, baseline), Week 12 and was performed at the following times relative to the administration of study drug (±5 minutes): 15 and 30 minutes and 1, 2, 3, 4, 6, 8, 10, and 12 hours.

The primary endpoint is the standardized baseline-adjusted FEV1 area under the effect curve from time zero to 12 hours after dosing at Week 12. FEV1 is the volume of air forcefully exhaled in the first second of a forced breath. The endpoint combines postdose measurements across the specified assessment times into a summary of the response over the observation period, rather than treating an isolated postdose measurement as the whole response.

For the area calculation, the record says that the trapezoidal rule was applied using actual measurement times. The resulting area was standardized by dividing it by the number of hours from dose administration to the last nonmissing FEV1 measurement. Baseline FEV1 was based on the average of the predose measurements at 30 and 10 minutes before dosing; if one was missing, the other was used, and if both were missing, baseline was treated as missing. Baseline adjustment means subtracting baseline FEV1 from each postdose FEV1 value before deriving the endpoint.

This continuous endpoint is useful for summarizing both the magnitude and time course of lung-function measurements after dosing. Its reported unit is liters. The primary estimate is a least-squares mean with a standard error, and the endpoint was assessed among the serial-spirometry subset. The registry record does not report whether the subset was defined before data collection or how missing postdose measurements were handled in the sponsor’s final model.

7. Results Posted in the Registry

• FS MDPI 200 / 12.5 mcg: mean 0.45 versus 0.12 on control; difference 0.33 (95% CI 0.20 to 0.45), standardized effect d = 0.87; z-test p = <0.001.
• FS MDPI 100 / 12.5 mcg: mean 0.44 versus 0.12 on control; difference 0.32 (95% CI 0.19 to 0.46), standardized effect d = 0.86; z-test p = <0.001.
• Fp MDPI 200 mcg: mean 0.27 versus 0.12 on control; difference 0.15 (95% CI 0.02 to 0.28), standardized effect d = 0.40; z-test p = 0.028.
• Fp MDPI 100 mcg: mean 0.26 versus 0.12 on control; difference 0.14 (95% CI 0.01 to 0.27), standardized effect d = 0.38; z-test p = 0.036.

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 the Weekly Average of the Daily Morning Trough Peak Expiratory Flow (PEF) Over the 12 Week 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:
  • FS MDPI 200 / 12.5 mcg: mean 20.23 versus -10.99 on control; difference 31.22 (95% CI 24.48 to 37.96), standardized effect d = 1.07; z-test p = <0.001.
  • FS MDPI 100 / 12.5 mcg: mean 18.61 versus -10.99 on control; difference 29.60 (95% CI 22.82 to 36.38), standardized effect d = 1.02; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for FS MDPI 200 / 12.5 mcg 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 higher for FS MDPI 100 / 12.5 mcg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Change From Baseline in the Weekly Average of the Total Daily Asthma Symptom Score Over the 12-Week 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:
  • FS MDPI 200 / 12.5 mcg: mean -0.39 versus -0.09 on control; difference -0.30 (95% CI -0.40 to -0.21), standardized effect d = -0.76; z-test p = <0.001.
  • FS MDPI 100 / 12.5 mcg: mean -0.36 versus -0.09 on control; difference -0.28 (95% CI -0.37 to -0.18), standardized effect d = -0.69; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for FS MDPI 200 / 12.5 mcg 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 FS MDPI 100 / 12.5 mcg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Change From Baseline in the Weekly Average of the Total Daily (24-hour) Use of Albuterol/Salbutamol Inhalation Aerosol Over the 12-Week 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:
  • FS MDPI 200 / 12.5 mcg: mean -0.90 versus 0.17 on control; difference -1.07 (95% CI -1.37 to -0.77), standardized effect d = -0.82; z-test p = <0.001.
  • FS MDPI 100 / 12.5 mcg: mean -0.82 versus 0.17 on control; difference -0.99 (95% CI -1.29 to -0.69), standardized effect d = -0.76; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for FS MDPI 200 / 12.5 mcg 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 FS MDPI 100 / 12.5 mcg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes cover different dimensions of the study: morning peak expiratory flow, asthma symptom scores, rescue albuterol or salbutamol use, quality of life, remaining in the study, timing of postdose FEV1 responses, and treatment-emergent adverse experiences. For the secondary measures with posted arm estimates, the descriptive pattern across the respiratory measures generally places the two FS groups in a more favorable direction than placebo, with Fp group estimates between those patterns and placebo for some outcomes. The exact interpretation depends on each outcome’s scale and direction.

The registry’s own reported secondary comparisons available in this record concern Fp MDPI versus placebo for peak expiratory flow, symptom score, and rescue inhaler use. Those model-based results report differences in the direction of the corresponding posted arm estimates. The secondary outcomes therefore add context about measures related to, but distinct from, the primary FEV1 summary. They do not replace the primary endpoint or constitute independent confirmation of it, because they concern different measurements and are drawn from the same trial.

The record lists other secondary outcome measures but does not report their results in the information available for this analysis. No results should be inferred for quality of life, study retention, time to FEV1 improvement, or treatment-emergent adverse experiences from outcome titles alone.

Secondary results generally carry less inferential weight when many outcomes or comparisons are assessed without a clearly reported multiplicity strategy. Repeated testing increases the chance of apparently notable findings arising by chance. The registry record does not report whether multiplicity adjustments were planned or applied. Secondary estimates are therefore best treated as supporting and exploratory context, with the sponsor’s reported methods and uncertainty in mind, rather than as a collection of separate definitive tests.

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

• Change From Baseline in the Weekly Average of the Daily Morning Trough Peak Expiratory Flow (PEF) Over the 12 Week Treatment
• Change From Baseline in the Weekly Average of the Total Daily Asthma Symptom Score Over the 12-Week Treatment Period
• Change From Baseline in the Weekly Average of the Total Daily (24-hour) Use of Albuterol/Salbutamol Inhalation Aerosol Over the 12-Week Treatment Period
• Kaplan-Meier Estimate of Probability of Remaining in Study At Week 12
• Change From Baseline in the Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ(S)) Score at Endpoint for Patients >=18 Years Old
• Kaplan-Meier Estimates for Time to 15% and 12% Improvement From Baseline in FEV1 Postdose on Day 1
• Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period

9. Statistical Interpretation

10. Statistical Methods Explained

What does the primary endpoint summarize?

FEV1 is a continuous measurement of forced expiratory volume in 1 second. This study’s primary outcome uses repeated postdose FEV1 assessments to capture the area under the response curve across the 12-hour period after dosing. In general, an area-under-the-curve measure combines information across measurement times; standardizing the area by elapsed hours expresses it on an average-per-hour scale. The registry describes using the trapezoidal rule with actual measurement times, so the calculation accounts for the timing of observed measurements rather than assuming every measurement occurred at an identical interval.

Baseline adjustment is intended to account for differences in the starting measurement. Here, the recorded method subtracts baseline FEV1 from postdose FEV1. The baseline definition uses predose measurements, with a stated fallback if one is missing. The outcome’s analysis population is a subset with serial spirometry at baseline and Week 12. How the sponsor handled other missing values within that subset is not reported in the registry record.

What are least-squares means and ANCOVA?

A least-squares mean is a model-based group mean. In general, it represents the estimated mean after accounting for variables included in the statistical model; it need not equal the simple arithmetic mean of observed values. ANCOVA is a model that compares groups while adjusting for covariates. The registry identifies ANCOVA as the method for its posted primary contrasts and reports least-squares mean differences. The covariates and full model specification are not reported in the registry record, so the adjustment cannot be reconstructed from the registry summary alone.

A mean difference expresses the model-estimated difference between two groups on the endpoint’s scale. In this case, positive reported differences indicate a larger adjusted endpoint estimate in the first named group than in its comparator, given the order of the listed groups. The difference is measured in liters. Statistical interpretation should consider the point estimate together with its confidence interval and the analysis population, rather than relying on a p-value alone.

Why can a recalculation differ from the reported analysis?

The simple recalculations use posted arm means and standard errors to estimate unadjusted between-group differences and intervals. They are not a reproduction of the sponsor’s ANCOVA. The posted summary standard errors can be used to approximate variability, but those approximations do not recover the individual-level observations, covariate adjustment, or analysis choices in the sponsor’s model. This trial is explicitly flagged as having a discrepancy between the recalculated results and the reported analysis. The sponsor’s own analysis therefore takes precedence when describing the trial’s formal comparisons; recalculated values are useful only as approximate, unadjusted checks on the posted summaries.

What does a confidence interval convey?

In general, a confidence interval describes uncertainty around an estimated effect under the assumptions of the statistical method. A narrower interval indicates greater statistical precision, while a wider interval indicates less precision. For the reported primary comparisons, the interval gives a range of effect values compatible with the model and data at the stated confidence level. It does not mean that the true effect has a specified probability of lying inside the particular interval after it has been calculated, and it does not measure clinical importance.

Similarly, a p-value describes how unusual the observed data, or more extreme data, would be under a specified null model and its assumptions. It is not the probability that the null hypothesis is true, nor is it a measure of the size or importance of an effect. The registry’s reported p-values should be read alongside the estimated differences and intervals. The registry record does not report whether or how multiplicity was controlled across the many outcomes and comparisons.

Why are repeated-measures methods relevant to secondary outcomes?

Some secondary measures were recorded repeatedly during treatment. A mixed model for repeated measures can account for correlation among a participant’s measurements over time while estimating group differences. In general, repeated measurements from the same participant are not independent; treating them as independent can misstate uncertainty. The registry identifies this model for certain secondary comparisons, but does not report its full specification, covariance structure, or missing-data assumptions. The reported model estimates are therefore the sponsor’s results as recorded, not independently reproducible from arm summaries alone.

The registry also lists a Kaplan-Meier estimate for remaining in study at Week 12 and estimates for time to specified postdose FEV1 improvements. Kaplan-Meier methods generally describe time-to-event patterns while accounting for incomplete follow-up under their assumptions. The record lists these outcomes but does not give their results in the registry record for this analysis. No conclusions about these time-to-event outcomes can be drawn from their titles alone.

How should planning illustrations be understood?

The sample-size illustrations are calculated from observed effects under stated planning assumptions. In general, power is the probability that a planned analysis will identify an effect of a specified size under the assumed model and significance threshold. These illustrations are not the trial’s original design calculations, and they do not establish how the trial was planned. The registry record does not report the trial’s original sample-size assumptions or justification. The illustrations also do not estimate the probability that the observed trial result is correct.

All model descriptions and general statistical explanations above are general context. The registry record does not provide every element needed to verify the sponsor’s analysis, including the full statistical analysis plan, all covariates, missing-data procedures, and multiplicity strategy. These limits matter when interpreting model-based estimates and when comparing them with unadjusted recalculations.

11. Confidence Intervals and Precision

The sponsor’s primary estimates include 95% confidence intervals for the reported comparisons. For FS MDPI 200 / 12.5 mcg versus Fp MDPI 200 mcg, the reported difference is 0.179 liters and the interval extends from 0.074 to 0.285 liters. For FS MDPI 100 / 12.5 mcg versus Fp MDPI 100 mcg, the estimate is 0.182 liters with an interval from 0.074 to 0.291 liters. For comparisons of FS MDPI with placebo, the estimates are 0.326 liters and 0.322 liters, with intervals from 0.221 to 0.431 and from 0.212 to 0.432 liters, respectively.

These intervals describe uncertainty in the model-based differences, conditional on the analysis method and its assumptions. The fact that the reported intervals do not include zero is consistent with the reported p-values for those contrasts. That statistical observation does not establish the clinical relevance of the size of a difference; a threshold for clinical importance is not reported in the registry record.

Precision also depends on which participants contributed to the analysis. The primary endpoint was evaluated in the serial-spirometry subset, and the posted endpoint arm counts differ from the study enrollment figure. The record does not report enough information to assess whether missing measurements or selection into the subset affected the estimates. Standard errors for the individual arm means describe estimated uncertainty in those means, not the variability of every participant’s measurement.

Finally, the posted recalculations are unadjusted approximations, and the record flags a discrepancy with the sponsor’s analysis. Their intervals should not be substituted for the sponsor’s ANCOVA intervals. The sponsor’s own reported estimates and confidence intervals are the appropriate results to use when describing the formal primary comparisons. Neither interval width nor exclusion of zero resolves the unreported questions about multiplicity, model specification, missing data, or clinical importance.

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 planning illustrations express sample sizes as participants per arm for these continuous outcomes. They are not totals of events. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each planning row uses a stated fraction of the observed effect as the effect to detect. The trial’s own original design assumptions are not reported in the registry record, so these figures should not be read as the rationale used when the trial was designed.

The 80% power column gives the illustrative number of participants per arm under which the calculation has 80% power to detect the selected effect, under the stated assumptions. The 90% power column gives the corresponding illustration for 90% power. In general, higher target power requires more participants when other assumptions are held constant. Likewise, the rows that plan for smaller effects require more participants per arm than rows planning for the full observed effect. This is because smaller differences are harder to distinguish from sampling variability.

The assumed effect is tied to the observed effect in this study, so the illustrations are sensitive to the size of the observed estimate. They do not account for every possible feature of a future study, such as changes in outcome variability, allocation, missingness, or analysis method. The posted figures are planning illustrations, not observed power; observed power is not a useful substitute for interpreting the estimate and its confidence interval.

The plotted planning values should be read as another view of the same assumptions and calculations, not as additional evidence from participants. These illustrations do not report how many people were actually analyzed in the trial or explain why the original study enrolled the number recorded in the registry. The original design justification and its assumptions are not reported in the registry record.

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 = 0.325; pooled standard deviation σ = 0.376.
2. n = 2 × (1.96 + 0.842)² × 0.376² / 0.325² = 21.0, rounded up to 21 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 <- 0.325                      # observed difference in means
sigma <- 0.375641666661572                     # 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(2141854)
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 = 21 (80% power), 29 (90% power)
 75% of observed effect: n per arm = 38 (80% power), 50 (90% power)
 50% of observed effect: n per arm = 84 (80% power), 113 (90% power)
power.t.test: 22 
Simulated power at n = 21 per arm: 0.780 (20000 replicates)

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

14. Analyses Reported by the Sponsor

The registry reports sponsor analyses for selected primary contrasts using ANCOVA and least-squares mean differences. These are the formal model-based comparisons recorded for the trial. The recalculated results use posted arm-level means and standard errors to form simple, unadjusted comparisons. They cannot reproduce the sponsor’s adjustment or recover its full model from summary data.

The registry record flags a discrepancy between the sponsor’s results and the recalculations. For example, the recalculated FS MDPI 200 / 12.5 mcg versus placebo difference is 0.325 liters, while the sponsor’s reported ANCOVA difference is 0.326 liters. Other contrasts also show differences between the recalculation and the sponsor’s reported estimate. The size and source of every discrepancy cannot be established from the registry summary.

Accordingly, the sponsor’s own analysis takes precedence in interpreting the trial’s reported contrasts. The unadjusted recalculations can serve as approximate checks on direction and scale, but should not be presented as the trial’s formal analysis or as a correction to it. The registry record does not report sufficient model details to independently reproduce the sponsor’s estimates.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists nine outcome measures and 43 analyses, but the record summarized for this interpretation does not describe a multiplicity strategy. It does not report whether a hierarchy of hypotheses was specified, whether the family of comparisons was defined in advance, or whether p-values or confidence intervals were adjusted for the number of outcomes and contrasts. Without this information, the reported p-values should not automatically be treated as if each came from a single isolated test. When many tests are considered, the chance of at least one small p-value under null effects can increase; this is a general statistical concern, not evidence that any particular reported result is false.

The registry record also does not report whether interim analyses were planned or conducted, or whether any statistical stopping rules were used. Those details should not be inferred from the study’s completion status. The original sample-size justification, its target effect, and its assumptions are likewise not reported. The planning illustrations based on observed effects do not fill in those missing design details.

Missing-data handling is an important limitation. The primary endpoint uses a subset of participants with serial spirometry at baseline and Week 12, and its description specifies how baseline was defined if a predose measurement was missing. It does not explain how missing postdose readings, missed visits, treatment discontinuation, or other incomplete outcome data were handled in the sponsor’s primary analysis. For repeated-measures secondary analyses, the model is named, but its missing-data assumptions and implementation details are not reported.

The record does not fully define the analysis populations used for each endpoint or explain how participants were included in each model. It gives arm counts for posted outcomes, but those counts do not establish the exact rules used to form analysis sets. These omissions limit independent verification and make it difficult to assess how sensitive the results might be to missing data, population definitions, or multiplicity decisions.

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: jaundice (0.7%), breast cancer (0.7%), asthma (0.7%), pneumonia (0.7%), grand mal convulsion (0.7%).

The registry reports serious adverse experiences and other adverse experiences by treatment group. For serious adverse experiences, the affected counts are 2 in each FS MDPI group, 1 in each Fp MDPI group, and 1 in placebo. The corresponding group counts at risk are 143, 145, 145, 146, and 144, respectively. For other adverse experiences, the affected counts are 21, 20, 26, 20, and 20, with group counts at risk of 143, 145, 145, 146, and 144, respectively.

These are descriptive event counts recorded during the treatment period. They do not establish that an event was caused by a study drug, and they are not a substitute for assessment of event type, severity, duration, or participant-level exposure. The registry lists jaundice, breast cancer, asthma, pneumonia, grand mal convulsion, and pyrexia among the top serious-event terms, each at 0.7%. The record does not give enough detail in this summary to interpret these terms as comparative risks across groups.

Deaths are not reported in the registry record. Differences in counts should be interpreted cautiously, particularly because the event counts are small and the record does not provide inferential comparisons for safety. These figures describe what was recorded; they do not provide medical advice or establish a treatment’s safety profile beyond the information posted.

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

The primary results describe model-adjusted comparisons of a continuous lung-function endpoint at Week 12 in the subset that performed serial spirometry. The sponsor’s reported estimates and confidence intervals indicate the size and uncertainty of selected contrasts among FS MDPI, Fp MDPI, and placebo groups. They provide a statistical summary of the posted data under the sponsor’s ANCOVA model.

They do not, by themselves, establish whether a difference is large enough to matter to patients. The registry record does not report a threshold for clinical importance for this endpoint. Nor do p-values establish the probability that a treatment effect is real or quantify the value of a change for an individual. The results also do not establish what would happen outside the study’s population, setting, duration, or measurement procedures.

The study enrolled adolescents and adults with persistent asthma symptomatic despite inhaled corticosteroid therapy, and the listed treatment period was 12 weeks. The primary endpoint’s analysis population was a serial-spirometry subset. These features delimit the population and time period represented by that endpoint. The registry record does not report enough information to assess how representative the subset was of all randomized participants.

There are multiple outcomes and comparisons, and the multiplicity approach is not reported. Some secondary results are available, while others are only listed as outcomes. These data should not be combined into a stronger conclusion than the registry analyses support. The reported findings are statistical evidence about particular endpoint contrasts under particular analyses, not a complete assessment of benefits, harms, long-term outcomes, or individual clinical decisions.

18. Why This Trial Matters Statistically

This trial is statistically informative because it reports a continuous primary endpoint built from repeated postdose measurements, together with model-based group comparisons and uncertainty intervals. The endpoint illustrates how a trial can summarize a response across time rather than focusing only on a single reading. Baseline adjustment also highlights the importance of defining the starting value and specifying how it enters the analysis.

The registry includes multiple active treatment groups, two Fp strengths, two FS combinations, and placebo. This structure supports more than one kind of comparison: combination inhaler versus the corresponding Fp strength, and active treatment versus placebo. The sponsor’s posted ANCOVA contrasts answer selected comparisons, while the unadjusted recalculations illustrate why arm summaries do not necessarily reproduce an adjusted analysis.

The record is also useful for understanding the limits of registry reporting. It gives outcome definitions, arm summaries, some sponsor analyses, and adverse-event counts, but does not report the full statistical plan, multiplicity approach, original sample-size assumptions, or complete missing-data procedures. Those gaps matter to researchers assessing reproducibility and strength of inference.

Finally, the sample-size illustrations show how planning estimates depend on the assumed effect size and target power. Because they are based on observed effects and not the original design rationale, they are not a substitute for prospective planning. Together, these features make the trial a practical example of distinguishing descriptive summaries, adjusted analyses, uncertainty, and design assumptions.

19. Limitations

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

The primary analysis applies to a subset of participants who performed serial spirometry at baseline and Week 12, not necessarily to everyone enrolled or randomized. The registry record does not report the reasons participants were absent from this analysis subset or whether subset membership could have introduced selection effects. It also does not report the handling of missing postdose measurements beyond the definition of baseline.

The sponsor’s primary comparisons are model-based, but the registry summary does not provide the complete ANCOVA specification, including all covariates and model diagnostics. The record flags a discrepancy with unadjusted recalculations, and the sponsor’s analysis takes precedence; nevertheless, the posted summary does not permit full independent reproduction of the sponsor’s result.

Multiplicity is another trial-specific limitation. The record lists numerous outcomes and analyses but does not report whether testing was controlled across them. Some secondary results are not available in the information, so the full pattern of secondary findings cannot be assessed. The record also lists study retention, quality of life, response timing, and treatment-emergent adverse experiences as secondary measures without providing their results in the registry record for this analysis.

The treatment period was 12 weeks, so the posted results address outcomes over that period. Longer-term outcomes are not reported in the registry record. Safety information is presented as event counts and selected serious-event terms; deaths are not reported, and the record does not provide enough information to assess comparative risk or causality. These limitations constrain interpretation but do not negate the descriptive and model-based results that are posted.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Efficacy and Safety Study of FP MDPI Compared With FS MDPI in Adolescent and Adult Patients With Persistent Asthma — NCT02141854.
• Registry record last updated 2021-11-09; status last verified 2021-11.
• Results first posted 2017-04-12.
• 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

This completed Phase 3 randomized, triple-masked, parallel-group study enrolled 882 adolescents and adults with persistent asthma symptomatic despite inhaled corticosteroid therapy. It compared two FS MDPI combinations, two Fp MDPI strengths, and placebo over 12 weeks. The primary endpoint was standardized baseline-adjusted FEV1 area under the effect curve from time zero to 12 hours postdose at Week 12, measured in a serial-spirometry subset.

The registry reports least-squares means and sponsor ANCOVA comparisons for selected primary contrasts, along with several secondary outcomes and adverse-event counts. Because recalculated comparisons differ from the sponsor’s own results, the sponsor’s reported analysis takes precedence. The registry record does not report the full statistical plan, multiplicity strategy, original sample-size justification, or complete missing-data procedures.