Randomised Study Comparing the Effects of Inhaled Fluticasone Furoate (FF)/Vilanterol (VI; GW642444M) Combination and FF on an Allergen Induced Asthmatic Response: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Randomised Study Comparing the Effects of Inhaled Fluticasone Furoate (FF)/Vilanterol (VI; GW642444M) Combination and FF on an Allergen Induced Asthmatic Response (NCT01128569), a randomized phase 2 study. The primary outcome is Weighted Mean Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Between 0-2 Hours, Following the 22-23 Hour Post-treatment Allergen Challenge on Day 29 of Each Treatment Period.

2. Clinical Question

The study was designed to explore component contributions in an allergen-challenge model, rather than to measure asthma outcomes over an extended period in usual clinical settings. Its primary endpoint is a short-term lung-function response under a controlled challenge. The registry record describes the endpoint calculation and the treatment conditions, but the detailed protocol rationale and original sample-size justification are not reported in the registry record.

3. Trial Design

The registry describes a randomized, double-blind, placebo-controlled, three-way crossover, repeat-dose pilot study in phase 2. The three treatment conditions were placebo, FF 100 µg OD, and FF/vilanterol 100/25 µg OD. The registry enrollment is 52, and the study status is completed. The listed study dates are 2010-01 for start and 2010-10 for primary completion.

In general, a crossover design allows treatment conditions to be compared within a participant across different periods. That structure can make within-participant comparisons informative, but it also means that period effects and the handling of repeated observations matter to the analysis. The record identifies period as a fixed effect in the primary mixed model ANCOVA description. It does not report details of treatment sequence, washout intervals, or how possible carryover effects were assessed; these details are not reported in the registry record.

The primary endpoint population is described as the intent-to-treat population: randomized participants who received at least one dose. Only participants available at the relevant time points were analyzed. The endpoint-specific group counts are 45 for placebo, 49 for FF, and 46 for FF/vilanterol. These are analyzed counts for the endpoint, not a replacement for the registry’s overall enrollment figure.

Participants received allergen by inhalation 22-23 hours after dosing on Day 28. FEV1 was measured at several scheduled times after the challenge on Day 29, across each treatment period. The primary outcome timeframe is baseline and Day 29 of each treatment period, up to Study Day 197. The registry record identifies the study as a pilot but does not report the planned sequence details, the rationale for the number enrolled, or a detailed account of the analysis population beyond the endpoint description.

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: This study was a multi-center, randomized, double-blind, placebo controlled, three-period crossover study in mild asthmatic male and female participants. Following the Run-in period, participants were randomized to 1 of 6 treatment sequences of placebo, FF 100 micrograms (µg) once daily (OD), and FF/VI 100/25 µg OD.

Treatment Period 1

Washout Period 1

Reasons for not completing this period:

Treatment Period 2

Reasons for not completing this period:

Washout Period 2

Analysis population for the primary outcome, as defined in the registry: Intent-to-Treat (ITT) Population: par. randomized to treatment who received \>=1 dose of study drug. Only those par. available at the specified time points were analyzed. Analysis was performed using mixed model analysis of covariance (ANCOVA) with fixed effects of treatment, period, par.-level Baseline, period level Baseline, country, sex, and age.

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 Weighted Mean Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Between 0-2 Hours, Following the 22-23 Hour Post-treatment Allergen Challenge on Day 29 of Each Treatment Period, measured over Baseline and Day 29 of each treatment period (up to Study Day 197).

The primary endpoint is the weighted mean change from baseline in FEV1 over 0-2 hours following the allergen challenge. FEV1 measures the maximal amount of air forcefully exhaled in one second and is used as a measure of lung function. The registry reports the outcome in liters and describes the treatment values as least-squares means, with standard errors.

For the endpoint, FEV1 was measured 5, 10, 15, 20, 30, and 45 minutes, and 1, 1.5, and 2 hours after allergen exposure. The weighted mean was calculated from the area under the curve divided by the relevant time interval. Change from baseline was the Day 29 weighted mean minus the post-saline baseline value measured on Day 29. Thus, a negative change reflects a lower weighted mean FEV1 than the stated baseline value during the post-challenge period.

This endpoint captures the average lung-function response across the specified observation window rather than relying on a single measurement. In general, averaging measurements over a defined interval can represent the overall time-course response more fully than a lone time point. The allergen challenge provides a controlled setting for studying a response to an inhaled trigger, but the endpoint remains a short-term physiological measure. It does not by itself describe longer-term symptoms, everyday function, or outcomes beyond the measured challenge period.

7. Results Posted in the Registry

• FF 100 µg OD: mean -0.21 versus -0.37 on control; difference 0.16 (95% CI 0.01 to 0.32), standardized effect d = 0.43; z-test p = 0.038.
• FF/VI 100/25 µg OD: mean -0.23 versus -0.37 on control; difference 0.14 (95% CI -0.01 to 0.30), standardized effect d = 0.39; z-test p = 0.064.

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.

Maximum Percent Decrease From Baseline in FEV1 Between 0 2 Hour, Following the 22-23 Hour Post-treatment Allergen Challenge on Day 29 of Each 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:
  • FF 100 µg OD: mean -14.04 versus -24.99 on control; difference 10.95 (95% CI 5.24 to 16.66), standardized effect d = 0.78; z-test p = <0.001.
  • FF/VI 100/25 µg OD: mean -13.21 versus -24.99 on control; difference 11.79 (95% CI 6.07 to 17.50), standardized effect d = 0.85; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for FF 100 µg OD 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 FF/VI 100/25 µg OD than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Minimum FEV1 Absolute Change From Baseline Between 0-2 Hour, Following the 22-23 Hour Post-treatment Allergen Challenge on Day 29 of Each 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:
  • FF 100 µg OD: mean -0.48 versus -0.81 on control; difference 0.33 (95% CI 0.12 to 0.54), standardized effect d = 0.62; z-test p = 0.002.
  • FF/VI 100/25 µg OD: mean -0.48 versus -0.81 on control; difference 0.33 (95% CI 0.12 to 0.54), standardized effect d = 0.64; z-test p = 0.002.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for FF 100 µg OD 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 FF/VI 100/25 µg OD than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes broadly follow the direction of the primary findings: the posted summaries describe less-negative FEV1 changes or decreases after challenge for the active-treatment conditions than for placebo. The secondary outcomes examine related aspects of the same challenge response, including the maximum percent decrease in FEV1 and the minimum absolute FEV1 change. They therefore offer additional views of short-term lung-function response, rather than independent evidence about longer-term outcomes.

These measures are related to the primary weighted mean endpoint but are not interchangeable. A maximum percent decrease focuses on the largest change during the observation window, while a minimum absolute change focuses on the lowest absolute change from baseline. The primary weighted mean summarizes the response over the interval. Similar direction across related endpoints can add context, but it does not make the results independent or resolve limitations in the primary analysis.

The registry reports unadjusted recalculated comparisons for the continuous secondary outcomes, and does not list sponsor-reported analyses for them. A number of outcomes and pairwise comparisons create opportunities for chance findings when each is considered separately. In general, multiplicity adjustment or a prespecified hierarchy can help control the risk of false-positive conclusions across multiple tests. The registry record does not report a multiplicity procedure or a testing hierarchy.

For that reason, unadjusted secondary results carry less weight than a clearly prespecified primary analysis and should be treated as supportive or exploratory. The adverse-event outcome is a different type of endpoint and should be read as a descriptive safety count rather than as another measure of the physiological response. Taken together, the secondary outcomes provide context for the primary pattern, but do not independently establish a broader or more durable effect.

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

• Maximum Percent Decrease From Baseline in FEV1 Between 0 2 Hour, Following the 22-23 Hour Post-treatment Allergen Challenge on Day 29 of Each Treatment Period
• Minimum FEV1 Absolute Change From Baseline Between 0-2 Hour, Following the 22-23 Hour Post-treatment Allergen Challenge on Day 29 of Each Treatment Period
• Number of Participants With Treatment-emergent Adverse Events (AEs)

9. Statistical Interpretation

10. Statistical Methods Explained

What does a least-squares mean represent?

The registry identifies the primary outcome values as least-squares means from a mixed model ANCOVA. In general, a least-squares mean is a model-based estimate of a group mean, adjusted for variables included in the model. It is not necessarily the same as a simple arithmetic average of all raw measurements. The registry’s model description names treatment, period, and participant-level baseline among the fixed effects, but the description is truncated after the baseline term. Further model details are not reported in the registry record.

The endpoint’s group values are -0.372 liters for placebo, -0.21 liters for FF, and -0.227 liters for FF/vilanterol. The associated standard errors are 0.056, 0.055, and 0.055 liters, respectively. A standard error describes the estimated precision of a mean, rather than the spread of individual participant measurements. In general, it tends to be smaller when an estimate is more precise, but it depends on the analysis and data structure.

Why use a mixed model and account for period?

In general, a mixed model can represent correlated observations, such as repeated measurements from the same participant, while estimating treatment contrasts. In a crossover study, measurements from a participant across treatment periods are not independent in the same way as measurements from unrelated participants. Accounting for the design’s repeated structure is therefore important. The registry specifically lists period as a fixed effect in the model description. The record does not provide enough detail to specify all model components or to determine exactly how within-participant correlation was handled.

ANCOVA, or analysis of covariance, compares outcomes while adjusting for baseline or other specified variables. Here, the endpoint is already expressed as a change from a baseline measurement, and the reported model description also refers to participant-level baseline. The complete model specification, including any additional terms, is not reported in the registry record. It is not appropriate to infer unreported assumptions or adjustments.

What do the recalculated contrasts mean?

The recalculated comparisons subtract the posted placebo mean from the posted treatment mean. For FF versus placebo, the recalculated mean difference is 0.162 liters; for FF/vilanterol versus placebo, it is 0.145 liters. These are simple, unadjusted re-calculations from posted summary statistics, not a reconstruction of the trial’s mixed model. The posted analysis includes a crossover structure and model adjustment, while the simplified re-calculation does not reproduce those features.

The recalculated p-values are 0.038 for FF versus placebo and 0.064 for FF/vilanterol versus placebo. They are explicitly unadjusted. In general, a p-value measures how incompatible data are with a specified null model under its assumptions; it is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. These recalculated p-values should not be interpreted as the trial’s own model-based p-values, which are not reported in the registry record.

The pooled standard deviations used in the simple comparisons are approximate, inferred from group standard errors and analyzed counts. This makes the recalculated confidence intervals approximate as well. In general, a standard deviation describes variation among observations, whereas a standard error describes uncertainty in an estimate. Using a standard error to approximate a standard deviation relies on assumptions about the relationship between the estimate and the observations; it cannot reproduce the original participant-level data or the crossover model.

Why can a confidence interval and a p-value tell different-looking stories?

The sponsor-reported 95% confidence intervals for placebo comparisons exclude zero, while one simple recalculated p-value is 0.064. These statistics come from different analyses: the registry reports confidence intervals for its own mean differences but no corresponding sponsor p-values, and the p-values in the recalculation are unadjusted approximations based on summary statistics. In general, results from different methods can differ because of model structure, standard-error estimation, and assumptions. The registry does not provide enough detail to reproduce the sponsor’s full model or explain the numerical difference between these analysis approaches.

A confidence interval gives a range of values compatible with the estimate under the analysis assumptions and procedure. It is not a guarantee that the true effect lies inside that specific interval. In general, intervals that include zero are compatible with no difference at the corresponding confidence level, as well as with differences in either direction. The sponsor-reported active-treatment interval, -0.091 to 0.057 liters, includes zero. This does not prove that the treatments are identical; it means the reported interval does not distinguish the estimated difference from zero at that level.

Why can over-dispersion matter?

Over-dispersion is a general issue for count outcomes when variability exceeds what a basic probability model expects. It is not the central issue for this primary continuous FEV1 endpoint, and the registry does not report an over-dispersion analysis. For a continuous outcome, the relevant concerns include the model’s error assumptions, the treatment of repeated observations, and the adequacy of the standard-error estimates. The registry record does not report model diagnostics, residual checks, or sensitivity analyses.

The primary outcome was measured at several time points after challenge and summarized using a weighted mean. In general, this approach uses the time pattern across measurements, but the resulting summary does not reveal every feature of that pattern. The registry record does not report the individual time-point estimates or participant-level data, so those patterns cannot be assessed from the posted summary statistics.

Overall, the sponsor’s model-based comparisons and the unadjusted recalculations answer related but not identical statistical questions. The recalculations are useful as a transparent, limited comparison of posted group summaries. They cannot replace the trial’s own crossover analysis or supply missing information about model specification, missing observations, or multiplicity handling.

11. Confidence Intervals and Precision

Precision is reflected partly by the width of a confidence interval: narrower intervals indicate less uncertainty about the estimated contrast under the analysis assumptions. For the sponsor-reported primary comparison of FF with placebo, the mean difference is 0.162 liters and the 95% confidence interval is 0.087 to 0.237. For FF/vilanterol compared with placebo, the mean difference is 0.145 liters and the interval is 0.069 to 0.222. For FF compared with FF/vilanterol, the difference is -0.017 liters and the interval is -0.091 to 0.057.

The first two intervals are entirely above zero, whereas the active-treatment comparison spans zero. That pattern indicates that the sponsor-reported estimates for the two placebo contrasts are more clearly separated from zero than the estimate comparing the active treatments. It does not establish the clinical importance of either placebo contrast. The registry record does not report a minimally important difference for the FEV1 endpoint.

In general, a 95% confidence interval is generated by a procedure that, under its assumptions and repeated use, would cover the true parameter in 95% of comparable applications. It is not a statement that there is a 95% probability that the fixed true effect lies in this particular interval. The interpretation also depends on the analysis method being appropriate.

These intervals come from the sponsor-reported analysis. The separately recalculated intervals are approximate, based on standard errors and group counts rather than the participant-level crossover model, and are not used as replacements for the sponsor’s estimates. The sponsor’s reported interval for the active-treatment comparison allows both a modest difference in either direction and no difference. The record does not provide additional information to narrow that uncertainty.

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 figures are participants per arm, not total events. They are illustrations based on the observed treatment contrasts, not the original trial’s sample-size justification. The calculation assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The target effect is set to a stated fraction of the observed effect.

The 80% power column gives the illustrative number of participants per arm for a design intended to have an 80% chance of detecting the specified effect under those assumptions. The 90% power column gives the corresponding number per arm for a 90% chance. These are planning probabilities under the assumed effect and model, not guarantees for a future study. The trial’s original design assumptions and sample-size justification are not reported in the registry record.

For the primary FF-versus-placebo contrast, planning for 100% of the observed effect gives 87 participants per arm for 80% power and 116 participants per arm for 90% power. Planning for 75% of the observed effect gives 153 participants per arm for 80% power and 205 participants per arm for 90% power. Planning for 50% of the observed effect gives 345 participants per arm for 80% power and 461 participants per arm for 90% power. For FF/vilanterol versus placebo, the corresponding figures are 105 and 140, 186 and 248, and 417 and 558 participants per arm.

Smaller effects require more participants to detect under the same assumptions, which is why the planning figures rise as the assumed fraction of the observed effect becomes smaller. These figures are planning illustrations, not observed power. They do not demonstrate the probability that this completed study had of detecting its true effect, and they do not replace a design calculation based on a prespecified target effect.

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 = 0.162; pooled standard deviation σ = 0.379.
2. n = 2 × (1.96 + 0.842)² × 0.379² / 0.162² = 86.0, rounded up to 87 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 <- 0.162                      # observed difference in means
sigma <- 0.379242404412202                     # 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(1128569)
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 = 87 (80% power), 116 (90% power)
 75% of observed effect: n per arm = 153 (80% power), 205 (90% power)
 50% of observed effect: n per arm = 345 (80% power), 461 (90% power)
power.t.test: 87 
Simulated power at n = 87 per arm: 0.803 (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 mean differences and 95% confidence intervals for the primary endpoint, but does not report p-values for those comparisons. The sponsor-reported contrasts are 0.162 liters for placebo versus FF, 0.145 liters for placebo versus FF/vilanterol, and -0.017 liters for FF versus FF/vilanterol. The corresponding confidence intervals are 0.087 to 0.237, 0.069 to 0.222, and -0.091 to 0.057.

The separate recalculations use posted group means and standard errors to make simple unadjusted comparisons. They reproduce the two placebo-comparison point estimates, and give unadjusted p-values of 0.038 and 0.064. Their standard deviations and confidence intervals are approximate; they do not recreate the mixed model ANCOVA described in the registry record or the crossover analysis structure.

There is no reported discrepancy flag for the posted results. Even so, the sponsor’s reported analysis and the recalculations should be kept distinct: the former is the trial’s own analysis, while the latter is a simplified check based on summary statistics. The registry does not report the full model specification or sponsor p-values, so the recalculation cannot explain all features of the sponsor analysis. In particular, the unadjusted p-values should not be substituted for missing model-based p-values.

15. Multiplicity, Missing Data and Analysis Populations

The registry identifies one primary endpoint and lists secondary outcomes that include maximum percent decrease in FEV1, minimum absolute FEV1 change, and treatment-emergent adverse events. There are also multiple treatment comparisons. Testing several outcomes and contrasts raises a general multiplicity concern: if each is interpreted separately without adjustment, the chance of at least one apparently positive result can increase.

The registry record does not report whether multiplicity was controlled, whether a hierarchy of hypotheses was prespecified, or whether any analyses were designated exploratory. The primary endpoint is explicitly identified, but that alone does not establish how secondary comparisons were handled. The unadjusted p-values from the simple recalculations should therefore be read as unadjusted comparisons, not as multiplicity-controlled evidence.

The primary population is described as randomized participants who received at least one dose of study drug. The record further says that only participants available at the specified time points were analyzed. This indicates that outcome availability affected inclusion in an endpoint analysis, but the registry does not report how many observations were missing at each time point, why they were missing, or what methods were used to handle missing measurements. The detailed missing-data assumptions and sensitivity analyses are not reported in the registry record.

The posted endpoint counts differ by treatment condition, and the safety risk counts are reported separately. In a crossover study, availability can vary across periods and treatment conditions. Without participant-level flow and missing-data details, the effect of incomplete endpoint data on the estimates cannot be assessed from the posted summary values alone.

The registry describes the primary analysis as a mixed model ANCOVA with fixed effects including treatment, period, and participant-level baseline, but the model description is truncated. It does not report the full covariance structure, all model terms, diagnostic checks, or sensitivity analyses. These omissions limit independent assessment of the model and its assumptions. They do not negate the posted estimates, but they constrain how fully the analysis can be evaluated from the registry record.

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 3% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse event figures list 0 affected participants among 51 at risk for placebo, 0 among 51 for FF 100 µg OD, and 0 among 51 for FF/vilanterol 100/25 µg OD. No serious adverse event terms are listed. Death counts are not reported in the registry record.

These are descriptive counts from the posted safety record. They indicate that no serious adverse events are recorded for the listed groups, but a zero count in a study does not establish that an event cannot occur. In general, safety estimates from a small pilot study can remain uncertain, particularly for uncommon events. The registry record does not provide a detailed account of event types or comparative statistical tests for serious events.

Other adverse events affected 15 participants in the placebo group, 18 in the FF group, and 11 in the FF/vilanterol group, each with 51 at risk. Those counts are separate from the serious adverse event figures. They should not be interpreted as rates or as evidence of a treatment difference without further detail about event definitions, exposure, duration, and analysis. The registry record does not supply a causal assessment for these counts.

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

The primary endpoint summarizes lung-function change over the 0-2 hour period after an inhaled-allergen challenge. The posted estimates are less negative for both active-treatment conditions than for placebo, and the sponsor-reported confidence intervals for those placebo comparisons exclude zero. The sponsor-reported interval for the comparison between the active treatments includes zero. These are statistical descriptions of the trial’s short-term endpoint, not conclusions about a patient’s overall health or likely experience.

The trial’s controlled challenge model addresses a specific question about response after an inhaled allergen exposure, at a defined time following dosing. It does not directly answer how symptoms, exacerbations, daily activity, or lung function change over longer periods or in settings without a controlled challenge. Those outcomes are not reported as the primary endpoint in this record.

A difference that is statistically distinguishable from zero is not automatically clinically important. The registry record does not report a threshold for a meaningful change in FEV1, so the clinical importance of the estimated differences cannot be determined from these values alone. Likewise, an interval spanning zero does not prove that two treatment conditions are identical; it reflects uncertainty that includes no difference.

The study is described as a phase 2 pilot with enrollment of 52. The endpoint-specific analyzed counts and the crossover structure should be kept in mind when considering precision and generalizability. The record does not report enough information to assess all aspects of missing observations, treatment sequence, or model assumptions. The findings should be understood within those limits rather than extended to claims about other populations, treatment durations, or outcomes not measured in the registry record.

18. Why This Trial Matters Statistically

This trial is statistically informative because it uses a controlled allergen-challenge model and a crossover structure to compare three treatment conditions in the same general experimental setting. The primary outcome is not a single isolated FEV1 reading: it is a weighted mean across scheduled measurements over the post-challenge interval. That design choice makes the estimand a summary of response over time, with a different interpretation from a maximum or minimum value.

The registry also illustrates why the analysis method matters. A mixed model ANCOVA is reported for the primary endpoint, with treatment, period, and participant-level baseline among the fixed effects. The simple recalculations from posted summaries do not reproduce that model. Comparing the two makes clear that summary statistics can support a limited check but cannot reveal all features of a repeated-measures crossover analysis.

The sponsor-reported intervals distinguish the placebo comparisons from the active-treatment comparison in terms of whether zero is included. The unadjusted recalculations give a different threshold-based impression for one placebo contrast. This highlights the need to identify which analysis produced a statistic, what assumptions it uses, and whether multiple comparisons were addressed. A p-value or interval should not be read apart from its method.

Finally, the record shows the value of separating statistical evidence from clinical interpretation. A short-term physiological response after controlled challenge is relevant to the stated research question, but it does not settle questions about duration, day-to-day outcomes, or clinical importance. Recognizing that boundary is part of interpreting the result accurately.

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 endpoint is a short-term response to an inhaled allergen challenge, measured over 0-2 hours after exposure. It does not represent all aspects of asthma or longer-term outcomes. The registry record does not report symptoms, exacerbations, daily function, or follow-up outcomes as primary measures.

The registry describes the study as a pilot and reports enrollment of 52. The outcome-specific counts are 45 for placebo, 49 for FF, and 46 for FF/vilanterol, and the primary analysis included only participants available at specified time points. The reasons for unavailable measurements and the handling of missing observations are not reported in the registry record. Those details matter when evaluating whether the analyzed data fully represent the randomized participants.

The crossover design creates analytical considerations involving repeated observations and treatment periods. Although the reported model description includes period, the record does not report treatment sequence, washout details, carryover assessment, or the full covariance specification. The primary model description is also truncated. These gaps limit independent appraisal of whether the analysis fully reflects the design.

The recalculated comparisons are approximations based on posted summary statistics, including standard deviations estimated from standard errors. They are not a reconstruction of the mixed model ANCOVA. The registry does not report sponsor p-values for the primary contrasts, and it does not report a multiplicity procedure for the multiple comparisons and secondary outcomes. Secondary recalculations are unadjusted and should be interpreted cautiously.

Finally, the registry record does not report a minimally important FEV1 difference, a detailed sample-size justification, or a complete account of model diagnostics and sensitivity analyses. These absences limit judgments about clinical importance, design adequacy, and robustness beyond the posted estimates.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Randomised Study Comparing the Effects of Inhaled Fluticasone Furoate (FF)/Vilanterol (VI; GW642444M) Combination and FF on an Allergen Induced Asthmatic Response — NCT01128569.
• Registry record last updated 2017-01-18; status last verified 2016-11.
• Results first posted 2013-09-11.
• 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

NCT01128569 is a completed phase 2, randomized, double-blind, placebo-controlled, three-way crossover repeat-dose pilot study in mild asthma. The registry reports enrollment of 52 and compares placebo, FF 100 µg OD, and FF/vilanterol 100/25 µg OD using an inhaled-allergen challenge model.

The primary outcome is weighted mean change from baseline in FEV1 over 0-2 hours after challenge on Day 29 of each treatment period. Sponsor-reported mean differences favor less-negative change for each active condition versus placebo; the reported interval for the active-treatment comparison includes zero. The registry describes a mixed model ANCOVA, but full model details, multiplicity handling, and missing-data details are not reported in the registry record.

Secondary outcomes assess other features of the post-challenge FEV1 response. Safety counts list no serious adverse events in the groups, while other adverse-event counts are also posted. The findings apply to this controlled short-term challenge setting and do not by themselves establish clinical importance or longer-term outcomes.